Perioperative Thromboseprophylaxe – Medikamentöse Thromboseprophylaxe in der Intensivmedizin

Zusammenfassung

Intensivmedizinisch betreute Patienten sind regelhaft als Hochrisikopatienten für venöse Thromboembolien einzuschätzen. Jenseits einer grundsätzlichen Empfehlung für eine medikamentöse Prophylaxe aus den Fachgesellschaften liegen aufgrund der unzureichenden Datenlage für dieses Patientenkollektiv keine Richtlinien für die Wahl der Substanz oder der Dosierung vor. Prinzipiell können UFH, NMH und Fondaparinux zur Anwendung kommen. Für Patienten mit akut vermuteter oder gesicherter HIT Typ II kann eine Antikoagulation mit Argatroban sicher fortgeführt werden. Für die neuen oral verfügbaren Antikoagulanzien zeichnet sich gegenwärtig noch kein Einsatzgebiet in der Intensivmedizin ab.

Abstract

Critical care patients have to be considered at high risk patients for thromboembolic events. The recommendations and guidelines support strongly a pharmacologic anticoagulant prophylaxis. Due to the fact that only very few data are available for this selected patient population there are still open questions concerning the ideal choice of drug and optimal dosages. Prophylactic administration of UFH, LMWH and Fondaparinux can be used safely and effectively. In case of acutely suspected or diagnosed HIT type II Argatroban seems to be a reasonable choice for anticoagulation. The new orally available anticoagulant drugs are not yet indicated in ICU patients.

Kernaussagen

• Patienten auf der Intensivstation sind auch bei unterschiedlichen Grunderkrankungen fast durchweg als Hochrisikopatienten einzuschätzen.

• Höhergradige Thrombozytopenien oder Zeichen einer verminderten plasmatischen Gerinnung (aPTT-Verlängerung / INR-Erhöhung) schließen ein erhöhtes VTE-Risiko keinesfalls aus. Sie sind unter Umständen sogar Ausdruck einer überschwelligen Gerinnungsaktivierung in einer primär prothrombogenen Situation.

• Eine medikamentöse Antikoagulation zur Prophylaxe ist auch bei kritisch Kranken wirksam: Durch die Propyhlaxe reduzierte sich die Inzidenz von Thromboembolien um etwa 50 Relativprozent.

• Die mechanische Prophylaxe ist wirksamer als keine Prophylaxe – eine medikamentöse Prophylaxe sollte sie aber nur bei guter Begründung ersetzen.

• Die Datenlage zu den parenteralen Antikoagulanzien UFH, NMH und Fondaparinux in der Intensivmedizin ist sehr spärlich.

• Welche Antikoagulanzien in welcher Dosierung bei Intensivpatienten gegeben werden, sollte wegen der schwachen Datenlage individuell entschieden werden. Ein Labormonitoring scheint auch bei prophylaktischer Dosierung sinnvoll zu sein.

• Für die Intensivmedizin gibt es durchaus vielversprechende Medikamente wie direkte parenterale Thrombininhibitoren – aufgrund der unzureichenden Erfahrung, mangelnden Datenlage und fehlenden Zulassung ist eine routinemäßige Anwendung direkter parenteraler Thrombininhibitoren aber nicht generell zu empfehlen.

• Für Patienten mit akut vermuteter oder gesicherter HIT Typ II kann eine Antikoagulation mit Argatroban sicher fortgeführt werden.

• Für die neuen oral verfügbaren Antikoagulanzien (NOAC) liegen keine Daten für die Anwendung bei kritisch kranken Patienten vor.

• Für die VTE-Prophylaxe im intensivmedizinischen Bereich zeichnet sich aufgrund der Applikationsweise, der pharmakologischen Eigenschaften und der bestehenden Alternativen gegenwärtig kein abgrenzbarer Einsatzbereich ab – jedenfalls nicht jenseits der postoperativen Thromboembolieprophylaxe im elektiven Knie- und Hüftgelenkersatz.

Schlüsselwörter:

Intensivmedizin - kritisch kranke Patienten - venöse Thromboembolie - Prophylaxe - Antikoagulanzien - UFH - NMH - Fondaparinux

Keywords:

ICU - critically ill patients - venous thromboembolism - prophylaxis - anticoagulants - UFH - LMWH - Fondaparinux

• Literatur

• 1 Cook D. Deep vein thrombosis in medical surgical critically ill patients: prevalence incidence and risk factors. Crit Care Med 2005; 3: 1565-1571
• 2 Crowther MA, Cook DJ, Griffith LE et al. Deep venous thrombosis: clinically silent in the intensive care unit. J Crit Care 2005; 20: 334-340
• 3 Edwards M, Felder S, Ley E et al. Venous thromboembolism in coagulopathic surgical intensive care unit patients: is there a benefit from chemical prophylaxis?. J Trauma 2011; 70: 1398-1400
• 4 Geerts WH, Bergqvist D, Pineo GF et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (Suppl. 06)
• 5 Geerts WH. Venous thromboembolism and its prevention in critical care. J Crit care 2002; 17: 95-104
• 6 Kudsk KA. Silent deep vein thrombosis in immobilized multiple trauma patients. Am J Surg 1989; 158: 515-519
• 7 Hirsch DR, Ingenito EP, Goldhaber SZ. Prevalence of deep venous thrombosis among patients in medical intensive care. JAMA 1995; 274: 335-337
• 8 Geerts WH, Code KI, Jay RM et al. A prospective study of venous thromboembolism after major trauma. N Engl J Med 1994; 331: 1601-1606
• 9 Cook DJ, Crowther MA. Thromboprophylaxis in the intensive care unit: focus on medical-surgical patients. Crit Care Med 2010; 38
• 10 Ibrahim EH, Iregui M, Prentice D et al. Deep vein thrombosis during prolonged mechanical ventilation despite prophylaxis. Crit Care Med 2002; 30: 771-774
• 11 Fraisse F, Holzapfel L, Couland JM et al. The Association of Non-University Affiliated Intensive Care Specialist Physicians of France. Nadroparin in the prevention of deep vein thrombosis in acute decompensated COPD. Am J Respir Crit Care Med 2000; 161: 1109-1114
• 12 Cade JF. High risk of the critically ill for venous thromboembolism. Crit Care Med 1982; 10: 448-450
• 13 Deutsche Gesellschaft für Anästhesiologie und Intensivmedizin. Rückenmarknahe Regionalanästhesien und Thromboembolieprophylaxe / antithrombotische Medikation. S1-Leitlinie, Registernummer 001-005 (02.12.2007). Im Internet: http://www.awmf.org/leitlinien/detail/ll/001-005.html Stand: 21.03.1982
• 14 Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften. AWMF-Leitlinie Prophylaxe der venösen Thromboembolie (VTE). S3-Leitlinie, Registernummer 003-001 (01.05.2010). Im Internet: http://www.awmf.org/leitlinien/detail/ll/003-001.html Stand: 21.03.1982
• 15 Dellinger RP. Surviving Sepsis Campaign. International guidelines for management of severe sepsis and septic shock. Crit Care Med 2008; 36: 297-327
• 16 Kahn SR, Lim W, Dunn AS et al. Antithrombotic Therapy and Prevention of Thrombosis (9th Edition): American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02)
• 17 Tapson VF, Decousus H, Pini M et al. IMPROVE Investigators. Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients: findings from the International Medical Prevention Registry on Venous Thromboembolism. Chest 2007; 132: 936-945
• 18 Crowther MA, Berry LR, Monagle PT, Chan AKC. Mechanisms responsible for the failure of protamine to inactivate low-molecular-weight heparin. Br J Haematol 2002; 116: 178-186
• 19 van Veen JJ, Maclean RM, Hampton KK et al. Protamine reversal of low molecular weight heparin: clinically effective?. Blood Coagul Fibrinolysis 2011; 22: 565-570
