Argatroban versus Lepirudin in critically ill patients (ALicia): a randomized controlled trial

Tanja A Treschan, Maximilian S Schaefer, Johann Geib, Astrid Bahlmann, Tobias Brezina, Patrick Werner, Elisabeth Golla, Andreas Greinacher, Benedikt Pannen, Detlef Kindgen-Milles, Peter Kienbaum, Martin Beiderlinden, Tanja A Treschan, Maximilian S Schaefer, Johann Geib, Astrid Bahlmann, Tobias Brezina, Patrick Werner, Elisabeth Golla, Andreas Greinacher, Benedikt Pannen, Detlef Kindgen-Milles, Peter Kienbaum, Martin Beiderlinden

Abstract

Introduction: Critically ill patients often require renal replacement therapy accompanied by thrombocytopenia. Thrombocytopenia during heparin anticoagulation may be due to heparin-induced thrombocytopenia with need for alternative anticoagulation. Therefore, we compared argatroban and lepirudin in critically ill surgical patients.

Methods: Following institutional review board approval and written informed consent, critically ill surgical patients more than or equal to 18 years with suspected heparin-induced thrombocytopenia, were randomly assigned to receive double-blind argatroban or lepirudin anticoagulation targeting an activated Partial Thromboplastin Time (aPTT) of 1.5 to 2 times baseline. In patients requiring continuous renal replacement therapy we compared the life-time of hemodialysis filters. We evaluated in all patients the incidence of bleeding and thrombembolic events.

Results: We identified 66 patients with suspected heparin-induced thrombocytopenia, including 28 requiring renal replacement therapy. Mean filter lifetimes did not differ between groups (argatroban 32 ± 25 hours (n = 12) versus lepirudin 27 ± 21 hours (n = 16), mean difference 5 hours, 95% CI -13 to 23, P = 0.227). Among all 66 patients, relevant bleeding occurred in four argatroban- versus eleven lepirudin-patients (OR 3.9, 95% CI 1.1 to 14.0, P = 0.040). In the argatroban-group, three thromboembolic events occurred compared to two in the lepirudin group (OR 0.7, 95% CI 0.1 to 4.4, P = 0.639). The incidence of confirmed heparin-induced thrombocytopenia was 23% (n = 15) in our study population.

Conclusions: This first randomized controlled double-blind trial comparing two direct thrombin inhibitors showed comparable effectiveness for renal replacement therapy, but suggests fewer bleeds in surgical patients with argatroban anticoagulation.

Trial registration: Clinical Trials.gov NCT00798525. Registered 25 November 2008.

Figures

Figure 1
Figure 1
Trial flow chart. Data are presented as mean ± SD, n = number of patients, sec = seconds. SD, standard deviation.
Figure 2
Figure 2
Kaplan-Meier analyses of time till filter clotting.

