Clinical Review

Decision Making in Venous Thromboembolism

Journal of Clinical Outcomes Management. 2015 May;22(5)

References

1. White RH. The epidemiology of venous thromboembolism. Circulation 2003;107(Suppl 1):I4-8.

2. Moster KM and Fedullo PF. The diagnosis of deep-vein thrombosis. N Engl J Med 1994;330:863–4.

3. Kearon C. Natural history of venous thromboembolism. Circulation 2003;(Suppl 1):122–30.

4. Heijboer H, Brandjes DP, Buller HR, et al. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl J Med 1990;323:1512–6.

5. Mateo J, Oliver A, Borrell M, et al. Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism—results of the Spanish Multicentric Study on Thrombophilia (EMET-Study). Thromb Haemost 1997;77:441–51.

6. Lyman GH. Venous thromboembolism in the patient with cancer: focus on burden of disease and benefits of thromboprophylaxis. Cancer 2011;117:1334–49.

7. White RH, Zhou H, Romano PS. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost 2003;90:446–55.

8. Marik PE, Plante LA. Venous thromboembolic disease and pregnancy. N Engl J Med 2008;359:2025–33.

9. Ageno W, Becattini C, Brighton T, et al. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation 2008;117:93–102.

10. Mahmoodi BK, Gansevoort RT, Naess IA, et al. Association of mild to moderate chronic kidney disease with venous thromboembolism: pooled analysis of five prospective general population cohorts. Circulation 2012;126:1964–71.

11. Landolfi R, Marchioli R, Patrono C. Mechanisms of bleeding and thrombosis in myeloproliferative disorders. Thromb Haemost 1997;78:617–21.

12. Hillmen P, Lewis SM, Bessler M, et al. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med1995;333:1253–8.

13.Grainge MJ, West J, Card TR. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study. Lancet 2010;375:657–63.

14. Flinterman LE, Van Der Meer FJ, Rosendaal FR, Doggen CJ. Current perspective of venous thrombosis in the upper extremity. J Thromb Haemost 2008;6:1262–6.

15. Kibbe MR, Ujiki M, Goodwin AL, et al. Iliac vein compression in an aymptomatic patient population. J Vasc Surg 2004;39:937–43.

16. Chee YL, Culligan DJ, Watson HG. Inferior vena cava malformation as a risk factor for deep venous thrombosis in the young. Br J Haematol 2001;114:878–80.

17. Stegeman BH, de Bastos M, Rosendaal FR, et al. Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis. BMJ 2013;347:f5298.

18. Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004;292:1573–80.

19. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998;90:1371–88.

20. Glueck CJ, Richardson-Royer C, Schultz R, et al. Testosterone therapy, thrombophilia-hypofibrinolysis, and hospitalization for deep venous thrombosis-pulmonary embolus: an exploratory, hypothesis-generating study. Clin Appl Thromb Hemost 2014;20:244–9.

21. Johannesdottir SA, Horvath-Puho E, Dekkers OM, et al. Use of glucocorticoids and risk of venous thromboembolism: a nationwide population-based case-control study. JAMA Intern Med 2013;173:743–52.

22. Spencer FA, Emery C, Lessard D, et al. The Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism. J Gen Intern Med 2006;21:722–7.

23. Ocak G, Vossen CY, Verduijn M, et al. Risk of venous thrombosis in patients with major illnesses: results from the MEGA study. J Thromb Haemost 2013;11:116-23.

24. Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003; 107 (Suppl 1): I9–16.

25. Clemetson KJ. Platelet GPIb-V-IX complex. Thromb Haemost 1997;78:266–70.

26. Kroll MH, Schafer AI. Biochemical mechanisms of platelet activation. Blood 1989;74:1181–95.

27. Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997;350:1795–8.

28. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize patients’ probability of pulmonary embolism: increasing the model’s utility with the SimpliRED D-dimer. Thromb Haemost 2000;416–20.

