New concepts in optimal management of anticoagulant therapy for extended treatment of venous thromboembolism

Summary

Recent trials on secondary prophylaxis after venous thromboembolism (VTE) have provided a wealth of data on the risk factors for recurrence and, to some extent, also for bleeding. Some of the results are consistent across the studies, but there are also conflicting data. Certain risk factors, such as pulmonary embolism versus deep vein thrombosis or presence of cardiolipin antibodies, have a more pronounced influence on the risk early in the course of disease. Others, such as hereditary throm- bophilic defects, seem to gain importance over many years of follow-up. Therefore, it can be difficult to make decisions on an individual patient basis. In this article,data from important and illustrative trials have been extracted and compared and controversies highlighted. The conclusions drawn should help clinicians make balanced decisions on the optimal duration of anticoagulation after an episode of VTE.

Keywords

Venous thromboembolism - risk factors - recurrence - bleeding

• References

• 1 Prandoni P, Lensing AW, Cogo A. et al. The longterm clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1-7.
• 2 Heit JA, Mohr DN, Silverstein MD. et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med 2000; 160: 761-8.
• 3 Schulman S, Lindmarker P, Holmstrom M. et al. Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. J Thromb Haemost 2006; 04: 734-42.
• 4 Pengo V, Lensing A, Prins MH. et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004; 350: 2257-64.
• 5 Meignan M, Rosso J, Gauthier H. et al. Systematic lung scans reveal a high frequency of silent pulmonary embolism in patients with proximal deep venous thrombosis. Arch Intern Med 2000; 160: 159-64.
• 6 Moser KM, LeMoine JR. Is embolic risk conditioned by location of deep venous thrombosis?. Ann Intern Med 1981; 94: 439-44.
• 7 Hull RD, Hirsh J, Carter CJ. et al. Pulmonary angiography, ventilation lung scanning, and venography for clinically suspected pulmonary embolism with abnormal perfusion lung scan. Ann Intern Med 1983; 98: 891-9.
• 8 Schulman S, Wahlander K, Lundstrom T. et al. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003; 349: 1713-21.
• 9 Boutitie F, Schulman S, Kearon C. et al. Factors at baseline influencing the risk of recurrence in venous thromboembolism: results of a meta-analysis on individual patient data. Blood. 2003. 102. Abstr 730..
• 10 Douketis JD, Kearon C, Bates S. et al. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. J Am Med Assoc 1998; 279: 458-62.
• 11 Murin S, Romano PS, White RH. Comparison of outcomes after hospitalization for deep venous thrombosis or pulmonary embolism. Thromb Haemost 2002; 88: 407-14.
• 12 Pinedé 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.
• 13 Agnelli G, Prandoni P, Santamaria MG. et al. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis Warfarin Optimal Duration Italian Trial Investigators.. N Engl J Med 2001; 345: 165-9.
• 14 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.
• 15 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: 523-6.
• 16 Büller HR, Agnelli G, Hull RD. et al. Antithrombotic therapy for venous thromboembolic disease. Chest 2004 126 (Suppl) 401S-28S.
• 17 Schulman S, Granqvist S, Holmström M. et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism The Duration of Anticoagulation Trial Study Group. N Engl J Med 1997; 336: 393-8.
• 18 Schulman S, Rhedin AS, Lindmarker P. et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group.N Engl J Med 1995; 332: 1661-5.
• 19 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.
• 20 White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107: I4-8.
