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

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

doi:10.3390/jcm9040963

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.

Highlights

Ill patients are highly susceptible to developing thrombosis as well as to bleeding
We show effect size and precision with estimated median differences for continuous data and odds ratios (OR) for binary variables, with 95% Confidence Intervals (CI)
For activated partial thromboplastin time (aPTT) measurements at V2 to V6, a linear mixed-effects model with random intercepts for patients, as well as time points and ITT group as fixed effects, was fitted and we provide the mean difference in aPTT as effect size with a 95% CI

Summary

Introduction

Ill patients are highly susceptible to developing thrombosis as well as to bleeding. The use of unfractionated heparin (UFH) or low molecular weight heparin (LMWH) for the prevention of venous thromboembolism (VTE) is recommended in critically ill patients [1,2]. Intravenous administration of UFH has been shown to be superior to subcutaneous administration preventing venous thrombotic events (VTE) [5]. A retrospective study showed no difference between LMWH and intravenously given UFH in patients with pulmonary embolism (PE), with respect to bleeding and change of PE severity [6]. For the use in critically ill patients, continuous intravenous administration of UFH is very advantageous as it enables constant plasma level and efficacy, with the option of expeditious dose adjustments. UFH can be completely reversed by the administration of protamine sulfate [7]

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