Sekundärprophylaxe der venösen Thromboembolie

Zusammenfassung

Der Standard in der Erhaltungstherapie (Sekundärprophylaxe) der venösen Thromboembolie ist die Gabe von Vitamin- K-Antagonisten mit einer Ziel-INR von 2,0 bis 3,0. Die Rezidivrate sinkt hierunter auf ein Minimum von ca. 1% pro Jahr. Allerdings muss in Abhängigkeit vom Patientenprofil mit größeren Blutungen in einer Häufigkeit von 1 bis 3% gerechnet werden. Die Standarddauer der Erhaltungstherapie beträgt 3-6 Monate. Zu diesem Zeitpunkt endet sie in jedem Fall bei Patienten mit einem vorübergehenden Risikofaktor (Operation, Trauma). Die Verlängerung der Erhaltungstherapie kommt nur für Patienten mit erhöhtem Rezidivrisiko in Frage. Bereits nach der ersten Episode kann sie auf unbestimmte Dauer angesetzt werden bei Patienten mit aktiver Krebserkrankung oder schweren thrombophilen Defekten (Antiphospholipidsyndrom, schwerem familiären Antithrombin-, Protein-C- oder Protein-S-Mangel). Zunächst auf ein Jahr befristen wird man die Erhaltungstherapie bei einer ersten idiopathischen Episode von VTE oder mittelschweren (z. B. kombinierten) thrombophilen Defekten. Der einfache heterozygote Faktor-V-Leiden-Defekt oder die Prothrombin-20210-Variante fallen nicht darunter. Das Rezidiv einer idiopathischen Thrombose wiederum sollte Anlass für eine längerfristige oder dauerhafte Erhaltungstherapie sein. Jede Entscheidung über die Dauer muss eine – periodisch wiederholte – Abschätzung des individuellen Blutungsrisikos beinhalten und individuelle Präferenzen des Patienten berücksichtigen. Als alternative Medikation zur Erhaltungstherapie stehen zurzeit niedermolekulare Heparine zur Verfügung. Neue parenterale und oral zu verabreichende Wirkstoffe befinden sich in der klinischen Erprobung.

Summary

Making decisions about any modality of secondary prophylaxis in patients with venous thromobembolism (VTE) has to balance the risk of bleeding induced by anticoagulants against the benefit of reducing the risk of recurrent disease. It has to be kept in mind that the magnitude of risk is not only defined by the number of events per time period but also by the impact of the event on the fate of the patient. With standard intensity vitamin K antagonists (VKA), the risk of bleeding is more closely related to comorbidities than to other factors, eg age. The risk of VTE recurrence differs largely between patient groups. The criterion of presence or absence of a permanent or transient clinical trigger factor for the actual VTE episode has a greater impact than an abnormal result in thrombophilia testing. The standard period of secondary prophylaxis for proximal DVT and for PE is three to six months. The concept of prolonging this period for several months according to the risk of recurrence is seriously challanged by the observation that the prolongation period seems to delay recurrencies rather than truly avoiding them. For this reason, patients who clearly are threatened by recurrent episodes should receive indefinitive secondary prophylaxis. This is the case for cancer patients, patients with the antiphospholipid syndrome, and those who belong to families with severe and symptomatic protein C, protein S, or antithrombin deficiencies. Patients with recurrent VTE, with idiopathic VTE, or with combined thrombophilic conditions may only benefit from indefinitive secondary prophylaxis if the bleeding risk of the anticoagulant regimen under consideration is very low.

Schlüsselwörter

Venöse Thromboembolie - Antikoagulation - Sekundärprophylaxe - Therapie

Keywords

Venous thromboembolism - anticoagulation - therapy of VTE - secondary prophylaxis of VTE