29. Le Gal G, Righini M, Roy PM, et al. Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern Med 2006; 144:165–71.

30. Stein PD, Hull RD, Patel KC, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Intern Med 2004;140:589–602.

31. Pasha SM, Klok FA, Snoep JD, et al. Safety of excluding acute pulmonary embolism based on an unlikely clinical probability by the Wells rule and normal D-dimer concentration: a meta-analysis. Thromb Res 2010;125:e123–27.

32. Crowther MA, Cook DJ, Griffith LE, et al. Neither baseline tests of molecular hypercoagulability nor D-dimer levels predict deep venous thrombosis in critically ill medical-surgical patients. Intensive Care Med 2005;31:48–55.

33. Karami-Djurabi R, Klok FA, Kooiman J, et al. D-dimer testing in patients with suspected pulmonary embolism and impaired renal function. Am J Med 2009;122:1050–3.

34. Chan WS, Chunilal S, Lee A, et al. A red blood cell agglutination D-dimer test to exclude deep venous thrombosis in pregnancy. Ann Intern Med 2007;147:165–70.

35. Righini M, Goehring C, Bounameaux H, Perrier A. Effects of age on the performance of common diagnostic tests for pulmonary embolism. Am J Med 2000; 109:357–61.

36. Woller SC, Stevens SM, Adams DM, et al. Assessment of the safety and efficiency of using an age-adjusted D-dimer threshold to exclude suspected pulmonary embolism. Chest 2014; 146:1444–51.

37. Zierler BK. Ultrasonography and diagnosis of venous thromboembolism. Circulation 2004; 109 (Suppl 1): I9–14.

38. Hirsh J, Lee AY. How we diagnose and treat deep vein thrombosis. Blood 2002;99:3102–10.

39. Tapson VF, Carroll BA, Davidson BL, et al. The diagnostic approach to acute venous thromboembolism. Clinical practice guideline. American Thoracic Society. Am J Respir Crit Care Med 1999;160:1043–66.

40. Bates SM, Jaeschke R, Stevens SM, et al. Diagnosis of DVT: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 2012; 141 (2 Suppl): e351S–418S.

41. Pezzullo JA, Perkins AB, Cronan JJ. Symptomatic deep vein thrombosis: diagnosis with limited compression US. Radiology 1996;198:67–70.

42. Frederick MG, Hertzberg BS, Kliewer MA, et al. Can the US examination for lower extremity deep venous thrombosis be abbreviated? A prospective study of 755 examinations Radiology 1996;199:45–7.

43. Remy-Jardin M, Remy J, Deschidre F, et al. Diagnosis of pulmonary embolism with spiral CT: comparison with pulmonary angiography and scintigraphy. Radiology 1996;200:699–706.

44. Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 2006;354:2317–27.

45. Goodacre S. In the clinic. Deep venous thrombosis. Ann Intern Med 2008;149:ITC3–1.

46. Agnelli G, Becattini C. Acute pulmonary embolism. N Engl J Med 2010;363:266–74.

47. Kucher N. Clinical practice. Deep-vein thrombosis of the upper extremities. N Engl J Med 2011;364:861–9.

48. Constans J, Salmi LR, Sevestre-Pietri MA, et al. A clinical prediction score for upper extremity deep venous thrombosis. Thromb Haemost 2008;99:202–7.

49. Meyer G, Vicault E, Danasys T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370:1402–11.

50. Kline JA, Nordenholz KE, Courtney DM, et al. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-bline, placebo-controlled randomized trial. J Thromb Haemost 2014;12:459–68.

51. Guyatt GH, Akl EA, Crowther M, et al. Executive summary: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 2012;141(2 Suppl):7S–47S.

52. Bounameaux H. Unfractionated versus low-molecular-weight heparin in the treatment of venous thromboembolism. Vasc Med 1998;3:41–6.

53. Erkens PM, Prins MH. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev 2010;9:CD001100.

54. Buller HR, Davidson BL, Decousus H, et al. Fondaprinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med 2004;140: 867–73.

