Abstract
About half of patients with a first unprovoked proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) will have a recurrent venous thromboembolism (VTE) within 10 years if they stop treatment, and randomized trials have shown clear benefit from extended anticoagulant therapy in these patients. Although the risk of recurrence varies among patients with a first unprovoked proximal DVT or PE, and a number of factors can identify patients with a lower risk of recurrence, the safety of routinely stopping anticoagulant therapy based on the presence of these factors needs to be established in prospective studies before this is done in clinical practice. As isolated distal DVT is associated with about half the risk of recurrence of proximal DVT or PE, a first episode of unprovoked distal DVT does not justify extended anticoagulation. High risk for bleeding, and patient preference, are good reasons not to treat unprovoked proximal DVT or PE indefinitely. New anticoagulants, because they are easier to use and may be associated with less bleeding that vitamin K antagonists, have the potential to increase the proportion of patients with unprovoked VTE who are candidates for extended anticoagulant therapy.
Similar content being viewed by others
References
Kearon C (2003) Natural history of venous thromboembolism. Circulation 107:I-22–I-30
Prandoni P, Noventa F, Ghirarduzzi A, Pengo V, Bernardi E, Pesavento R et al (2007) The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 92:199–205
Iorio A, Kearon C, Filippucci E, Marcucci M, Macura A, Pengo V et al (2010) Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med 170:1710–1716
Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob G, Comerota AJ (2008) Antithrombotic thereapy for venous thromboembolic disease. ACCP evidence-based clinical practice guidelines (8th edition). Chest 133:454S–545S
Baglin T, Luddington R, Brown K, Baglin C (2003) Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 362:523–526
Palareti G, Legnani C, Lee A, Manotti C, Hirsh J, D’Angelo A et al (2000) 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 84:805–810
Prandoni P, Lensing AW, Piccioli A, Bernardi E, Simioni P, Girolami B et al (2002) Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 100:3484–3488
Palareti G, Legnani C, Cosmi B, Guazzaloca G, Pancani C, Coccheri S (2002) Risk of venous thromboembolism recurrence: high negative predictive value of d-dimer performed after oral anticoagulation is stopped. Thromb Haemost 87:7–12
Prandoni P, Lensing AWA, Cogo A, Cuppini S, Villalta S, Carta M et al (1996) The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 125:1–7
Heit JA, Mohr DN, Silverstein MD, Petterson TM, O’Fallon WM, Melton LJ III (2000) Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med 160:761–768
Cosmi B, Legnani C, Tosetto A, Pengo V, Ghirarduzzi A, Testa S et al (2010) Comorbidities, alone and in combination with d-dimer, as risk factors for recurrence after a first episode of unprovoked venous thromboembolism in the extended follow-up of the PROLONG study. Thromb Haemost 103:1152–1160
Schulman S, Rhedin A-S, Lindmarker P, Carlsson A, Lärfars G, Nicol P et al (1995) A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 332:1661–1665
Pinede L, Ninet J, Duhaut P, Chabaud S, Demolombe-Rague S, Durieu I et al (2001) 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 103:2453–2460
Hansson PO, Sorbo J, Eriksson H (2000) Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med 160:769–774
Johnson SA, Stevens SM, Woller SC, Lake E, Donadini M, Cheng J et al (2010) Risk of deep vein thrombosis following a single negative whole-leg compression ultrasound: a systematic review and meta-analysis. JAMA 303:438–445
Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR et al (2003) Long-term, low-intensity warfarin therapy for prevention of recurrent venous thromboembolism. N Eng J Med 348:1425–1434
Schulman S, Wahlander K, Lundström T, Clason SB, Eriksson H, THRIVE III Investigators (2003) Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Eng J Med 349:1713–1721
Schulman S, Lindmarker P, Holmstrom M, Larfars G, Carlsson A, Nicol P et al (2006) 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 4:734–742
Agnelli G, Prandoni P, Santamaria MG, Bagatella P, Iorio A, Bazzan M et al (2001) Three months versus one year of oral anticoagulant therapy for idiopathic deep vein thrombosis. N Eng J Med 345:165–169
Agnelli G, Prandoni P, Becattini C, Silingardi M, Taliani MR, Miccio M et al (2003) Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med 139:19–25
Siragusa S, Malato A, Anastasio R, Cigna V, Milio G, Amato C et al (2008) Residual vein thrombosis to establish duration of anticoagulation after a first episode of deep vein thrombosis: the duration of anticoagulation based on compression ultrasonography (DACUS) study. Blood 112:511–515
Kearon C, Ginsberg JS, Kovacs MJ, Anderson DR, Wells PS, Julian JA et al (2003) Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Eng J Med 349:631–639
Farraj RS (2004) Anticoagulation period in idiopathic venous thromboembolism. How long is enough? Saudi Med J 25:848–851
