Orale Thromboembolieprophylaxe mit Rivaroxaban und Dabigatran: Sind die Neuzulassungen Innovationen für die operative Orthopädie und Unfallchirurgie?

Zusammenfassung

Operativ tätige Orthopäden und Unfallchirurgen befassen sich täglich mit der Indikationsstellung einer Thromboembolieprophylaxe. Aktuell ergeben sich diesbezüglich relevante Veränderungen. Einerseits wurde im Mai eine neue, streng evidenzbasierte AWMF-Leitlinie von insgesamt 27 Fachgesellschaften verabschiedet. Erstmals werden hier konkrete Empfehlungen zu den einzelnen Indikationsgebieten ausgesprochen, die die Art der medikamentösen Prophylaxe und auch deren Dauer beschreiben. Viele der Empfehlungen werden dazu führen, dass bisher gängige Prozesse in den Kliniken und auch im ambulanten Bereich geändert werden. Nahezu zeitgleich wurden in Deutschland 2 neue orale Antikoagulanzien für die Prophylaxe der Thromboembolie nach Hüft- und Kniegelenkendoprothesen zugelassen. Dabigatran ist ein oraler Thrombinhemmer. Bei vergleichbarem Nebenwirkungs- und Komplikationsprofil zeigt er auch hinsichtlich der Wirksamkeit gegenüber Enoxaparin in der oben genannten Indikation keine klinisch relevanten Unterschiede. Rivaroxaban ist ein oraler Faktor-Xa-Hemmer, der gegenüber Enoxaparin bei ebenfalls vergleichbaren Nebenwirkungs- und Komplikationsraten eine signifikant bessere Effektivität bei der Reduktion thrombotischer Komplikationen nach Hüft- und Kniegelenkendoprothesen zeigen konnte. Diese signifikante Überlegenheit gilt in gepoolten Analysen aus der Phase 3 auch für symptomatische Ereignisse. Die Übersichtsarbeit diskutiert relevante Aspekte der neuen AWMF-Leitlinie ebenso wie die möglichen Effekte der neuen Antikoagulanzien auf Prozesse in der Klinik.

Abstract

Today the indication for thrombosis prophylaxis is a relevant and daily concern in orthopaedic surgery. Recently there are some changes concerning the German guidelines, which are approved by 27 German medical societies. For the first time the guidelines give distinct recommendations for the different indications, the kind of thrombosis prophylaxis and its duration. Some of the recommendations will lead to changes of both processes in outpatient and inpatient management. In parallel 2 new oral anticoagulants have been approved for the prevention of thromboembolic events after elective knee and hip replacement. Dabigatran is an oral thrombin inhibitor. Compared to enoxaparin it has a comparable profile of side effects and efficacy. Rivaroxaban is an oral Xa inhibitor which shows a sigificantly better efficacy compared to enoxaparin and no difference in side effects. The significant reduction of symptomatic thromboembolisms after elective knee and hip replacement was shown for rivaroxaban compared to enoxaparin in a pooled analysis of phase III data. This review discusses the main topics of the new German guideline and impact of the new oral anticoagulants on in- and outpatient treatment procedures.

AWMF‐Leitlinien - Thromboembolie - Prophylaxe - Gelenkendoprothesen - Dabigatran - Rivaroxaban

guideline - thromboembolism - prophylaxis - joint replacement - dabigatran - rivaroxaban