• 20 Levine MN, Hirsh J, Gent M et al. A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin. Arch Intern Med 1994; 154: 49-56
• 21 Uprichard J, Manning RA, Laffan MA. Monitoring heparin anticoagulation in the acute phase response. Br J Haematol 2010; 149: 613-613
• 22 Becker RC, Corrao JM, Bovill EG et al. Intravenous nitroglycerine-induced heparin resistance: a qualitative antithrombin III abnormality. Am Heart J 1990; 119: 1254-1261
• 23 Krauel K, Pötschke C, Weber C et al. Platelet factor 4 binds to bacteria, [corrected] inducing antibodies cross-reacting with the major antigen in heparin-induced thrombocytopenia. Blood 2011; 117: 1370-1378
• 24 Lim W, Dentali F, Eikelboom JW, Crowther MA. Meta-analysis: low-molecular-weight heparin and bleeding in patients with severe renal insufficiency. Ann Intern Med 2006; 144: 673-684
• 25 Bauersachs R, Schellong SM, Haas S et al. CERTIFY: prophylaxis of venous thromboembolism in patients with severe renal insufficiency. Thromb Haemost 2011; 105: 981-988
• 26 Cook D, Douketis J, Meade M et al. Canadian Critical Care Trials Group: Venous thromboembolism and bleeding in critically ill patients with severe renal insufficiency receiving dalteparin thromboprophylaxis: prevalence, incidence and risk factors. Crit Care 2008; 12
• 27 Douketis J, Cook D, Meade M et al. Canadian Critical Care Trials Group. Prophylaxis against deep vein thrombosis in critically ill patients with severe renal insufficiency with the low-molecular-weight heparin dalteparin: an assessment of safety and pharmacodynamics: the DIRECT study. Arch Intern Med 2008; 168: 1805-1812
• 28 Clark NP. Low-molecular-weight heparin use in the obese, elderly, and in renal insufficiency. Thromb Res 2008; 123 (Suppl. 01) 58-61
• 29 Robinson S, Zincuk A, Strøm T et al. Enoxaparin, effective dosage for intensive care patients: double-blinded, randomised clinical trial. Crit Care 2010; 14
• 30 Priglinger U, Delle KarthG, Geppert A et al. Prophylactic anticoagulation with enoxaparin: Is the subcutaneous route appropriate in the critically ill?. Crit Care Med 2003; 31: 1405-1409
• 31 Mayr AJ, Dünser M, Jochberger S et al. Antifactor Xa activity in intensive care patients receiving thromboembolic prophylaxis with standard doses of enoxaparin. Thromb Res 2002; 105: 201-204
• 32 Dörffler-Melly J, de Jonge E, Pont AC et al. Bioavailability of subcutaneous low-molecular-weight heparin to patients on vasopressors. Lancet 2002; 359: 849-850
• 33 Rommers MK, Van der Laan N, Egberts TC, van den Bemt PM. Anti-Xa activity after subcutaneous administration of dalteparin in ICU patients with and without subcutaneous oedema: a pilot study. Crit Care 2006; 10
• 34 Haas CE, Nelsen JL, Raghavendran K et al. Pharmacokinetics and pharmacodynamics of enoxaparin in multipletrauma patients. J Trauma 2005; 59: 1336-1344
• 35 Cumbo-Nacheli G, Samavati L, Guzman JA. Bioavailability of fondaparinux in critcal ill patients. J Crit Care 2011; 26: 342-346
• 36 Montalescot G, Zeymer U, Silvain J et al. Intravenous enoxaparin or unfractionated heparin in primary percutaneous coronary intervention for ST-elevation myocardial infarction: the international randomised open-label ATOLL trial. Lancet 2011; 378: 693-703
• 37 Schinzel H, Berghoff K, Beuermann I et al. Anticoagulation with low-molecular-weight heparin (dalteparin) in plasmapheresis therapy: initial experience. Transfusion 2006; 46: 624-629
