Management of patients with unprovoked venous thromboembolism: An evidence-based and practical approach

Current Treatment Options in Cardiovascular Medicine

Volumn 15, Issue 2, 2013, Pages 224-239

  Marcucci, Maura ^a   Iorio, Alfonso ^a   Douketis, James ^a  

^a MCMASTER UNIVERSITY   (Canada)

Author keywords

Clinical prediction guide; D Dimer; Extended anticoagulation; Inherited thrombophilia; Residual vein occlusion; Risk factors; Unprovoked; Venous thromboembolism

Indexed keywords

ACETYLSALICYLIC ACID; ALTEPLASE; D DIMER; DABIGATRAN; DALTEPARIN; ENOXAPARIN; ESTROGEN; FONDAPARINUX; HEPARIN; RIVAROXABAN; TINZAPARIN; WARFARIN;

ANTICOAGULATION; DEEP VEIN THROMBOSIS; EVIDENCE BASED MEDICINE; GENDER; HUMAN; HYPERHOMOCYSTEINEMIA; LOADING DRUG DOSE; LUNG EMBOLISM; MEDICAL DECISION MAKING; PREDICTION; RECURRENCE RISK; REVIEW; RISK FACTOR; THROMBOPHILIA; TREATMENT DURATION; UNPROVOKED VENOUS THROMBOEMBOLISM; VEIN OCCLUSION; VENOUS THROMBOEMBOLISM;

EID: 84879605067     PISSN: 10928464     EISSN: 15343189     Source Type: Journal    
DOI: 10.1007/s11936-012-0225-2     Document Type: Review

References (100)

1. Kearon C. A conceptual framework for two phases of anticoagulant treatment of venous thromboembolism. J Thromb Haemost. 2012;10:507-11. An interesting narrative review on the biphasic nature of venous thromboembolic disease and resultant treatment approach.
2. Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrom J. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost. 2007;5:692-9.
3. Goldhaber SZ. Pulmonary embolism. Lancet. 2004;363:1295-305.
4. Agnelli G, Becattini C. Acute pulmonary embolism. N Engl J Med. 2010;363:266-74.
5. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, Nelson ME, Wells PS, Gould MK, Dentali F, Crowther M, Kahn SR. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e419S-94S.These guidelines are a synthesis of evidence for the short and long term treatment of venous thromboembolism. For patients with a first unprovoked event, the recommendations for the long-term management consider a three months or indefinite anticoagulation and also consider bleeding risk and patient values and preferences.
6. Hansson PO, Sorbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med. 2000;160:769-74.
7. Kahn SR, Shrier I, Julian JA, Ducruet T, Arsenault L, Miron MJ, Roussin A, Desmarais S, Joyal F, Kassis J, Solymoss S, Desjardins L, Lamping DL, Johri M, Ginsberg JS. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med. 2008;149:698-707.
8. Piazza G, Goldhaber SZ. Chronic thromboembolic pulmonary hypertension. N Eng J Med. 2011;364:351-60.
9. Schulman S, Wahlander K, Lundstrom T, Clason SB, Eriksson H. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med. 2003;349:1713-21.
10. Schulman S, Rhedin AS, Lindmarker P, Carlsson A, Larfars G, Nicol P, Loogna E, Svensson E, Ljungberg B, Walter H. 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.
11. Agnelli G, Prandoni P, Santamaria MG, Bagatella P, Iorio A, Bazzan M, Moia M, Guazzaloca G, Bertoldi A, Tomasi C, Scannapieco G, Ageno W. 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.
12. Agnelli G, Prandoni P, Becattini C, Silingardi M, Taliani MR, Miccio M, Imberti D, Poggio R, Ageno W, Pogliani E, Porro F, Zonzin P. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med. 2003;139:19-25.
13. Boutitie F, Pinede L, Schulman S, Agnelli G, Raskob G, Julian J, Hirsh J, Kearon C. Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants' data from seven trials. BMJ. 2011;342:d3036.This meta-analysis compares different lengths of anticoagulation for venous thromboembolism, showing that three months of treatment results in a lower risk of recurrence compared to a shorter course but in a similar risk compared to a longer duration.
14. Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:257S-98S.
15. Iorio A, Kearon C, Filippucci E, Marcucci M, Macura A, Pengo V, Siragusa S, Palareti G. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med. 2010;170:1710-6.This meta-analysis considers the risk of recurrence in patients with provoked venous thromboembolism, whether related to surgical and nonsurgical transient risk factors.
16. Douketis J, Tosetto A, Marcucci M, Baglin T, Cushman M, Eichinger S, Palareti G, Poli D, Tait RC, Iorio A. 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. Arch Intern Med. 2010;153:523-31.This patient level meta-analysis provides further support for the D-dimer as predictor of recurrent venous thromboembolism, irrespective of the timing of testing after stopping anticoagulation, the assay used and the patient age.
17. Eichinger S, Heinze G, Jandeck LM, Kyrle PA. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model. Circulation. 2010;121:1630-6.This study provides a clinical prediction guide for the risk of recurrence in patient with a first unprovoked venous thromboembolism based on clinical and laboratory risk factors.
18. Prandoni P, Noventa F, Ghirarduzzi A, Pengo V, Bernardi E, Pesavento R, Iotti M, Tormene D, Simioni P, Pagnan A. 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. 2007;92:199-205.
19. Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Female hormones and thrombosis. Arterioscler Thromb Vasc Biol. 2002;22:201-10.
20. Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA. 2005;293:2352-61.
21. 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;362:523-6.
22. Cushman M, Glynn RJ, Goldhaber SZ, Moll S, Bauer KA, Deitcher S, Shrivastava S, Ridker PM. Hormonal factors and risk of recurrent venous thrombosis: the prevention of recurrent venous thromboembolism trial. J Thromb Haemost. 2006;4:2199-203.
23. Douketis J, Tosetto A, Marcucci M, Baglin T, Cosmi B, Cushman M, Kyrle P, Poli D, Tait RC, Iorio A. Risk of recurrence after venous thromboembolism in men and women: patient level meta-analysis. BMJ. 2011;342:d813.This patient data meta-analysis supports the higher risk of recurrence after a first unprovoked venous thromboembolism in men compared to women.
24. Kyrle PA, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Eichinger S. The risk of recurrent venous thromboembolism in men and women. N Engl J Med. 2004;350:2558-63.