55. Buller HR, Davidson BL, Decousus H, et al. Subcutaenous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003;349:1695–702.

56. Bates SM, Weitz JI. Coagulation assays. Circulation 2005;112:e53–60.

57. Pon TK, Dager WE, Roberts AJ, White RH. Subcutaneous enoxaparin for therapeutic anticoagulation in hemodialysis patients. Thromb Res 2014;133:1023–8.

58. Speeckaert MM, Devreese KM, Vanholder RC, Dhondt A. Fondaparinux as an alternative to vitamin K antagonists in haemodialysis patients. Nephrol Dial Transplant 2013;28:3090–5.

59. Aujesky D, Obrosky DS, Stone RA, et al. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med 2005;172:1041–6.

60. Jiminez D, Aujesky D, Moores L, et al. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med 2010; 170:1383–9.

61. Schulman S. Advances in the management of venous thromboembolism. Best Pract Res Clin Haematol 2012;25:361–77.

62. Erkens PM, Gandara E, Wells P, et al. Safety of outpatient treatment in acute pulmonary embolism. J Thromb Haemost 2010;8:2412–7.

63. Chan YC, Valenti D, Mansfield AO, Stansby G. Warfarin induced skin necrosis. Br J Surg 2000; 87:266–72.

64. Brandjes DP, Heijboer H, Buller HR, et al. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med 1992;327:1485–9.

65. Segal JB, Streiff MB, Hofmann LV, et al. Management of venous thromboembolism: a systematic review for a practice guideline. Ann Intern Med 2007;146:211–22.

66. Pinede L, Duhaut P, Cucherat M, et al. 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.

67. 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.

68. Boutitie F, Pinede L, Schulman S, et al. 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.

69. 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;340:901-07.

70. 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.

71. 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.

72. Bauer KA. Long-term management of venous thromboembolism: a 61-year old woman with unprovoked venous thromboembolism. JAMA 2011;305:1336–45.

73. Kearon C, Akl EA. Duration of anticoagulant therapy for deep vein thrombosis and pulmonary embolism. Blood 2014;123:
1794–801.

74. Schulman S, Beyth RJ, Kearon C, et al. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American college of chest physicians evidence-based clinical practice guidelines (8th edition). Chest 2008;133(6 Suppl):257S–298S.

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

76. Ruiz-Gimenez N, Suarez C, Gonzalez R, et al. 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.

77. Kearon C, Akl EA, Comerota AJ. 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 (2 Suppl): e419S–94S.

78. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess one-year risk of major bleeding in atrial fibrillation patients: The Euro Heart Survey. Chest 2010;138:1093–1100.

79. Gage BF, Yan Y, Milligan PE, et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J 2006;151:713–9.

80. Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated hemorrhage: the ATRIA (Anticoagulation and risk factors in atrial fibrillation) study. J Am Coll Cardiol 2011;58:395–401.

81. Caldeira D, Costa J, Fernandes RM, et al. Performance of the HAS-BLED high bleeding-risk category, compared to ATRIA and HEMORR2HAGES in patients with atrial fibrillation: a systematic review and meta-analysis. J Interv Card Electrophysiol 2014;40:277–84.

82. Douketis JD, Crowther MA, Foster GA, Ginsberg JS. Does the location of thrombosis determine the risk of disease recurrence in patients with proximal deep vein thrombosis? Am J Med 2001;110:515–9.

83. 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.

84. Palareti G, Cosmi B, Legnani C, et al. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006;355:1780–9.

85. Bruinstroop E, Klok FA, Van De Ree MA, et al. Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism: a meta-analysis. J Thromb Haemost 2009;611–8.

86. Verhovsek M, Douketis JD, Yi Q, et al. Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern Med 2008;149:481–90.

87. Tosetto A, Iorio A, Marcucci M, et al. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost 2012;10:1019–25.

88. Eichinger S, Heinze G, Jandeck LM, et al. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna Prediction Model. Circulation2010; 121:1630–6.