• 21 OÖgren M, Eriksson H, Bergqvist D. et al. Subcutaneous fat accumulation and BMI associated with risk for pulmonary embolism in patients with proximal deep vein thrombosis: a population study based on 23 796 consecutive autopsies. J Intern Med 2005; 258: 166-71.
• 22 Baglin T, Luddington R, Brown K. et al. High risk of recurrent venous thromboembolism in men. J Thromb Haemost 2004; 02: 2152-5.
• 23 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.
• 24 Nieto JA, Monreal M. Recurrent venous thromboembolism in men and women. N Engl J Med. 2004 351. 2015-8; author reply 2015-8..
• 25 Agnelli G, Becattini C, Prandoni P. Recurrent venous thromboembolism in men and women. N Engl J Med. 2004 351. 2015-8; author reply 2015-8..
• 26 Goldhaber SZ, Grodstein F, Stampfer MJ. et al. A prospective study of risk factors for pulmonary embolism in women. J Am Med Assoc 1997; 277: 642-5.
• 27 Goldhaber SZ, Savage DD, Garrison RJ. et al. Risk factors for pulmonary embolism The Framingham Study. AmJ Med 1983; 74: 1023-8.
• 28 Blaszyk H, Bjornsson J. Factor V Leiden and morbid obesity in fatal postoperative pulmonary embolism. Arch Surg 2000; 135: 1410-3.
• 29 Blaszyk H, Wollan PC, Witkiewicz AK. et al. Death from pulmonary thromboembolism in severe obesity: lack of association with established genetic and clinical risk factors. Virchows Archiv 1999; 434: 529-32.
• 30 Samama MM. An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study. Arch Intern Med 2000; 160: 3415-20.
• 31 Abdollahi M, Cushman M, Rosendaal FR. Obesity: risk of venous thrombosis and the interaction with coagulation factor levels and oral contraceptive use. Thromb Haemost 2003; 89: 493-8.
• 32 Tosetto A, Frezzato M, Rodeghiero F. Prevalence and risk factors of non-fatal venous thromboembolism in the active population of the VITA Project. J Thromb Haemost 2003; 01: 1724-9.
• 33 Hansson PO, Eriksson H, Welin L. et al. Smoking and abdominal obesity: risk factors for venous thromboembolism among middle-aged men: „the study of men born in 1913”. Arch Intern Med 1999; 159: 1886-90.
• 34 Juul K, Tybjaerg-Hansen A, Schnohr P. et al. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med 2004; 140: 330-7.
• 35 Zakai NA, Wright J, Cushman M. Risk factors for venous thrombosis in medical inpatients: validation of a thrombosis risk score. J Thromb Haemost 2004; 02: 2156-61.
• 36 De Lorenzo F, Mukherjee M, Kadziola Z. et al. Association of overall adiposity rather than body mass index with lipids and procoagulant factors. Thromb Haemost 1998; 80: 603-6.
• 37 Procare Group. Is recurrent venous thromboembolism more frequent in homozygous patients for the factorV Leiden mutation than in heterozygous patients?. Blood Coagul Fibrinolysis 2003; 14: 523-9.
• 38 Christiansen SC, Cannegieter SC, Koster T. et al. Thrombophilia, clinical factors, and recurrent venous thrombotic events. J Am Med Assoc 2005; 293: 2352-61.
• 39 Procare Group. Is recurrent venous thromboembolism more frequent in homozygous patients for the factorV Leiden mutation than in heterozygous patients?. Blood Coagul Fibrinolysis 2003; 14: 523-9.
• 40 Lindmarker P, Schulman S, Sten-Linder M. et al. The risk of recurrent venous thromboembolism in carriers and noncarriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene DURAC Trial Study Group. Duration of Anticoagulation. Thromb Haemost 1999; 81: 684-9.
• 41 Eichinger S, Pabinger I, Stümpflen A. et al. The risk of recurrent venous thromboembolism in patients with and without factor V Leiden. Thromb Haemost 1997; 77: 624-8.
• 42 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 prothrombin mutation. N Engl J Med 1999; 341: 801-6.
• 43 Eichinger S, Minar E, Hirschl M. et al. The risk of early recurrent venous thromboembolism after oral anticoagulant therapy in patients with the G20210A transition in the prothrombin gene. Thromb Haemost 1999; 81: 14-7.