25. Agnelli G, Becattini C, Prandoni P. Recurrent venous thromboembolism in men and women. N Engl J Med. 2004;351:2015-8.
26. Nieto JA, Monreal M. Recurrent venous thromboembolism in men and women. N Engl J Med. 2004;351:2015-8.
27. Kahn SR. Recurrent venous thromboembolism in men and women. N Engl J Med. 2004;351:2015-8.
28. McRae S, Tran H, Schulman S, Ginsberg J, Kearon C. Effect of patient's sex on risk of recurrent venous thromboembolism: a meta-analysis. Lancet. 2006;368:371-8.
29. Hull R, Delmore T, Genton E, Hirsh J, Gent M, Sackett D, McLoughlin D, Armstrong P. Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. N Engl J Med. 1979;301:855-8.
30. Baglin T, Douketis J, Tosetto A, Marcucci M, Cushman M, Kyrle P, Palareti G, Poli D, Tait RC, Iorio A. Does the clinical presentation and extent of venous thrombosis predict likelihood and type of recurrence? A patient-level meta-analysis. J Thromb Haemost. 2010;8:2436-42.This patient data meta-analysis supports a comparable risk of recurrence in patients presenting with a pulmonary embolism or proximal deep vein thrombosis and that patients presenting with pulmonary embolism are more likely to develop recurrent disease manifest by pulmonary embolism.
31. Eichinger S, Weltermann A, Minar E, Stain M, Schonauer V, Schneider B, Kyrle PA. Symptomatic pulmonary embolism and the risk of recurrent venous thromboembolism. Arch Intern Med. 2004;164:92-6.
32. Douketis JD, Gu CS, Schulman S, Ghirarduzzi A, Pengo V, Prandoni P. The risk for fatal pulmonary embolism after discontinuing anticoagulant therapy for venous thromboembolism. Ann Intern Med. 2007;147:766-74.
33. Murin S, Romano PS, White RH. Comparison of outcomes after hospitalization for deep venous thrombosis or pulmonary embolism. Thromb Haemost. 2002;88:407-14.
34. Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med. 2001;344:1222-31.
35. Middeldorp S, Van Hylckama Vlieg A. Does thrombophilia testing help in the clinical management of patients? Br J Haematol. 2008;143:321-35.
36. Kyrle PA, Rosendaal FR, Eichinger S. Risk assessment for recurrent venous thrombosis. Lancet. 2010;376:2032-9.
37. Kearon C, Ginsberg JS, Anderson DR, Kovacs MJ, Wells P, Julian JA, Mackinnon B, Demers C, Douketis J, Turpie AG, Van Nguyen P, Green D, Kassis J, Kahn SR, Solymoss S, Desjardins L, Geerts W, Johnston M, Weitz JI, Hirsh J, Gent M. 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. 2004;2:743-9.
38. Eichinger S, Pabinger I, Stumpflen A, Hirschl M, Bialonczyk C, Schneider B, Mannhalter C, Minar E, Lechner K, Kyrle PA. The risk of recurrent venous thromboembolism in patients with and without factor V Leiden. Thromb Haemost. 1997;77:624-8.
39. Eichinger S, Minar E, Hirschl M, Bialonczyk C, Stain M, Mannhalter C, Stumpflen A, Schneider B, Lechner K, Kyrle PA. 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.
40. Simioni P, Prandoni P, Lensing AW, Scudeller A, Sardella C, Prins MH, Villalta S, Dazzi F, Girolami A. The risk of recurrent venous thromboembolism in patients with an Arg506 - >Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med. 1997;336:399-403.
41. Simioni P, Prandoni P, Lensing AW, Manfrin D, Tormene D, Gavasso S, Girolami B, Sardella C, Prins M, Girolami A. Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis. Blood. 2000;96:3329-33.
42. van den Belt AG, Sanson BJ, Simioni P, Prandoni P, Buller HR, Girolami A, Prins MH. Recurrence of venous thromboembolism in patients with familial thrombophilia. Arch Intern Med. 1997;157:2227-32.
43. De Stefano V, Simioni P, Rossi E, Tormene D, Za T, Pagnan A, Leone G. The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants antithrombin, protein C and protein S. Haematologica. 2006;91:695-8.
44. Brouwer JL, Lijfering WM, Ten Kate MK, Kluin-Nelemans HC, Veeger NJ, van der Meer J. High long-term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C or antithrombin. Thromb Haemost. 2009;101:93-9.
45. Ho WK, Hankey GJ, Quinlan DJ, Eikelboom JW. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med. 2006;166:729-36.
46. Marchiori A, Mosena L, Prins MH, Prandoni P. The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies. Haematologica. 2007;92:1107-14.
47. Cohn D, Vansenne F, de BC, Middeldorp S.Thrombophilia testing for prevention of recurrent venous thromboembolism. Cochrane Database Syst Rev. 2009,CD007069.
48. Cosmi B, Legnani C, Bernardi F, Coccheri S, Palareti G. Role of family history in identifying women with thrombophilia and higher risk of venous thromboembolism during oral contraception. Arch Intern Med. 2003;163:1105-9.
49. Pernod G, Biron-Andreani C, Morange PE, Boehlen F, Constans J, Couturaud F, Drouet L, Jude B, Lecompte T, Le GG, Trillot N, Wahl D. Recommendations on testing for thrombophilia in venous thromboembolic disease: a French consensus guideline. J Mal Vasc. 2009;34:156-203.
50. Baglin T, Gray E, Greaves M, Hunt BJ, Keeling D, Machin S, Mackie I, Makris M, Nokes T, Perry D, Tait RC, Walker I, Watson H. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol. 2010;149:209-20.