89. Eichinger S, Heinze G, Kyrle PA. D-dimer levels over time and the risk of recurrent venous thromboembolism: an update of the Vienna prediction model. J Am Heart Assoc 2014; 3: e000467.

90. Douketis J, Tosetto A, Marcucci M, et al. 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 2010;153:523–31.

91. 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.

92. Prandoni P, Prins MH, Lensing AW, et al. 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.

93. Marcucci M, Iorio A, Douketis J. Management of patients with unprovoked venous thromboembolism: an evidence-based and practical approach. Curr Treat Options Cardiovasc Med 2013;15:224–39.

94. 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.

95. 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.

96. Brighton TA, Eikelboom JW, Mann K, et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 2012;367:1979–87.

97. Becattini C, Agnelli G, Schenone A, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012;366:1959–67.

98. Simes J, Becattini C, Agnelli G, et al. Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circulation 2014;130:1062–71.

99. Makris M. Thrombophilia: grading the risk. Blood 2009;113:5038–9.

100. Segal JB, Brotman DJ, Necochea AJ, et al. Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review. JAMA 2009;30:2472.

101. Ho WK, Hankey GH, Quinlan DJ, Eikelboom JW. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med 2006;166:729–36.

102. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4:295–306.

103. Pengo V, Tripodi A, Reber G, et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on lupus anticoagulant/antiphospholipid antibody of the scientific and standardization committee of the international society on thrombosis and haemostasis. J Thromb Haemost 2009; 7:1737–40.

104. Brandt JT, Barna LK, Triplett DA. Laboratory identification of lupus anticoagulants: results of the Second International Workship for identification of lupus anticoagulants. On behalf of the subcommittee on lupus anticoagulants/antiphospholipid antibodies of the ISTH. Thromb Haemost 1995;74: 1597–603.

105. Gale AJ, Gordon SG. Update on tumor cell procoagulant factors. Acta Haematol 2001;106:25-32.

106. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood 2013;122:1712–23.

107. Lee AY, Levine MN. Venous thromboembolism and cancer: risks and outcomes. Circulation 2003; 107 (Suppl 1): I17–21.

108. Van Doormaal FF, Terpstra W, Van Der Griend R, et al. Is extensive screening for cancer in idiopathic venous thromboembolism warranted? J Thromb Haemost 2011;9:79–84.

109. Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000;343:1846–50.

110. Lee AY, 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.

111. Streiff MB, Bockenstedt PL, Cataland SR, et al. Venous thromboembolic disease. J Natl Compr Canc Netw 2013;11:1402-29.

112. Elias EG, Sepulveda F, Mink IB. Increasing the efficiency of cancer chemotherapy with heparin: “clinical study.” J Surg Oncol 1973;5:189–93.

113. Lazo-Langner A, Goss GD, Spaans JN, Rodger MA. The effect of low-molecular-weight heparin on cancer survival. A systematic review and meta-analysis of randomized trials. J Thromb Haemost 2007;5:729–37.

114. Bremme KA. Haemostatic changes in pregnancy. Best Pract Res Clin Haematol 2003;16:153–68.

115. Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000;342:374–80.

116. Rott H. Thrombotic risks of oral contraceptives. Curr Opin Obstet Gynecol 2012;24:235-40.

117. Marchiori A, Mosena L, Prandoni P. Superficial vein thrombosis: risk factors, diagnosis, and treatment. Semin Thromb Hemost 2006;32:737–43.

118. Decousus H, Quere I, Presles E, et al. Superficial venous thrombosis and venous thromboembolism: a large, prospective epidemiologic study. Ann Intern Med 2010;152:218–24.

119. Galanaud JP, Genty C, Sevestre MA, et al. Predictive factors for concurrent deep-vein thrombosis and symptomatic venous thromboembolic recurrence in case of superficial venous thrombosis. The OPTIMEV study. Thromb Haemost 2011;105:31–9.

