Argatroban Versus Lepirudin in Critically Ill Patients

Phase 4

Terminated

• Conditions: Heparin Induced Thrombocytopenia (HIT)
• Interventions: Drug: Argatroban; Drug: Lepirudin

• Registration Number: NCT00798525
• Lead Sponsor: Heinrich-Heine University, Duesseldorf

Brief Summary

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

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 Timeline

• Study First Submitted: 2008-11-25
• Study First Submitted QC: 2008-11-25
• Study First Posted: 2008-11-26
• Study Start: 2009-01
• Primary Completion: 2012-03
• Study Completion: 2012-03
• Status Verified: 2012-06
• Last Update Submitted: 2012-06-20
• Last Update Posted: 2012-06-21

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 70

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
PR1	Argatroban	Patients treated with Argatroban (Argatra®), a direct thrombin inhibitor
PR2	Lepirudin	Patients treated with Lepirudin (Refludan®), a direct thrombin inhibitor

Primary Outcome Measures

Name	Time	Method
Mean running time of a maximum of two consecutive haemodialysis circuits	seven days starting at time of HIT suspicion

Secondary Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (1)

Universitätsklinikum Düsseldorf Klinik für Anästhesiologie; 🇩🇪 Düsseldorf, Germany