Literatur

• 1 AWMF .Prophylaxe der venösen Thromboembolie (VTE). AWMF Leitlinienregister 2009 003/001: 1-152
• 2 Bauersachs R M. [New anticoagulants].  Hamostaseologie. 2008;  28 21-26
• 3 Encke A, Haas S, Krauspe R et al. Stationäre und ambulante Thromboembolieprophylaxe in der Chirurgie und der perioperativen Medizin: Interdisziplinäre Leitlinie.  Phlebologie. 2003;  32 164-169
• 4 Geerts W H, Bergqvist D, Pineo G F et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest. 2008;  133 (Suppl. 6) 381S-453S
• 6 Warwick D, Friedman R J, Agnelli G et al. Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events: findings from the Global Orthopaedic Registry.  J Bone Joint Surg [Br]. 2007;  89 799-807
• 8 Harenberg J, Wehling M. Current and future prospects for anticoagulant therapy: inhibitors of factor Xa and factor II a.  Semin Thromb Hemost. 2008;  34 39-57
• 9 Stangier J, Rathgen K, Stahle H et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects.  Br J Clin Pharmacol. 2007;  64 292-303
• 10 Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate.  Clin Pharmacokinet. 2008;  47 285-295
• 11 Stangier J, Stahle H, Rathgen K et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects.  Clin Pharmacokinet. 2008;  47 47-59
• 12 Blech S, Ebner T, Ludwig-Schwellinger E et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans.  Drug Metab Dispos. 2008;  36 386-399
• 13 Eriksson B I, Dahl O E, Rosencher N et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial.  Lancet. 2007;  370 949-956
• 15 EMEA Europa .CHMP assessment report for Pradaxa. http://www.emea.europa.eu/humandocs/PDFs/EPAR/pradaxa/H-829-en6.pdf Stand: 24.11.2008
• 16 Eriksson B I, Dahl O E, Rosencher N et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial.  J Thromb Haemost. 2007;  5 2178-2185
• 18 The RE-MOBILIZE Writing Committee . The oral thrombin inhibitor Dabigatran etexilate vs. the North American enoxaparin regimen for the prevention of venous thromboembolism after knee arthroplasty surgery.  J Arthroplasty. 2009;  24 1-9
• 19 Mueck W, Borris L C, Dahl O E et al. Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement.  Thromb Haemost. 2008;  100 453-461
• 20 Mueck W, Eriksson B I, Bauer K A et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban – an oral, direct factor Xa inhibitor – in patients undergoing major orthopaedic surgery.  Clin Pharmacokinet. 2008;  47 203-216
• 21 Fisher W D, Eriksson B I, Bauer K A et al. Rivaroxaban for thromboprophylaxis after orthopaedic surgery: pooled analysis of two studies.  Thromb Haemost. 2007;  97 931-917
• 17 EMEA Europa .CHMP assessment report for Xarelto (2008). Im Internet:. http://www.emea.europa.eu/humandocs/PDFs/EPAR/xarelto/H-944-en1.pdf Stand: 24.11.2008
• 22 Eriksson B I, Borris L C, Friedman R J et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty.  N Engl J Med. 2008;  358 2765-2775
• 23 Kakkar A K, Brenner B, Dahl O E et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial.  Lancet. 2008;  372 31-39
• 24 Lassen M R, Ageno W, Borris L C et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty.  N Engl J Med. 2008;  358 2776-2786
• 25 Turpie A G, Lassen M R, Davidson B L et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial.  Lancet. 2009;  373 1673-1680
• 26 Eriksson B I, Kakkar A K, Turpie A G et al. Oral rivaroxaban for the prevention of symptomatic venous thromboembolism after elective hip and knee replacement.  J Bone Joint Surg [Br]. 2009;  91 636-644
• 27 Planes A, Vochelle N, Fagola M. Total hip replacement and deep vein thrombosis. A venographic and necropsy study.  J Bone Joint Surg [Br]. 1990;  72 9-13
• 28 Dahl O E, Aspelin T, Arnesen H et al. Increased activation of coagulation and formation of late deep venous thrombosis following discontinuation of thromboprophylaxis after hip replacement surgery.  Thromb Res. 1995;  80 299-306
• 29 Eisele R, Greger W, Weikert E et al. [Ambulatory prevention of thrombosis in traumatology].  Unfallchirurg. 2001;  104 240-245
• 30 Douketis J D, Eikelboom J W, Quinlan D J et al. Short-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of prospective studies investigating symptomatic outcomes.  Arch Intern Med. 2002;  162 1465-1471
• 31 White R H, Romano P S, Zhou H et al. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty.  Arch Intern Med. 1998;  158 1525-1531
• 32 Antiplatelet Trialists' Collaboration . Collaborative overview of randomised trials of antiplatelet therapy – III: reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients.  BMJ. 1994;  308 235-246
• 33 Hull R D, Pineo G F, Stein P D et al. Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: a systematic review.  Ann Intern Med. 2001;  135 858-869
