Argatroban Versus Lepirudin in Critically Ill Patients

Overview

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

Full Title of Study: “Argatroban Versus Lepirudin in Critically Ill Patients – A Randomized Double-blind Trial”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: March 2012

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

Interventions

  • 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.
  • 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.

Arms, Groups and Cohorts

  • Active Comparator: PR1
    • Patients treated with Argatroban (Argatra®), a direct thrombin inhibitor
  • Active Comparator: PR2
    • Patients treated with Lepirudin (Refludan®), a direct thrombin inhibitor

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

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

Participating in This Clinical Trial

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
  • Gender Eligibility: All

    Minimum Age: 18 Years

    Maximum Age: N/A

    Are Healthy Volunteers Accepted: No

    Investigator Details

    • Lead Sponsor
      • Heinrich-Heine University, Duesseldorf
    • Provider of Information About this Clinical Study
      • Sponsor
    • Overall Official(s)
      • Peter Kienbaum, MD, Principal Investigator, Uniklinik Düsseldorf, Klinik für Anästhesiologie

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