• Literatur

• 1 Agnelli G, Prandoni P, Santamaria MG. et al. the Warfarin Optimal Duration Italian Trial Investigators. Three Months versus One Year of Oral Anticoagulant Therapy for Idiopathic Deep Venous Thrombosis. N Engl J Med 2001; 345: 165-9.
• 2 Agnelli G, Prandoni P, Becattini C. et al. Investigators WODIT.. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med 2003; 139: 19-25.
• 3 Agnelli G. Long-term low-dose warfarin use is effective in the prevention of recurrent venous thromboembolism: No. J Thromb Haemost 2004; 2: 1038-40.
• 4 Baglin T, Luddington R, Brown K. et al. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003; 362: 523-36.
• 5 Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism. Lancet 1960; 1309-12.
• 6 Bernardi E, Piccioli A, Oliboni G. et al. Nomograms for the administration of unfractionated heparin in the inital treatment of acute thromboembolism – an overview. Thromb Haemost 2000; 84: 22-6.
• 7 Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med 1998; 105: 91-9.
• 8 Brandjes DP, Heijboer H, Buller HR. et al. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximalvein thrombosis. N Engl J Med 1992; 327: 1485-9.
• 9 Boudes PF. The challenges of new drugs benefits and risks analysis: lessons from the ximelagatran FDA Cardiovascular Advisory Committee. Contemp Clin Trials 2006; 27: 432-40.
• 10 Büller HR, Cohen AT, Lensing AWA. et al. A novel long-acting synthetic factor Xa inhibitor (SanOrg34006) to replace warfarin for secondary prevention in deep vein thrombosis. A phase II evaluation. J Thromb Haemost 2004; 2: 47-53.
• 11 Büller HR, Davidson BL, Decousus H. et al. Fondaparinux or Enoxaparin for the initial treatment of symptomatic deep venous thrombosis. Ann Int Med 2004; 140: 867-73.
• 12 Büller HR, Davidson BL, Decousus H. et al. Subcutaneous Fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2004; 349: 1695-702.
• 13 Büller HR, Agnelli G, Hull RD. et al. Antithrombotic Therapy for Venous Thromboembolic Disease. The Seventh ACCP Conference on Antithrom- botic an Thrombolytic Therapy. Chest 2004; 126: 401S-28.
• 14 CARS Study Investigators.. Randomised doubleblind trial of fixed low-dose warfarin with aspirin after myocardial infarction: Coumadin Aspirin Reinfarction Study. Lancet 1997; 350: 389-96.
• 15 Crowther MA, Ginsberg JS, Julian J. et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003; 349: 1133-8.
• 16 De Stefano V, Martinelli I, Mannucci PM. et al. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A transition in the prothrombin gene. N Engl J Med 1999; 341: 801-6.
• 17 Douketis JD, Kearon C, Bates S. et al. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA 1998; 279: 458-62.
• 18 Eichinger S, Stumpflen A, Hirschl M. et al. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism. Thromb Haemost 1998; 80: 566-9.
• 19 Eichinger S, Minar E, Bialonczyk C. et al. D-dimer levels and risk of recurrent venous thromboembolism. JAMA 2003; 290: 1071-4.
• 20 Eichinger S, Weltermann A, Minar E. et al. Symptomatic pulmonary embolism and the risk of recurrent venous thromboembolism. Arch Intern Med 2004; 164: 92-6.
• 21 Fiessinger JN, Huisman MV, Davidson BL. et al. THRIVE Treatment Study Investigators. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. JAMA 2005; 293: 681-9.
• 22 Fihn SD, Callahan CM, Martin DC. et al. The risk for and severity of bleeding complicatins in elderly patients treated with warfarin. The National Consortium of Anticoagulation clinics. Ann Intern Med 1996; 124: 970-9.
• 23 Hansson PO, Sörbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med 2000; 160: 769-74.
• 24 Heit JA, Mohr DN, Silverstein MD. et al. Predictors of recurence after deep vein thrombosis and pulmonary embolism: a populationbased cohort study. Arch Intern Med 2000; 160: 761-8.
• 25 Hull R, Hirsh J, Jay R. et al. Different intensities of oral anticoagulant therapy in the treatment of proximal- vein thrombosis. N Engl J Med 1982; 307: 1676-81.
• 26 Hull RD, Raskob GE, Pineo GF. et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992; 326: 975-82.
• 27 Hull RD, Raskob GE, Brant RF. et al. Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis. Arch Intern Med 1997; 157: 2562-8.
• 28 Hutten BA, Prins MH. Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism. Cochrane Database Syst Rev 2006; CD001367.
• 29 Hyers TM. Management of venous thromboembolism. Arch Intern Med 2003; 163: 759-68.
• 30 Hylek EM, Skates SJ, Sheehan MA. et al. An analysis of the lowest effective intensity of prophy-lactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996; 335: 540-6.
• 31 Interdisziplinäre S2-Leitlinie. Diagnostik und Therapie der Bein- und Beckenvenenthrombose und der Lungenembolie. VASA. 2005 35. Suppl 66.
• 32 Iorio A, Guercini F, Pini M. Low-molecularweight heparin for the long-term treatment of symptomatic venous thromboembolism: metaanalysis of the randomized comparisons with oral anticoagulants. J Thromb Haemost 2003; 1: 1906-13.
• 33 Kearon C, Gent M, Hirsh J. et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340: 901-7.
• 34 Kearon C, Ginsberg JS, Kovacs MJ. et al. Comparison of low-intensity warfarin therapy with conventional- intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003; 349: 631-9.