• 36 Westrich G H, Haas S B, Mosca P et al. Meta-analysis of thromboembolic prophylaxis after total knee arthroplasty.  J Bone Joint Surg [Br]. 2000;  82 795-800
• 37 Abelseth G, Buckley R E, Pineo G E et al. Incidence of deep-vein thrombosis in patients with fractures of the lower extremity distal to the hip.  J Orthop Trauma. 1996;  10 230-235
• 40 Comp P C, Spiro T E, Friedman R J et al. Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement. Enoxaparin Clinical Trial Group.  J Bone Joint Surg [Am]. 2001;  83 336-345
• 41 Kock H J, Schmit-Neuerburg K P, Hanke J et al. Thromboprophylaxis with low-molecular-weight heparin in outpatients with plaster-cast immobilisation of the leg.  Lancet. 1995;  346 459-461
• 42 Kujath P, Spannagel U, Habscheid W et al. [Thrombosis prevention in outpatients with lower limb injuries].  Dtsch Med Wochenschr. 1992;  117 6-10
• 43 Kujath P, Spannagel U, Habscheid W. Incidence and prophylaxis of deep venous thrombosis in outpatients with injury of the lower limb.  Haemostasis. 1993;  23 (Suppl. 1) 20-26
• 44 Rogers F B, Cipolle M D, Velmahos G et al. Practice management guidelines for the prevention of venous thromboembolism in trauma patients: the EAST practice management guidelines work group.  J Trauma. 2002;  53 142-164
• 45 Jorgensen P S, Warming T, Hansen K et al. Low molecular weight heparin (Innohep) as thromboprophylaxis in outpatients with a plaster cast: a venografic controlled study.  Thromb Res. 2002;  105 477-480
• 46 Lassen M R, Borris L C, Nakov R L. Use of the low-molecular-weight heparin reviparin to prevent deep-vein thrombosis after leg injury requiring immobilization.  N Engl J Med. 2002;  347 726-730
• 49 Mizel M S, Temple H T, Michelson J D et al. Thromboembolism after foot and ankle surgery. A multicenter study.  Clin Orthop Relat Res. 1998;  348 180-185
• 50 Radl R, Kastner N, Aigner C et al. Venous thrombosis after hallux valgus surgery.  J Bone Joint Surg [Am]. 2003;  85 1204-1208
• 51 Solis G, Saxby T. Incidence of DVT following surgery of the foot and ankle.  Foot Ankle Int. 2002;  23 411-414
• 52 Collins J J. Knee-joint arthroscopy – early complications.  Med J Aust. 1989;  150 702-703 706
• 53 Delis K T, Hunt N, Strachan R K et al. Incidence, natural history and risk factors of deep vein thrombosis in elective knee arthroscopy.  Thromb Haemost. 2001;  86 817-821
• 54 Demers C, Marcoux S, Ginsberg J S et al. Incidence of venographically proved deep vein thrombosis after knee arthroscopy.  Arch Intern Med. 1998;  158 47-50
• 55 Christie I W, McCabe S. Major complications of epidural analgesia after surgery: results of a six-year survey.  Anaesthesia. 2007;  62 335-341
• 56 Cook T M, Counsell D, Wildsmith J A. Major complications of central neuraxial block: report on the Third National Audit Project of the Royal College of Anaesthetists.  Br J Anaesth. 2009;  102 179-190
• 57 Moen V, Dahlgren N, Irestedt L. Severe neurological complications after central neuraxial blockades in Sweden 1990–1999.  Anesthesiology. 2004;  101 950-959
• 58 Gogarten W. The influence of new antithrombotic drugs on regional anesthesia.  Curr Opin Anaesthesiol. 2006;  19 545-550
• 59 Gogarten W, Van Aken H, Büttner J et al. Rückenmarksnahe Regionalanästhesie und Thromboembolieprophylaxe/antithrombotische Medikation. 2. überarbeitete Empfehlung der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin.  Anaesth Intensivmed. 2007;  48 S109-S124
• 60 Fleisher L A, Beckman J A, Brown K A et al. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery).  Anesth Analg. 2008;  106 685-712
• 61 Burger W, Chemnitius J M, Kneissl G D et al. Low-dose aspirin for secondary cardiovascular prevention – cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation – review and meta-analysis.  J Intern Med. 2005;  257 399-414
• 62 Collet J P, Montalescot G, Blanchet B et al. Impact of prior use or recent withdrawal of oral antiplatelet agents on acute coronary syndromes.  Circulation. 2004;  110 2361-2367
• 64 Strebel N, Prins M, Agnelli G et al. Preoperative or postoperative start of prophylaxis for venous thromboembolism with low-molecular-weight heparin in elective hip surgery?.  Arch Intern Med. 2002;  162 1451-1456
• 65 McBride D, Brüggenjürgen B, Roll S et al. Management patterns of thrombosis prophylaxis and related costs in hip and knee replacement in Germany.  Central European Journal of Medicine. 2007;  2 47-65
• 68 Greinacher A. Heparin-induced thrombocytopenia – pathogenesis and treatment.  Thromb Haemost. 1999;  82 (Suppl. 1) 148-156
• 69 Fachinformation Dabigatran. Boehringer Ingelheim 2008
• 72 Cohen A T, Tapson V F, Bergmann J F et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study.  Lancet. 2008;  371 387-394
• 75 Fachinformation Xarelto. Bayer Vital 2008