120. Sullivan V, Denk PM, Sonnad SS, et al. Ligation versus anticoagulation: treatment of above-knee superficial thrombophlebitis not involving the deep venous system. J Am Coll Surg 2001;193:556–62.

121. Lohr JM, McDevitt DT, Lutter KS, et al. Operative management of greater saphenous thrombophlebitis involving the saphenofemoral junction. Am J Surg 1992;164:269–75.

122. Chengelis DL, Benedick PJ, Glover JL, et al. Progression of superficial venous thrombosis to deep vein thrombosis. J Vasc Surg 1996;24:745–9.

123. Verlato F, Zuccetta P, Prandoni P, et al. An unexpectedly high rate of pulmonary embolism in patients with superficial thrombophlebitis of the leg. J Vasc Surg 1999;30:1113–5.

124. Cosmi B, Filippini M, Tonti D, et al. A randomized double-blind study of low-molecular-weight heparin (parnaparin) for superficial vein thrombosis: STEFLUX (Superficial ThromboEmbolism and Fluxum). J Thromb Haemost 2012;10:1026–35.

125. Decousus H, Prandoni P, Mismetti P, et al. Fondaparinux for the treatment of superficial-vein thrombosis in the legs. N Engl J Med 2010;363:1222–32.

126. Di Nisio M, Wichers IM, Middeldorp S. Treatment for superficial thrombophlebitis of the leg. Cochrane Database Syst Rev 2013;4:CD004982.

127. Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007;64:292–303.

128. RE-MOBILIZE Writing Committee, Ginsberg JS, Davidson BL, et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009;24:1–9.

129. Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007;5:2178–85.

130. Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomized, double-blind, non-inferiority trial. Lancet 2007;370:949–56.

131. Eriksson BI, Dahl OE, Huo MH, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomized, double-blind, non-inferiority trial. Thromb Haemost2011;105:721–9.

132. Friedman RJ, Dahl OE, Rosencher N, et al. Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials. Thromb Res 2010;126:175–82.

133. Wolowacz SE, Roskell NS, Plumb JM, et al. Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty. A meta-analysis. Thromb Haemost 2009;101:77–85.

134. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;36:2342–52.

135. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013;368:709–18.

136. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358:2765–75.

137. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomized controlled trial. Lancet 2008;372:31–9.

138. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358:2776–86.

139. Cao YB, Zhang JD, Shen H, Jiang YY. Rivaroxaban versus enoxaparin for thromboprophylaxis after total hip or knee arthroplasty: a meta-analysis of randomized controlled trials. Eur J Clin Pharmacol 2010;66:1099–108.

140. Cohen AT, Spiro TE, Buller HR, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013;368:513–23.

141. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499–510.

142. EINSTEIN-PE Investigators, Buller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287–97.

143. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369:799–808.

144. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699–708.

145. Hokusai-VTE investigators, Buller HR, Decousus H, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406–15.

146. Khadzhynov D, Wagner F, Formella S, et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost 2013;109:596–605.

147. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood 2013;121:3554–62.

148. Glund S, Stangier J, Schmohl M, et al. Idarucizumab, a specific antidote for dabigatran: immediate, complete, and sustained reversal of dabigatran induced anticoagulation in elderly and renally impaired subjects. Presented at the American Society of Hematology 2014 Annual Meeting; San Francisco, CA.

149. Crowther MA, Levy GG, Lu G, et al. A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of edoxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (fXa) inhibitors. Abstract #4269. Presented at the American Society of Hematology 2014 Annual Meeting, San Francisco, CA.

150. Crowther M, Levy GG, Lu G, et al. ANNEXATM-A: A phase 3 randomized, double-blind, placebo-controlled trial, demonstrating reversal of apixaban-induced anticoagulation in older subjects by andexanet alfa (PRT 064445), a universal antidote for factor Xa (fa) inhibitors. Presented at the American Heart Association 2014 Annual Meeting, Chicago, IL.