Prandoni P, Prins MH, Lensing AW, Ghirarduzzi A, Ageno W, Imberti D et al (2009) Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. Ann Intern Med 150:577–585
Pinede L, Duhaut P, Cucherat M, Ninet J, Pasquier J, Boissel JP (2000) 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 247:553–562
Campbell IA, Bentley DP, Prescott RJ, Routledge PA, Shetty HG, Williamson IJ (2007) Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial. Br Med J 334:674–677
Piovella F, Crippa L, Barone M, Vigano DS, Serafini S, Galli L et al (2002) 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 87:515–522
Prandoni P, Lensing AW, Prins MH, Bernardi E, Marchiori A, Bagatella P et al (2002) Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 137:955–960
Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR et al (1999) A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 340:901–907
Kearon C, Ginsberg JS, Anderson DR, Kovacs MJ, Wells P, Julian JA et al (2004) Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor. J Thromb Haemost 2:743–749
Cosmi B, Legnani C, Cini M, Guazzaloca G, Palareti G (2005) 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 94:969–974
Rodger MA, Kahn SR, Wells PS, Anderson DA, Chagnon I, Le Gal G et al (2008) Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ. 179:417–426
Cosmi B, Legnani C, Iorio A, Pengo V, Ghirarduzzi A, Testa S et al (2010) Residual venous obstruction, alone and in combination with d-dimer, as a risk factor for recurrence after anticoagulation withdrawal following a first idiopathic deep vein thrombosis in the prolong study. Eur J Vasc Endovasc Surg 39:356–365
Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A et al (2006) d-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 355:1780–1789
Schulman S, Granqvist S, Holmström M, Carlsson A, Lindmarker P, Nicol P et al (1997) The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 336:393–398
Kearon C (2007) Indefinite anticoagulation after a first episode of unprovoked venous thromboembolism: yes. J Thromb Haemost 5:2330–2335
Schulman S, Beyth RJ, Kearon C, Levine MN (2008) Hemorrhagic complications of anticoagulant and thrombolytic treatment: American college of chest physicians evidence-based clinical practice guidelines (8th Edition). Chest 133:257S–298S
Gage BF, Yan Y, Milligan PE, Waterman AD, Culverhouse R, Rich MW et al (2006) Clinical classification schemes for predicting hemorrhage: results from the national registry of atrial fibrillation (NRAF). Am Heart J 151:713–719
Levi M, Hovingh GK, Cannegieter SC, Vermeulen M, Buller HR, Rosendaal FR (2008) Bleeding in patients receiving vitamin K antagonists who would have been excluded from trials on which the indication for anticoagulation was based. Blood 111:4471–4476
McRae S, Tran H, Schulman S, Ginsberg J, Kearon C (2006) Effect of patient’s sex on risk of recurrent venous thromboembolism: a meta-analysis. Lancet 368:371–378
Verhovsek M, Douketis JD, Yi Q, Shrivastava S, Tait RC, Baglin T et al (2008) Systematic review: d-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern Med 149:481–490 W94
Douketis J, Tosetto A, Marcucci M, Baglin T, Cushman M, Eichinger S et al (2010) Patient-level meta-analysis: effect of measurement timing, threshold, and patient age on ability of d-dimer testing to assess recurrence risk after unprovoked venous thromboembolism. Ann Intern Med 153:523–531
Cosmi B, Legnani C, Tosetto A, Pengo V, Ghirarduzzi A, Testa S et al (2010) Usefulness of repeated d-dimer testing after stopping anticoagulation for a first episode of unprovoked venous thromboembolism: the PROLONG II prospective study. Blood 115:481–488
Eichinger S, Heinze G, Jandeck LM, Kyrle PA (2010) Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model. Circulation 121:1630–1636
Murin S, Romano PS, White RH (2002) Comparison of outcomes after hospitalization for deep vein thrombosis or pulmonary embolism. Thromb Haemost 88:407–414
Baglin T, Douketis J, Tosetto A, Marcucci M, Cushman M, Kyrle P et al (2010) Does the clinical presentation and extent of venous thrombosis predict likelihood and type of recurrence? A patient level meta-analysis. J Thromb Haemost 8(11):2436–2442
Kearon C, Iorio A, Palareti G (2010) Risk of recurrent venous thromboembolism after stopping treatment in cohort studies: recommendation for acceptable rates and standardized reporting. J Thromb Haemost 8:2313–2315
Locadia M, Bossuyt PM, Stalmeier PF, Sprangers MA, van Dongen CJ, Middeldorp S et al (2004) Treatment of venous thromboembolism with vitamin K antagonists: patients’ health state valuations and treatment preferences. Thromb Haemost 92:1336–1341
Merli G. (2011) Novel anticoagulants. J Thromb Thrombolys. x:x
Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H et al (2009) Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 361:2342–2352
Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS et al (2010) Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 363:2499–2510
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kearon, C. Extended anticoagulation for unprovoked venous thromboembolism: a majority of patients should be treated. J Thromb Thrombolysis 31, 295–300 (2011). https://doi.org/10.1007/s11239-011-0573-x
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11239-011-0573-x