Argatroban Versus Lepirudin in Critically Ill Patients (ALiCia)

Argatroban Versus Lepirudin in Critically Ill Patients - A Randomized Double-blind Trial

The purpose of this study is to test the hypotheses that argatroban significantly increases efficacy and safety of renal replacement therapy measured as life time of haemodialysis filters as compared to lepirudin

Study Overview

• Status: Terminated
• Conditions: Heparin Induced Thrombocytopenia (HIT)
• Intervention / Treatment: Drug: Argatroban; Drug: Lepirudin

Detailed Description

Critically ill patients are at increased risk to develop deep vein thrombosis due to immobilisation and/or the underlying disease. Usually, heparin is used for anticoagulation in these patients. However, a serious complication of heparin therapy is heparin-induced thrombocytopenia type II (HIT). HIT is an immune-mediated syndrome caused by antibodies directed against the heparin-PF4-complex, which bind to platelets via the Fc part, thereby activating platelets causing aggregation and hypercoagulability. Thus, with HIT the risk of thrombosis and organ damage paradoxically even increases during heparin administration. HIT is associated with significant morbidity and mortality if unrecognized. Therefore, patients, who develop thrombocytopenia and/or thrombosis during heparin therapy are suspicious for HIT and have to receive alternative anticoagulants2.

The direct thrombin inhibitor lepirudin (Refludan®) is equally effective as heparin in prevention of deep vein thrombosis and lung embolism3. The elimination half life of lepirudin averages 60 min, but in renal failure it may increase up to 48 hours. Critically ill patients often develop acute renal failure requiring continuous renal replacement therapy. Thus, if lepirudin is used in these patients, intensive dose adjustment is necessary to avoid accumulation and severe bleeding. In contrast, effective anticoagulation is needed to prevent clot formation within the extracorporeal circuit, as clotting substantially increases the patients´ risks and costs of therapy.

Argatroban (Argatra®), another direct thrombin inhibitor, has recently been shown to be safe and effective in prevention of deep vein thrombosis in patients with HIT. Interestingly, argatroban is eliminated by hepatic metabolism. Therefore, no initial dose adjustment is necessary in patients with renal failure. Preliminary reports document the feasibility of argatroban for anticoagulation during haemodialysis. Observational data in patients undergoing continuous haemodialysis suggest that life time of filters during argatroban anticoagulation is not limited due to clot formation. Thus, argatroban would be safer and more effective than lepirudin in critically ill patients requiring continuous renal replacement therapy.

Therefore, we propose a prospective randomized double-blinded trial to test the hypotheses that argatroban significantly increases efficacy and safety of renal replacement therapy measured as life time of haemodialysis filters as compared to lepirudin

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Düsseldorf, Germany, 40225
    • Universitätsklinikum Düsseldorf Klinik für Anästhesiologie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Thrombocytopenia suspicious for HIT with decrease in platelet count >50% from baseline obtained at hospital admission
• 4 T´s score for HIT probability >3 AND/OR positive ELISA for HIT
• Age ≥18 years
• Informed consent (if applicable)

Exclusion Criteria:

• Transient thrombocytopenia due to intraoperative bleeding
• Active bleeding
• Intracranial operations
• Liver dysfunction with spontaneous aPTT> 60 sec.
• History of adverse events or sensitivity against study drugs
• Pregnancy
• Age<18 years
• Preexisting psychiatric/neurologic disorders with long-term inability to provide informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: PR1; Patients treated with Argatroban (Argatra®), a direct thrombin inhibitor	Drug: Argatroban; Argatra (Argatroban) will be diluted to 0.6 mg/ml and 0.5 µg/kg/min will be administered continuously in patients without liver disfunction. In patients with liver disfunction, defined by a bilirubin of > 4mg/dl, argatroban will be administered as a continuous infusion of 0,25 µg/kg/min with a final concentration of 0,3 mg/ml.; Other Names: Argatra®; MA number: 62085.00.0
Active Comparator: PR2; Patients treated with Lepirudin (Refludan®), a direct thrombin inhibitor	Drug: Lepirudin; Refludan (Lepirudin) will be diluted to a final concentration of 0.1mg/ml and initiated as a continuous infusion of 5µg/kg/h in patients with continuous renal replacement therapy. In patients with moderate renal impairment (Creatinine ≥1,3 mg/dl) a final concentration 0,2 mg/ml of will be used to provide continuous infusion of 10 µg/kg/h. Patients without renal impairment (Creatinine < 1,3 mg/dl) will receive a continuous infusion of 50 µg/kg/h by a final concentration of 1 mg/ml of Lepirudin.; Other Names: Refludan®; MA number: EU/1/97/035/003

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Mean running time of a maximum of two consecutive haemodialysis circuits	seven days starting at time of HIT suspicion

Secondary Outcome Measures

Outcome Measure	Time Frame
Incidence of bleeding, transfusion requirements, thromboembolic events, anaphylactic reactions, and SUSARs, length of hospital stay, mortality, time till target aPTT	seven days starting at time of HIT suspicion

Collaborators and Investigators

• Sponsor: Heinrich-Heine University, Duesseldorf
• Investigators: Principal Investigator: Peter Kienbaum, MD, Uniklinik Düsseldorf, Klinik für Anästhesiologie

Publications and helpful links

General Publications

• Tsujimoto H, Tsujimoto Y, Nakata Y, Fujii T, Takahashi S, Akazawa M, Kataoka Y. Pharmacological interventions for preventing clotting of extracorporeal circuits during continuous renal replacement therapy. Cochrane Database Syst Rev. 2020 Dec 14;12(12):CD012467. doi: 10.1002/14651858.CD012467.pub3.
• Beiderlinden M, Werner P, Bahlmann A, Kemper J, Brezina T, Schafer M, Gorlinger K, Seidel H, Kienbaum P, Treschan TA. 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. BMC Anesthesiol. 2018 Feb 9;18(1):18. doi: 10.1186/s12871-018-0475-y.
• Treschan TA, Schaefer MS, Geib J, Bahlmann A, Brezina T, Werner P, Golla E, Greinacher A, Pannen B, Kindgen-Milles D, Kienbaum P, Beiderlinden M. Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial. Crit Care. 2014 Oct 25;18(5):588. doi: 10.1186/s13054-014-0588-8.

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): March 1, 2012
• Study Completion (Actual): March 1, 2012

Study Registration Dates

• First Submitted: November 25, 2008
• First Submitted That Met QC Criteria: November 25, 2008
• First Posted (Estimate): November 26, 2008

Study Record Updates

• Last Update Posted (Estimate): June 21, 2012
• Last Update Submitted That Met QC Criteria: June 20, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: critically ill patients; thrombocytopenia; Heparin; Argatroban; Lepirudin
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Hematologic Diseases; Blood Platelet Disorders; Critical Illness; Thrombocytopenia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Protease Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Argatroban; Lepirudin
• Other Study ID Numbers: 2006-003122-28