• 38 De A, Roy P, Garg VK et al. Low–molecular-weight heparin and unfractionated heparin in prophylaxis against deep vein thrombosis in critically ill patients undergoing major surgery. Blood Coagul Fibrinolysis 2010; 21: 57-61
• 39 Geerts WH, Jay RM, Code KI et al. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med 1996; 335: 701-707
• 40 Levi M, Levy M, William MD et al. Xigris in Prophylactic Heparin Evaluation in Severe Sepsis (XPRESS) Study Group. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am Rev Resp Crit Care Med 2007; 176: 483-490
• 41 Cook D, Meade M, Guyatt G et al. Prophylaxis for Thromboembolism in Critical Care Trial protocol and analysis plan. Critical Care 2011; 26: 1-9
• 42 Wester JP, Leyte A, Oudemans-van Straaten HM et al. Low-dose fondaparinux in suspected heparin-induced thrombocytopenia in the critically ill. Neth J Med 2007; 65: 101-108
• 43 Crowther MA, Cook DJ. Preventing venous thromboembolism in critically ill patients. Semin Thromb Hemost 2008; 34: 469-474
• 44 Lacherade JC, Cook D, Heyland D et al. French and Canadian ICU Directors Groups. Prevention of venous thromboembolism in critically ill medical patients: a Franco-Canadian cross-sectional study. J Crit Care 2003; 18: 228-237
• 45 Hilbert P, Teumer P, Stuttmann R. Prevention of thromboembolism in German intensive care units: Results of a nationwide survey. Anaesthesist 2008; 57: 242-250
• 46 Smythe MA, Warkentin TE, Stephens JL et al. Venous limb gangrene during overlapping therapy with warfarin and a direct thrombin inhibitor for immune heparin-induced thrombocytopenia. Am J Hematol 2002; 71: 50-52
• 47 Kiser TH, Fish DN. Evaluation of bivalirudin treatment for heparin-induced thrombocytopenia in critically ill patients with hepatic and/or renal dysfunction. Pharmacotherapy 2006; 26: 452-460
• 48 Dang CH, Durkalski VL, Nappi JM. Evaluation of treatment with direct thrombin inhibitors in patients with heparin-induced thrombocytopenia. Pharmacotherapy 2006; 26: 461-468
• 49 Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 2000; 20: 318-329
• 50 Guzzi LM, McCollum DA, Hursting MJ. Effect of renal function on argatroban therapy in heparin-induced thrombocytopenia. J Thromb Thrombolysis 2006; 22: 169-176
• 51 Lewis BE, Wallis DE, Berkowitz SD et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001; 103: 1838-1843
• 52 Saugel B, Phillip V, Moessmer G et al. Argatroban therapy for heparin-induced thrombocytopenia in ICU patients with multiple organ dysfunction syndrome: a retrospective study. Crit Care 2010; 14
• 53 Beiderlinden M, Treschan TA, Görlinger K, Peters J. Argatroban anticoagulation in critically ill patients. Ann Pharmacother 2007; 41: 749-754
• 54 Link A, Girndt M, Selejan S et al. Argatroban for anticoagulation in continuous renal replacement therapy. Crit Care Med 2009; 37: 105-110
• 55 Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47: 285-295
• 56 Van Ryn J, Standier J, Liesenfeld K et al. Dabigatran etexilate: A novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116-1127
• 57 Turpie AG, Lassen MR, Kakkar AK et al. Pooled Analysis of Four Pivotal Studies of Rivaroxaban for the Prevention of Venous Thromboembolism after Orthopaedic Surgery: Effect on Symptomatic Venous Thromboembolism, Death, and Bleeding. Blood (ASH Annual Meeting Abstracts) 2008; 112: 36-36
• 58 Ufer M. Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development. Thromb Haemost 2010; 103: 572-585