51. MacLean S, Mulla S, Akl EA, Jankowski M, Vandvik PO, Ebrahim S, McLeod S, Bhatnagar N, Guyatt GH. Patient values and preferences in decision making for antithrombotic therapy: a systematic review: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e1S-e23S.
52. Runchey SS, Folsom AR, Tsai MY, Cushman M, McGovern PD. Anticardiolipin antibodies as a risk factor for venous thromboembolism in a population-based prospective study. Br J Haematol. 2002;119:1005-10.
53. de Groot PG, Lutters B, Derksen RH, Lisman T, Meijers JC, Rosendaal FR. Lupus anticoagulants and the risk of a first episode of deep venous thrombosis. J Thromb Haemost. 2005;3:1993-7.
54. Naess IA, Christiansen SC, Cannegieter SC, Rosendaal FR, Hammerstroem J. A prospective study of anticardiolipin antibodies as a risk factor for venous thrombosis in a general population (the HUNT study). J Thromb Haemost. 2006;4:44-9.
55. 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.
56. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, de Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295-306.
57. Piovella F, Crippa L, Barone M, Vigano DS, Serafini S, Galli L, Beltrametti C, D'Angelo A. 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.
58. Prandoni P, Lensing AW, Prins MH, Bernardi E, Marchiori A, Bagatella P, Frulla M, Mosena L, Tormene D, Piccioli A, Simioni P, Girolami A. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med. 2002;137:955-60.
59. Young L, Ockelford P, Milne D, Rolfe-Vyson V, Mckelvie S, Harper P. Post-treatment residual thrombus increases the risk of recurrent deep vein thrombosis and mortality. J Thromb Haemost. 2006;4:1919-24.
60. Siragusa S, Malato A, Anastasio R, Cigna V, Milio G, Amato C, Bellisi M, Attanzio MT, Cormaci O, Pellegrino M, Dolce A, Casuccio A, Bajardi G, Mariani G. 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. 2008;112:511-5.
61. Prandoni P, Prins MH, Lensing AW, Ghirarduzzi A, Ageno W, Imberti D, Scannapieco G, Ambrosio GB, Pesavento R, Cuppini S, Quintavalla R, Agnelli G. Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. Ann Intern Med. 2009;150:577-85.
62. Siragusa S, Malato A, Saccullo G, Iorio A, Di IM, Caracciolo C, Coco LL, Raso S, Santoro M, Guarneri FP, Tuttolomondo A, Pinto A, Pepe I, Casuccio A, Abbadessa V, Licata G, Battista RG, Mariani G, Di FG. Residual vein thrombosis for assessing duration of anticoagulation after unprovoked deep vein thrombosis of the lower limbs: the extended DACUS study. Am J Hematol. 2011;86:914-7.
63. Douketis, J. (Personal Communication, November, 2012).
64. Malato A, Saccullo G, Iorio A, Ageno W, Siragusa S. Residual vein thrombosis and D-dimer for optimizing duration of anticoagulation in idiopathic deep vein thrombosis. Curr Pharm Des. 2010;16:3483-6.
65. Palareti G, Legnani C, Cosmi B, Valdre L, Lunghi B, Bernardi F, Coccheri S. 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.
66. Eichinger S, Minar E, Bialonczyk C, Hirschl M, Quehenberger P, Schneider B, Weltermann A, Wagner O, Kyrle PA. D-dimer levels and risk of recurrent venous thromboembolism. JAMA. 2003;290:1071-4.
67. Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A, Pengo V, Ghirarduzzi A, Pattacini C, Testa S, Lensing AW, Tripodi A. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med. 2006;355:1780-9.
68. Shrivastava S, Ridker PM, Glynn RJ, Goldhaber SZ, Moll S, Bounameaux H, Bauer KA, Kessler CM, Cushman M. D-dimer, factor VIII coagulant activity, low-intensity warfarin and the risk of recurrent venous thromboembolism. J Thromb Haemost. 2006;4:1208-14.
69. Tait RC, Lowe GD, McColl MD, MacMahon AD, Robertson L, King L. Predicting risk of recurrent venous thrombosis using a 5-point scoring system including fibrin D-dimer. J Thromb Haemost. 2007;2:1873-8.
70. Poli D, Antonucci E, Ciuti G, Abbate R, Prisco D. Combination of D-dimer, F1 + 2 and residual vein obstruction as predictors of VTE recurrence in patients with first VTE episode after OAT withdrawal. J Thromb Haemost. 2008;6:708-10.
71. Baglin T, Palmer CR, Luddington R, Baglin C. Unprovoked recurrent venous thrombosis: prediction by D-dimer and clinical risk factors. J Thromb Haemost. 2008;6:577-82.
72. Verhovsek M, Douketis JD, Yi Q, Shrivastava S, Tait RC, Baglin T, Poli D, Lim W. Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern Med. 2008;149:481-90. W94
73. Bruinstroop E, Klok FA, Van De Ree MA, Oosterwijk FL, Huisman MV. Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism: a meta-analysis. J Thromb Haemost. 2009;7:611-8.
74. Cosmi B, Legnani C, Cini M, Guazzaloca G, Palareti G. D-dimer levels in combination with residual venous obstruction and the risk of recurrence after anticoagulation withdrawal for a first idiopathic deep vein thrombosis. J Thromb Haemost. 2005;94:969-74.
75. Cosmi B, Legnani C, Tosetto A, Pengo V, Ghirarduzzi A, Testa S, Prisco D, Poli D, Tripodi A, Marongiu F, Palareti G. Usefulness of repeated D-dimer testing after stopping anticoagulation for a first episode of unprovoked venous thromboembolism: the PROLONG II prospective study. Blood. 2010;115:481-8This study shows that repeat post-anticoagulation D-dimer testing may help to better distinguish patients with a high or low risk of recurrent venous thromboembolism.
