A Prospective Pilot Trial to Assess the Efficacy of Argatroban (Argatra®) in Critically Ill Patients with Heparin Resistance

Mirjam Bachler, Tobias Hell, Johannes Bösch, Benedikt Treml, Bettina Schenk, Benjamin Treichl, Barbara Friesenecker, Ingo Lorenz, Daniel Stengg, Stefan Hruby, Bernd Wallner, Elgar Oswald, Mathias Ströhle, Christian Niederwanger, Christian Irsara, Dietmar Fries, Mirjam Bachler, Tobias Hell, Johannes Bösch, Benedikt Treml, Bettina Schenk, Benjamin Treichl, Barbara Friesenecker, Ingo Lorenz, Daniel Stengg, Stefan Hruby, Bernd Wallner, Elgar Oswald, Mathias Ströhle, Christian Niederwanger, Christian Irsara, Dietmar Fries

Abstract

The current study aims to evaluate whether prophylactic anticoagulation using argatroban or an increased dose of unfractionated heparin (UFH) is effective in achieving the targeted activated partial thromboplastin time (aPTT) of more than 45 s in critically ill heparin-resistant (HR) patients. Patients were randomized either to continue receiving an increased dose of UFH, or to be treated with argatroban. The endpoints were defined as achieving an aPTT target of more than 45 s at 7 h and 24 h. This clinical trial was registered on clinicaltrials.gov (NCT01734252) and on EudraCT (2012-000487-23). A total of 42 patients, 20 patients in the heparin and 22 in the argatroban group, were included. Of the patients with continued heparin treatment 55% achieved the target aPTT at 7 h, while only 40% of this group maintained the target aPTT after 24 h. Of the argatroban group 59% reached the target aPTT at 7 h, while at 24 h 86% of these patients maintained the targeted aPTT. Treatment success at 7 h did not differ between the groups (p = 0.1000), whereas at 24 h argatroban showed significantly greater efficacy (p = 0.0021) than did heparin. Argatroban also worked better in maintaining adequate anticoagulation in the further course of the study. There was no significant difference in the occurrence of bleeding or thromboembolic complications between the treatment groups. In the case of heparin-resistant critically ill patients, argatroban showed greater efficacy than did an increased dose of heparin in achieving adequate anticoagulation at 24 h and in maintaining the targeted aPTT goal throughout the treatment phase.

Keywords: Argatroban; critical illness; hemorrhage; prophylactic anticoagulation; thrombosis; unfractionated heparin.

Conflict of interest statement

Mirjam Bachler has received research funding and travel grants from LFB Biomedicaments, Baxter GmbH, CSL Behring GmbH, and Mitsubishi Tanabe, as well as non-financial support from TEM International outside the submitted work. Benedikt Treml has received travel grants from Pfizer. Bettina Schenk has received travel grants, and honoraria for speaking or participation at meetings from CSL Behring, BBraun, and Biotest. Dietmar Fries has received study funding, as well as honoraria for consultancy and board activity from Astra Zeneca, AOP orphan, Baxter, Baer, BBraun, Biotest, CSL Behring, Delta Select, Dae Behring, Edwards, Fresenius, Glaxo, Haemoscope, Hemogem, Lilly, LFB, Mitsubishi Pharma, NovoNordisk, Octapharm, Pfizer, and Tem-Innovation outside the submitted work. The other authors (Tobias Hell, Johannes Bösch, Barbara Friesenecker, Benjamin Treichl, Ingo Lorenz, Daniel Stengg, Stefan Hruby, Bernd Wallner, Elgar Oswald, Mathias Ströhle, Christian Niederwanger, and Christian Irsara) declared no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Trial profile Therapy failure in the heparin group = aPTT

Figure 2

Achievement of the target activated…

Figure 2

Achievement of the target activated partial thromboplastin time (aPTT) of more than 45…

Figure 2
Achievement of the target activated partial thromboplastin time (aPTT) of more than 45 s. Patients who achieved the targeted aPTT of more than 45 s under heparin treatment (orange bars) and argatroban treatment (blue bars) in the intention-to-treat (ITT) groups. V indicates the study visits at pre-defined time points.

Figure 3

Median aPTT (95% CIs) during…

Figure 3

Median aPTT (95% CIs) during the study treatment from Baseline to Visit 6…

Figure 3
Median aPTT (95% CIs) during the study treatment from Baseline to Visit 6 (day 5) The dotted line at an aPTT of 45 s represents the targeted aPTT. Values below the visit labels indicate the estimated differences with 95% CIs between the aPTT for the argatroban and the heparin group. V indicates the study visits at pre-defined time points.

Figure 4

Number of patients per visit…

Figure 4

Number of patients per visit in the heparin, argatroban, and switch group. V…

Figure 4
Number of patients per visit in the heparin, argatroban, and switch group. V indicates the study visits at pre-defined time points.

Figure 5

Median aPTT (95% CIs) during…

Figure 5

Median aPTT (95% CIs) during the study treatment from Baseline to Visit 6…

Figure 5
Median aPTT (95% CIs) during the study treatment from Baseline to Visit 6 (day 5) Depicted is the aPTT during treatment with heparin (orange) and argatroban (blue) after switch for only the patients who had to be switched. The upper dotted line at aPTT of 45 s represents the targeted aPTT. The black line indicates the difference between the aPTT during administration of heparin or argatroban in the patients that had to switch. Values below the visit labels indicate the estimated differences with 95% CIs between the aPTTs. V indicates the study visits at pre-defined time points.
Figure 2
Figure 2
Achievement of the target activated partial thromboplastin time (aPTT) of more than 45 s. Patients who achieved the targeted aPTT of more than 45 s under heparin treatment (orange bars) and argatroban treatment (blue bars) in the intention-to-treat (ITT) groups. V indicates the study visits at pre-defined time points.
Figure 3
Figure 3
Median aPTT (95% CIs) during the study treatment from Baseline to Visit 6 (day 5) The dotted line at an aPTT of 45 s represents the targeted aPTT. Values below the visit labels indicate the estimated differences with 95% CIs between the aPTT for the argatroban and the heparin group. V indicates the study visits at pre-defined time points.
Figure 4
Figure 4
Number of patients per visit in the heparin, argatroban, and switch group. V indicates the study visits at pre-defined time points.
Figure 5
Figure 5
Median aPTT (95% CIs) during the study treatment from Baseline to Visit 6 (day 5) Depicted is the aPTT during treatment with heparin (orange) and argatroban (blue) after switch for only the patients who had to be switched. The upper dotted line at aPTT of 45 s represents the targeted aPTT. The black line indicates the difference between the aPTT during administration of heparin or argatroban in the patients that had to switch. Values below the visit labels indicate the estimated differences with 95% CIs between the aPTTs. V indicates the study visits at pre-defined time points.

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