Clinical trial NCT00798525: Argatroban Versus Lepirudin in Critically Ill Patients
Official title: Argatroban Versus Lepirudin in Critically Ill Patients - A Randomized Double-blind Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Heparin Induced Thrombocytopenia (HIT)
Keywords: thrombocytopenia
Heparin
Lepirudin
Argatroban
critically ill patients
Lead sponsor: Heinrich-Heine University, Duesseldorf
Sponsor class: OTHER
First posted: 2008-11-26
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: Mean running time of a maximum of two consecutive haemodialysis circuits
timeFrame: seven days starting at time of HIT suspicion
Secondary outcomes:
measure: Incidence of bleeding, transfusion requirements, thromboembolic events, anaphylactic reactions, and SUSARs, length of hospital stay, mortality, time till target aPTT
timeFrame: seven days starting at time of HIT suspicion
Other outcomes:
Locations:
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf Klinik für Anästhesiologie
Study officials:
affiliation: Uniklinik Düsseldorf, Klinik für Anästhesiologie
name: Peter Kienbaum, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.