• 44 Miles JS, Miletich JP, Goldhaber SZ. et al. G20210A mutation in the prothrombin gene and the risk of recurrent venous thromboembolism. J Am Coll Cardiol 2001; 37: 215-8.
• 45 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.
• 46 Legnani C, Cosmi B, Cini M. et al. High plasma levels of factor VIII and risk of recurrence of venous thromboembolism. BrJ Haematol 2004; 124: 504-10.
• 47 Goldenberg NA, Knapp-Clevenger R, MancoJohnson MJ. Elevated plasma factor VIII and D-dimer levels as predictors of poor outcomes of thrombosis in children. N Engl J Med 2004; 351: 1081-8.
• 48 Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy Duration of Anticoagulation Study Group. Am J Med 1998; 104: 332-8.
• 49 den Heijer M, Rosendaal FR, Blom HJ. Hyperhomocysteinemia and venous thrombosis: a meta-analysis. Thromb Haemost 1998; 80: 874-7.
• 50 Ray JG. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. Arch Intern Med 1998; 158: 2101-6.
• 51 Eichinger S, Stümpflen A, Hirschl M. et al. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism. Thromb Haemost 1998; 80: 566-9.
• 52 Prandoni P, Lensing AW, Piccioli A. et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100: 3484-8.
• 53 Palareti G, Legnani C, Lee A. et al. A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy. Thromb Haemost 2000; 84: 805-10.
• 54 Hutten BA, Prins MH, Gent M. et al. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 2000; 18: 3078-83.
• 55 Prandoni P, Lensing AW, Büller HR. et al. Deepvein thrombosis and the incidence of subsequent symptomatic cancer. N EnglJ Med 1992; 327: 1128-33.
• 56 Palareti G, Legnani C, Cosmi B. et al. Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped. Thromb Haemost 2002; 87: 7-12.
• 57 Cosmi B, Legnani C, Cini M. et al. D-dimer levels in combination with residual venous obstruction and the risk of recurrence after anticoagulation withdrawal for a first idiopathic deep vein thrombosis. Thromb Haemost 2005; 94: 969-74.
• 58 Eichinger S, Minar E, Bialonczyk C. et al. D-dimer levels and risk of recurrent venous thromboembolism. J Am Med Assoc 2003; 290: 1071-4.
• 59 Levine MN, Hirsh J, Gent M. et al. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thromb Haemost 1995; 74: 606-11.
• 60 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.
• 61 Young L, Ockelford P, Milne D. et al. Post treatment residual thrombus is associated with an increased risk of DVT recurrence, mortality and a trend towards increased vascular death. J Thromb Haemost. 2005; 03 (Suppl. 01) Abstr OR365.
• 62 Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 03: 692-4.
• 63 Levine MN, Raskob G, Beyth RJ. et al. Hemorrhagic complications of anticoagulant treatment: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 287S-310S.
• 64 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.
• 65 Fiessinger JN, Huisman MV, Davidson BL. et al. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. J Am Med Assoc 2005; 293: 681-9.
• 66 Baron JA, Gridley G, Weiderpass E. et al. Venous thromboembolism and cancer. Lancet 1998; 351: 1077-80.
• 67 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.
• 68 Punthakee X, Doobay J, Anand SS. Oral-anticoagulant-related intracerebral hemorrhage. Thromb Res 2002; 108: 31-6.
• 69 Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting risk of major bleeding in outpatients treated with warfarin. Am J Med 1998; 105: 91-9.
• 70 Forfar JC. A 7-year analysis of haemorrhage in patients on long-term anticoagulant treatment. Br HeartJ 1979; 42: 128-32.
• 71 Research Committee of the British Thoracic Society. Optimum duration of anticoagulation for deepvein thrombosis and pulmonary embolism. Lancet 1992; 340: 873-6.
• 72 Pini M, Aiello S, Manotti C. et al. Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis. Thromb Haemost 1994; 72: 191-7.
• 73 Agnelli G, Prandoni P, Becattini C. et al. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med 2003; 139: 19-25.