References

    1. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schünemann HJ. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: american college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141:7S–47S. doi: 10.1378/chest.1412S3.
    1. Arnold DM, Donahoe L, Clarke FJ, Tkaczyk AJ, Heels-Ansdell D, Zytaruk N, Cook R, Webert KE, McDonald E, Cook DJ. Bleeding during critical illness: a prospective cohort study using a new measurement tool. Clin Invest Med. 2007;30:E93–E102.
    1. Franchini M. Heparin-induced thrombocytopenia: an update. Thromb J. 2005;3:14. doi: 10.1186/1477-9560-3-14.
    1. Warkentin TE. Heparin-induced thrombocytopenia in the ICU: a transatlantic perspective. Chest. 2012;142:815–816. doi: 10.1378/chest.12-0979.
    1. Trehel-Tursis V, Louvain-Quintard V, Zarrouki Y, Imbert A, Doubine S, Stéphan F. Clinical and biologic features of patients suspected or confirmed to have heparin-induced thrombocytopenia in a cardiothoracic surgical ICU. Chest. 2012;142:837–844. doi: 10.1378/chest.11-3074.
    1. Hess CN, Becker RC, Alexander JH, Lopes RD. Antithrombotic therapy in heparin-induced thrombocytopenia: guidelines translated for the clinician. J Thromb Thrombolysis. 2012;34:552–561. doi: 10.1007/s11239-012-0785-8.
    1. Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, Bartholomew J, Sham R, Lerner RG, Zeigler ZR, Rustagi PK, Jang IK, Rifkin SD, Moran J, Hursting MJ, Kelton JG, ARG-911 Study Investigators Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001;103:1838–1843. doi: 10.1161/01.CIR.103.14.1838.
    1. Walenga JM. An overview of the direct thrombin inhibitor argatroban. Pathophysiol Haemost Thromb. 2002;32:9–14. doi: 10.1159/000069103.
    1. Dager WE, White RH. Argatroban for heparin-induced thrombocytopenia in hepato-renal failure and CVVHD. Ann Pharmacother. 2003;37:1232–1236. doi: 10.1345/aph.1D010.
    1. Galvagno SM, Jr, Hong CM, Lissauer ME, Baker AK, Murthi SB, Herr DL, Stein DM. Practical considerations for the dosing and adjustment of continuous renal replacement therapy in the intensive care unit. J Crit Care. 2013;28:1019–1026. doi: 10.1016/j.jcrc.2013.05.018.
    1. Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4:759–765. doi: 10.1111/j.1538-7836.2006.01787.x.
    1. Cuker A, Gimotty PA, Crowther MA, Warkentin TE. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood. 2012;120:4160–4167. doi: 10.1182/blood-2012-07-443051.
    1. Landefeld CS, Anderson PA, Goodnough LT, Moir TW, Hom DL, Rosenblatt MW, Goldman L. The bleeding severity index: validation and comparison to other methods for classifying bleeding complications of medical therapy. J Clin Epidemiol. 1989;42:711–718. doi: 10.1016/0895-4356(89)90066-8.
    1. Juhl D, Eichler P, Lubenow N, Strobel U, Wessel A, Greinacher A. Incidence and clinical significance of anti-PF4/heparin antibodies of the IgG, IgM, and IgA class in 755 consecutive patient samples referred for diagnostic testing for heparin-induced thrombocytopenia. Eur J Haematol. 2006;76:420–426. doi: 10.1111/j.1600-0609.2005.00621.x.
    1. Discontinued Drug Bulletin: Lepirudin Injection [] accessed on 6th of November 2014.
    1. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group KDIGO clinical practice guideline for acute kidney injury. Kidney Int. 2012;2:1–138. doi: 10.1038/kisup.2012.1.
    1. Warkentin TE, Greinacher A, Koster A, Lincoff AM. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest. 2008;133:340S–380S. doi: 10.1378/chest.08-0677.
    1. Ivandic B, Zorn M. Monitoring of the anticoagulants argatroban and lepirudin: a comparison of laboratory methods. Clin Appl Thromb Hemost. 2011;17:549–555. doi: 10.1177/1076029610382651.
    1. Lutz J, Menke J, Sollinger D, Schinzel H, Thürmel K. Haemostasis in chronic kidney disease. Nephrol Dial Transplant. 2014;29:29–40. doi: 10.1093/ndt/gft209.
    1. Beiderlinden M, Treschan TA, Gorlinger K, Peters J. Argatroban anticoagulation in critically Ill patients. AnnPharmacother. 2007;41:749–754.
    1. Beiderlinden M, Treschan T, Görlinger K, Peters J. Argatroban in extracorporeal membrane oxygenation. Artif Organs. 2007;31:461–465. doi: 10.1111/j.1525-1594.2007.00388.x.
    1. Doepker B, Mount KL, Ryder LJ, Gerlach AT, Murphy CV, Philips GS. Bleeding risk factors associated with argatroban therapy in the critically ill. J Thromb Thrombolysis. 2012;34:491–498. doi: 10.1007/s11239-012-0758-y.
    1. Watson H, Davidson S, Keeling D, Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: second edition. Br J Haematol. 2012;159:528–540.
    1. Wanat M, Fitousis K, Hall J, Rice L. PF4/heparin antibody testing and treatment of heparin-induced thrombocytopenia in the intensive care unit. Clin Appl Thromb Hemost. 2013;19:297–302. doi: 10.1177/1076029612438709.
    1. Warkentin TE, Sheppard JA. Testing for heparin-induced thrombocytopenia antibodies. Transfus Med Rev. 2006;20:259–272. doi: 10.1016/j.tmrv.2006.05.001.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe