‡Long term treatment with low-molecular-weight-heparin instead of warfarin may be preferred.

Background

            Demonstration that 3 months of warfarin markedly reduced the frequency of recurrent DVT compared to 3 months of low-dose subcutaneous heparin established the need for a prolonged phase of treatment for venous thromboembolism (VTE) after initial treatment with full-dose intravenous heparin.(1;2)   Subsequently, high-dose subcutaneous heparin and low-molecular-weight-heparin (LMWH; 50-75% of the acute treatment dose) were shown to be as effective as warfarin for this phase of treatment.(2)  However, whether 3 months of treatment is longer than necessary, or is long enough, for all patients with VTE has been uncertain.

            Recurrent episodes of VTE appear to fall into two categories.  First, recurrences may be due to reactivation and extension of the original thrombosis; this risk, which is very high when patients present with acute thrombosis, persists for a limited period.(3;4)  Second, recurrences may be due to a new episode of VTE that is not directly related to the initial episode of thrombosis; this risk, which reflects the patients underlying predisposition to VTE, persists for a longer period of time and often indefinitely.(3;5;6) The length of time after starting treatment that patients remain at risk of recurrence of their original thrombosis, and the magnitude of the long term risk for a new episode of VTE, is thought to differ among patients. The risk of bleeding during anticoagulant therapy also differs with the duration of therapy, and among patients.(7;8)

            Anticoagulant therapy should be stopped when it’s benefits no longer clearly outweigh it's risks.(9)  This assessment, which is dominated by balancing the risk of recurrent VTE if anticoagulation is stopped against the risk of bleeding if anticoagulation  is continued, needs to be individualized.(9) When comparing the risk of recurrent VTE with the risk of anticoagulant-induced bleeding (each usually expressed as a percentage per year or number of events per 100 patient-years) it is important to take into consideration that the consequences of a major bleed are generally mores severe than the consequences of a recurrent episode of VTE (e.g., case-fatality of ~20% versus ~5%).(9-11)

Factors that influence the duration of anticoagulant therapy

            During the last decade, a series of well-designed studies have helped to define the optimal duration of anticoagulation.  Their findings can be summarized as follows:

• Shortening the duration of anticoagulation from 3(12;13) or 6(14) months to 4(12;13) or 6(14) weeks results in a doubling of the frequency of recurrent VTE during one(12;13) to two(14) years of follow-up.
• Patients with VTE provoked by a transient risk factor have a lower (about one-third) risk of recurrence than those with an unprovoked VTE or a persistent risk factor.(5;12-15)
• Three months of anticoagulation is adequate treatment for VTE provoked by a transient risk factor; subsequent risk of recurrence is about 3% per patient-year.(12;13;15-17)
• Three months of anticoagulation may not be adequate treatment for an unprovoked ('idiopathic') episode of VTE; subsequent early risk of recurrence has varied from 5% to 25% per patient-year.(14;16;18;19)
• After six months of anticoagulation, recurrent DVT is at least as likely to effect the contralateral leg; this suggests that 'systemic' rather than 'local' (including inadequate treatment) factors are responsible for recurrences after 6 months of treatment.(4)
• There is a persistently elevated risk of recurrent VTE after a first episode; this appears to be 5 - 12% per year after six or more months of treatment for an unprovoked episode.(14;16;19-21)
• Extending duration of anticoagulation beyond 3 to 6 months may delay but, ultimately, not reduce the risk of recurrence if therapy is then stopped.(19;21)
• After 3 months of initial treatment of unprovoked VTE with oral anticoagulants targeted at an INR of 2.5 (INR range 2.0-3.0), continuing treatment with:
• Oral anticoagulants targeted at an INR of ~2.5 reduces the risk of recurrent VTE by over 90%.(6;18)
• Oral anticoagulants targeted at an INR of ~1.75 reduces the risk of recurrent VTE by about 75%.(22)
• Oral anticoagulants targeted to an INR of ~2.5 are more effective than using an INR target of ~1.75, without evidence of increased bleeding.(23)  
• A second episode of VTE suggests a higher risk of recurrence but not necessarily high enough to justify indefinite anticoagulation.(24;25)
• Risk of recurrence is lower (about half) following an isolated calf (distal) DVT than after proximal DVT or PE; this favors a shorter duration of treatment.(14;16)
• Risk of recurrence is similar after an episode of proximal DVT or PE.(3;10;14;24)
• Recurrent VTE is usually (about 60% of episodes) a PE after an initial PE, and usually (about 80% of episodes) a DVT after an initial DVT(10;24;26); this effect is expected to increase mortality from recurrent VTE by 2 to 3-fold after a PE compared to after a DVT.(27)
• Risk of recurrence is about 3-fold higher in patients with active cancer.(3;5;28)
• Long term treatment with low-molecular-weight-heparin is more effective than warfarin in patients with VTE associated with cancer, and may be a preferred option for such patients (see 'Cancer and Thrombosis' guideline).(29) 
• Estrogen therapy is an important risk factor for first (30;31) and recurrent (32) episodes of VTE; consequently, if VTE occurred while on estrogen therapy, the risk of recurrent VTE is expected to be lowered by stopping estrogens.(3)
• Risk of recurrence is higher with antiphospholipid antibodies (anticardiolipin antibodies and/or lupus anticoagulants)(18;25), homozygous Factor V Leiden(33) and, probably, deficiencies of protein C, protein S and antithrombin(5;34), and combined heterozygous Factor V Leiden and heterozygous G20210A prothrombin gene mutations(35); these favor a longer duration of treatment.
• Heterozygous Factor V Leiden and the G20210A prothrombin gene mutations do not appear to be clinically important risk factors for recurrence.(33)
• Other risk factors for recurrences may include: advanced age; elevated levels of clotting factors VIII, IX, XI and homocysteine; elevated d-dimer levels after stopping anticoagulant therapy; venal caval filters; and residual deep vein thrombosis on ultrasound; they have uncertain implications for duration of treatment.(27)
• The risk of anticoagulant-induced bleeding is highest during the first three months of treatment and stabilizes after the first year.(7)
• Risk of bleeding differs markedly among patients depending on the prevalence of risk factors (e.g., advanced age; previous bleeding or stroke; renal failure; anaemia; antiplatelet therapy; malignancy; poor anticoagulant control).(7;8;23)
• The risk of major bleeding in younger patients (e.g. less than 60 years) that do not have risk factors for bleeding and have good anticoagulant control (target INR 2-3) is about 1% per year.(7;23;36)  The risk of major bleeding is expected to be at least 10-fold higher in patients with multiple risk factors for bleeding.(8)

Reference List

(1)    Hull R, Delmore T, Genton E, Hirsh J, Gent M, Sackett D et al. Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. N Engl J Med. 1979;301:855-58.

(2)    Hyers TM, Agnelli G, Hull RD, Morris TA, Samama M, Tapson V et al. Antithrombotic therapy for venous thromboembolic disease. Chest. 2001;119:176S-93S.

(3)    Heit JA, Mohr DN, Silverstein MD, Petterson TM, O'Fallon WM, Melton LJ, III. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med. 2000;160:761-68.

(4)    Lindmarker P, Schulman S. The risk of ipsilateral versus contralateral recurrent deep vein thrombosis in the leg. The DURAC Trial Study Group. J Intern Med. 2000;247:601-6.

(5)    Prandoni P, Lensing AWA, Cogo A, Cuppini S, Villalta S, Carta M et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;125:1-7.

(6)    Schulman S, Granqvist S, Holmstrom M, Carlsson A, Lindmarker P, Nicol P et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med. 1997;336:393-98.

(7)    Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic Complications of Anticoagulant Treatment. Chest. 2001;119:108S-21S.

(8)    Beyth RJ, Quinn LM, Landefeld S. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med. 1998;105:91-99.

(9)    Kearon, C. Duration of anticoagulation for venous thromboembolism. Journal of Thrombosis and Thrombolysis 12, 59-65. 2002.

(10)  Douketis JD, Kearon C, Bates S, Duku EK, Ginsberg JS. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA. 1998;279:458-62.

(11)  Landefeld CS, Beyth RJ. Anticoagulant-related bleeding:  clinical epidemiology, prediction, and prevention. Am J Med. 1993;95:315-28.

(12)  Research Committee of the British Thoracic Society. Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Lancet. 1992;340:873-76.