76. Altman DG, Lausen B, Sauerbrei W, Schumacher M. Dangers of using "optimal" cutpoints in the evaluation of prognostic factors. J Natl Cancer Inst. 1994;86:829-35.
77. Legnani C, Cini M, Cosmi B, Carraro P, Tripodi A, Erba N, Palareti G. Age and gender specific cut-off values to improve the performance of D: -dimer assays to predict the risk of venous thromboembolism recurrence. Intern Emerg Med. 2011.
78. Cosmi B, Legnani C, Tosetto A, Pengo V, Ghirarduzzi A, Testa S, Prisco D, Poli D, Tripodi A, Palareti G. 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. 2010;103:1152-60.
79. Douma RA, Le GG, Sohne M, Righini M, Kamphuisen PW, Perrier A, Kruip MJ, Bounameaux H, Buller HR, Roy PM. Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts. BMJ. 2010;340:c1475.
80. Hron G, Kollars M, Binder BR, Eichinger S, Kyrle PA. Identification of patients at low risk for recurrent venous thromboembolism by measuring thrombin generation. JAMA. 2006;296:397-402.
81. Besser M, Baglin C, Luddington R, Van HV. Baglin T. High rate of unprovoked recurrent venous thrombosis is associated with high thrombin-generating potential in a prospective cohort study. J Thromb Haemost. 2008;6:1720-5.
82. Rodger MA, Kahn SR, Wells PS, Anderson DA, Chagnon I, Le GG, Solymoss S, Crowther M, Perrier A, White R, Vickars L, Ramsay T, Betancourt MT, Kovacs MJ. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ. 2008;179:417-26.
83. Le Gal G, Kovacs MJ, Carrier M, Do K, Kahn SR, Wells PS, Anderson DA, Chagnon I, Solymoss S, Crowther M, Righini M, Lacut K, White RH, Vickars L, Rodger M. Risk of recurrent venous thromboembolism after a first oestrogen-associated episode. Data from the REVERSE cohort study. Thromb Haemost. 2010;104:498-503.This study represents the first attempt of building a clinical prediction guide based on clinical and laboratory risk factors with the aim of identifying patients with a risk of venous thromboembolic recurrence below or above an "acceptable" rate.
84. Tosetto A, Iorio A, Marcucci M, Baglin T, Cushman M, Eichinger S, Palareti G, Poli D, Tait RC, Douketis J. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost. 2012;10:1019-25.This study provides a clinical prediction guide to estimate recurrence risk in patients with unprovoked venous thromboembolism who have received approximately six months of anticoagulant therapy.
85. Moons KG, Royston P, Vergouwe Y, Grobbee DE, Altman DG. Prognosis and prognostic research: what, why, and how? BMJ. 2009;338:b375.
86. Kearon C, Iorio A, Palareti G. Risk of recurrent venous thromboembolism after stopping treatment in cohort studies: recommendation for acceptable rates and standardized reporting. J Thromb Haemost. 2010;8:2313-5.
87. Kuijer PM, Hutten BA, Prins MH, Büller HR. Prediction of the risk of bleeding during the anticoagulant treatment for venous thromboembolism. Arch Intern Med. 1999;159:457-60.
88. Ruíz-Giménez N, Suárez C, González R, Nieto JA, Todolí JA, Samperiz AL, Monreal M, RIETE Investigators. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost. 2008;100:26-31.
89. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138:1093-100.
90. 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.
91. 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.
92. Carrier M, Le GG, Wells PS, Rodger MA. Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med. 2010;152:578-89.This study compares the clinical burden due to venous thromboembolic recurrences with that due to anticoagulant-related bleeding in terms of case fatality rate.
93. Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, Bianchi M, Moia M, Ageno W, Vandelli MR, Grandone E, Prandoni P. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012;366:1959-67.
94. Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Ockelford P, Gibbs H, Hague W, Xavier D, Diaz R, Kirby A, Simes J. Low-Dose Aspirin for Preventing Recurrent Venous Thromboembolism. N Engl J Med. 2012. This and the previous study provide evidence on the efficacy of aspirin, given after a first course of anticoagulant, in reducing the risk of venous thromboembolic recurrence of 25-30 % over 2-4 years of follow up.
95. Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, Svensson PJ, Veenstra DL, Crowther M, Guyatt GH. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e152S-84S.
96. Andras A, Sala TA, Crawford F. Vitamin K antagonists or low-molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism. Cochrane Database Syst Rev. 2012, 10:CD002001.
97. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-510.
98. Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-97.
99. Schulman S. Treatment of venous thromboembolism with dabigatran. Curr Opin Pulm Med. 2012;18:410-5.
100. Le GG, Kovacs MJ, Carrier M, Do K, Kahn SR, Wells PS, Anderson DA, Chagnon I, Solymoss S, Crowther M, Righini M, Lacut K, White RH, Vickars L, Rodger M. Risk of recurrent venous thromboembolism after a first oestrogen-associated episode. Data from the REVERSE cohort study. Thromb Haemost. 2010;104:498-503.