151. Ansell JE, Bakhru SH, Lauliche BE, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014;371:2141–2.

152. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573–9.

153. Korber MK, Langer E, Ziemer S, et al. Measurement and reversal of prophylactic and therapeutic peak levels of rivaroxaban: an in vitro study. Clin Appl Thromb Hemost 2014;20:735–40.

154. Fawole A, Daw HA, Crowther MA. Practical management of bleeding due to the anticoagulants dabigatran, rivaroxaban, and apixaban. Cleve Clin J Med 2013;80:443–51.

155. Siegal DM, Garcia DA, Crowther MA. How I treat target-specific oral anticoagulant-associated bleeding. Blood 2014;123:1152–8.

Imaging Analysis

Imaging analysis may also assist with risk stratification. Clinical assessment modules have been developed that incorporate repeat imaging studies for assessment of recannulization of affected veins. In patients with residual vein thrombosis (RVT) at the time anticoagulation was stopped, the hazard ratio for recurrence was 2.4 compared to those without RVT [91].There are a number of ways RVT could impact recurrence, including inpaired venous flow leading to stasis and activation of the coagulation cascade. Subsequent studies used serial ultrasound to determine when to stop anticoagulation. In one study, patients were anticoagulated for 3 months and for those that had RVT, anticoagulation was continued for up to 9 months for provoked and 21 months for unprovoked VTE. In comparison to fixed dosing of 6 months of anti-coagulation, those who had their length of anticoagulation tailored to ultrasonography findings had a lower rate of recurrent VTE [92].Limitations to using RVT in clinical decision-making include lack of a standard definition of RVT and variability in both timing of ultrasound (operator variability) and interpretation of results [93].

Other Options

Another option in patients who are being considered for indefinite anticoagulation is to decrease the intensity of anticoagulation. Since this would theoretically lower the risk of bleeding, the perceived benefit of long-term, low-intensity anticoagulation would be reduction in both bleeding and clotting risk. The PREVENT trial randomized patients who had received full-dose anticoagulation for a median of 6.5 months to either low-intensity warfarin (INR goal of 1.5-2.0 instead of 2.0-3.0) or placebo. In the anticoagulation group, there was a 64% risk reduction in recurrent VTE (hazard ratio 0.36, 95% CI 0.19 to 0.67) but an increased risk of bleeding (hazard ratio 1.92, 95% CI 1.26 to 2.93) [94].The ELATE study randomized patients with unprovoked VTE who had completed 3 or more months of full-intensity warfarin therapy (target INR 2.0–3.0) to continue therapy with either low-intensity warfarin (target INR 1.5–2.0) or full-intensity warfarin (target INR 2.0-3.0). Compared to the low-intensity group, the conventional-intensity group had lower rates of recurrent VTE and no increased rates of major bleeding [95].This study, however, has been criticized because of its overall low bleeding rate in both treatment groups.

Aspirin is an option in patients in whom long-term anticoagulation is untenable. The ASPIRE trial demonstrated that in patients with unprovoked VTE who had completed a course of initial anticoagulation, aspirin 100 mg daily reduced the risk of major vascular events compared to placebo with no increase in bleeding [96].However, aspirin was not associated with a significant reduction in risk of VTE alone (only the composite vascular event endpoint). The WARFASA trial, however, demonstrated that aspirin 100 mg daily was associated with a significant reduction in recurrent VTE compared to placebo after 6 to 18 months of anticoagulation without an increase in major bleeding [97].The absolute risk of recurrence was 11% in the placebo group and 5.9% in the aspirin group. More recently, the INSPIRE collaboration analyzed data from both trials and found that aspirin after initial anticoagulation reduced the risk of recurrent VTE by approximately 42% with a low rate of major bleeding [98].The absolute risk reduction was even larger in men and older patients. For this reason, we recommend aspirin to those patients in whom indefinite anticoagulation may be warranted from the standpoint of reducing risk of recurrent VTE but in whom the risk of bleeding precludes its use.