(13)  Levine MN, Hirsh J, Gent M, Turpie AG, Weitz J, Ginsberg J 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.

(14)  Schulman S, Rhedin A-S, Lindmarker P, Carlsson A, Lärfars G, Nicol P et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med. 1995;332:1661-65.

(15)  Pini M, Aiello S, Manotti C, Pattacini C, Quintavalla R, Poli T et al. Low molecular weight heparin versus warfarin the prevention of recurrence after deep vein thrombosis. Thromb Haemost. 1994;72(2):191-97.

(16)  Pinede L, Ninet J, Duhaut P, Chabaud S, Demolombe-Rague S, Durieu I 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.

(17)  Pinede L, Duhaut P, Cucherat M, Ninet J, Pasquier J, Boissel JP. Comparison of long versus short duration of anticoagulant therapy after a first episode of venous thromboembolism: a meta-analysis of randomized, controlled trials. J Intern Med. 2000;247:553-62.

(18)  Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR 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.

(19)  Agnelli G, Prandoni P, Santamaria MG, Bagatella P, Iorio A, Bazzan M et al. Three months versus one year of oral anticoagulant therapy for idiopathic deep vein thrombosis. N Eng J Med. 2001;345:165-69.

(20)  Baglin T, Luddington R, Brown K, Baglin C. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet. 2003;362:523-26.

(21)  Agnelli G, Prandoni P, Becattini C, Silingardi M, Taliani MR, Miccio M et al. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med. 2003;139:19-25.

(22)  Ridker PM, Goldhaber S Z, Danielson E, Rosenberg Y, Eby CS, Deitcher SR et al. Long-term, low-intensity warfarin therapy for prevention of recurrent venous thromboembolism. N Eng J Med. 2003;348:1425-34.

(23)  Kearon C, Ginsberg JS, Kovacs MJ, Anderson DR, Wells PS, Julian JA et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Eng J Med. 2003;349:631-39.

(24)  Murin S, Romano PS, White RH. Comparison of outcomes after hospitalization for deep vein thrombosis or pulmonary embolism. Thromb Haemost. 2002;88:407-14.

(25)  Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Am J Med. 1998;104:332-38.

(26)  Kniffin WDJr, Baron JA, Barrett J, Birkmeyer JD, Anderson FA. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med. 1994;154:861-66.

(27)  Kearon C. Duration of therapy for acute venous thromboembolism. Clin Chest Med. 2003;24:63-72.

(28)  Palareti G, Legnani C, Cosmi B, Guazzaloca G, Pancani C, Coccheri S. Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped. Thromb Haemost. 2002;87:7-12.

(29)  Lee AYY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M et al. A randomized comparison of low-molecular-weight heparin with an oral anticoagulant for the prevention of recurrent venous thromboembolism in patients with cancer. N Eng J Med. 2003;349:146-53.

(30)  Grady D, Wenger NK, Herrington D, Khan S, Furberg C, Hunninghake D et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med. 2000;132:689-96.

(31)  Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-33.

(32)  Hoibraaten E, Qvigstad E, Arnesen H, Larsen S, Wickstrom E, Sandset PM. Increased risk of recurrent venous thromboembolism during hormone replacement therapy--results of the randomized, double-blind, placebo- controlled estrogen in venous thromboembolism trial (EVTET). Thromb Haemost. 2000;84:961-67.

(33)  Lindmarker P, Schulman S, Sten-Linder M, Wiman B, Egberg N, Johnsson H. The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A Allele in the coagulation factor V gene and the G20210A Allele in the prothrombin gene. Thromb Haemost. 1999;81:684-89.

(34)  Kearon C, Crowther M, Hirsh J. Management of patients with hereditary hypercoagulable disorders. Annu Rev Med. 2000;51:169-85.

(35)  Miles JS, Miletich JP, Goldhaber SZ, Hennekens CH, Ridker PM. G20210A mutation in the prothrombin gene and the risk of recurrent venous thromboembolism. J Am Coll Cardiol. 2001;37:215-18.

(36) Ansell J, Hirsh J, Dalen J, Bussey H, Anderson D, Poller L et al. Managing oral anticoagulant therapy. Chest. 2001;119:22S-38S.