• 35 Khamashta MA, Cuadrado MJ, Mujic F. et al. The management of thrombosis in the antiphospholipid- antibody syndrome. N Engl J Med 1995; 332: 993-7.
• 36 Kovacs MJ. Long-term low-dose warfarin use is effenctive in the prevention of recurrent venous thromboembolism: No. J Thromb Haemost 2004; 2: 1041-3.
• 37 Kubitza D, Becka M, Voith B. et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59–7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005; 78: 412-21.
• 38 Kyrle PA, Minar E, Hirschl M. et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000; 343: 457-62.
• 39 Kyrle PA, Eichinger S. The risk of recurrent venous thromboembolism. VASA 2002; 31: 163-6.
• 40 Kyrle PA, Minar E, Bialonczyk C. et al. The risk of recurrent venous thromboembolism in men and women. N Engl J Med 2004; 350: 2558-63.
• 41 Lee AYY, Levine MN, Baker RI. et al. Low-molecular- weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349: 146-53.
• 42 Levine MN, Raskob G, Landefeld S. et al. Hemorrhagic complications of anticoagulant treatment. Chest 2001; 119: 108S-21S.
• 43 Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003; 139: 893-900.
• 44 Ma Q, Fareed J. Idraparinux sodium. Sanofi- Aventis. IDrugs 2004; 7: 1028-34.
• 45 McMahan DA, Smith DM, Carey MA. et al. Risk of major hemorrhage for outpatients treated with warfarin. J Gen Intern Med 1998; 13: 311-6.
• 46 The Medical Research Council’s General Practice Research Framework.. Thrombosis prevention trial: Randomised trial of low intensity oral antaicoagulation with warfarin and low-dose aspirin in the primary prevention in ischemic heart disease in men at increased risk. Lancet 1998; 351: 233-41.
• 47 Murin S, Romano PS, White RH. Comparison of outcomes after hospitalization for deep venous thrombosis or pulmonary embolism. Thromb Haemost 2002; 88: 407-14.
• 48 Palareti G, Legnani C, Cosi B. et al. Predictive value of D-dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idiopathic event and in carriers of congenital thrombophilia. Circulation 2003; 108: 313-8.
• 49 Palareti G, Cosmi B, Legnani C. et al. for the PROLONG Investigators. D-Dimer Testing to Determine the Duration of Anticoagulation Therapy. N Engl J Med 2006; 355: 1780-9.
• 50 Pinede L, Ninet J, Duhaut P. et al. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation 2001; 103: 2453-60.
• 51 Pineo GF, Hull RD. Tinzaparin in the treatment of venous thromboembolism. Expert Opin Pharmacother 2003; 4: 2355-62.
• 52 Piovella F, Crippa L, Barone M. et al. Normalization rates of compression ultrasonography in patients with a first episode of deep vein thrombosis of the lower limbs: association with recurrence and new thrombosis. Haematologica 2002; 87: 515-22.
• 53 Prandoni P, Lensing AW, Cogo A. et al. The longterm clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1-7.
• 54 Prandoni P, Lensing AW, Bagatella P. et al. Low rate of warfarin-related major bleeding in patients with recurrent venous thromboembolism. Thromb Haemost 1999; 82: 158-9.
• 55 Prandoni P, Lensing AW, Prins MH. et al. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 2002; 137: 955-60.
• 56 Ridker PM, Goldhaber SZ, Danielson E. et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003; 348: 1425-34.
• 57 Ridker PM. Long-term low-dose warfarin use is effective in the prevention of recurrent venous thromboembolism: Yes. J Thromb Haemost 2004; 2: 1034-7.
• 58 Schellong S, Bounameaux H, Büller H. Venous Thromboembolism. In: Camm JA, Lüscher TF, Serruys P. (eds). The ESC Textbook of Cardiovascular Medicine. Chapter 36. Blackwell; 2006
• 59 Schulman S, Rhedin A-S, Lindmarker P. et al The Duration of Anticoagulation Trial Study Group.. A Comparison of Six Weeks with Six Months of Oral Anticoagulant Therapy after a First Episode of Venous Thromboembolism. N Engl J Med 1995; 332: 1661-5.
• 60 Schulman S, Granqvist S, Holmstrom M. et al. The Duration of Anticoagulation Trial Study Group. The Duration of Oral Anticoagulant Therapy after a Second Episode of Venous Thromboembolism. N Engl J Med 1997; 336: 393-8.
• 61 Schulman S, Wahlander K, Lundstrom T. et al. THRIVE III Investigators. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med. 2003; 349: 1713-21.
• 62 Schulman S, Ogren M. New concepts in optimal management of anticoagulant therapy for extended treatment of venous thromboembolism. Thromb Haemost 2006; 96: 258-66.
• 63 Stangier J, Eriksson BI, Dahl OE. et al. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol 2005; 45: 555-63.
• 64 Van den Belt AG, Prins MH, Lensing AW. et al. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev 2000; CD001100.
• 65 Van der Heijden JF, Hutten BA, Buller HR. et al. Vitamin K antagonists or low-molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism. Cochrane Database Syst Rev 2002; CD002001.
• 66 Van der Meer J, Rosendaal FR, Vandenbroucke JP. et al. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Ann Intern Med 1993; 153: 1557-62.
• 67 Van Dongen CJ, Vink R, Hutten BA. et al. The incidence of recurrent venous thromboembolism after treatment with vitamin K antagonists in relation to time since first event: a meta-analysis. Arch Intern Med 2003; 163: 1285-93.
• 68 Weltermann A, Eichinger S, Bialonczyk C. et al. The risk of recurrent venous thromboembolism among patients with high factor IX levels. J Thromb Haemost 2003; 1: 28-32.