Download PDF
Thromb Haemost 2015; 113(06): 1210-1215
DOI: 10.1160/TH14-04-0396
Theme Issue Article
Schattauer GmbH

Optimal duration of anticoagulation

Provoked versus unprovoked VTE and role of adjunctive thrombophilia and imaging tests
Paolo Prandoni
1   Department of Medicine, Vascular Medicine Unit, University of Padua, Italy
,
Sofia Barbar
1   Department of Medicine, Vascular Medicine Unit, University of Padua, Italy
,
Marta Milan
1   Department of Medicine, Vascular Medicine Unit, University of Padua, Italy
,
Elena Campello
1   Department of Medicine, Vascular Medicine Unit, University of Padua, Italy
,
Luca Spiezia
1   Department of Medicine, Vascular Medicine Unit, University of Padua, Italy
,
Chiara Piovella
1   Department of Medicine, Vascular Medicine Unit, University of Padua, Italy
,
Raffaele Pesavento
1   Department of Medicine, Vascular Medicine Unit, University of Padua, Italy
› Author Affiliations
Further Information

Publication History

Received: 30 April 2014

Accepted after major revision: 24 June 2014

Publication Date:
22 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Once anticoagulation is stopped, the risk of recurrent venous thromboembolism (VTE) over years after a first episode is consistently around 30%. This risk is higher in patients with unprovoked than in those with (transient) provoked VTE, and among the latter in patients with medical than in those with surgical risk factors. Baseline parameters that have been found to be related to the risk of recurrent VTE are the proximal location of deep-vein thrombosis, obesity, old age, male sex and non-0 blood group, whereas the role of inherited thrombophilia is controversial. The persistence of residual vein thrombosis at ultrasound assessment has consistently been shown to increase the risk, as do persistently high values of D-dimer and the early development of the post-thrombotic syndrome. Although the latest international guidelines suggest indefinite anticoagulation for most patients with the first episode of unprovoked VTE, strategies that incorporate the assessment of residual vein thrombosis and D-dimer have the potential to identify subjects in whom anticoagulation can be safely discontinued. Moreover, new opportunities are offered by a few emerging anti-Xa and anti-IIa oral compounds, which are likely to induce fewer haemorrhagic complications than vitamin K antagonists while preserving the same effectiveness; and by low-dose aspirin, which has the potential to prevent the occurrence of both venous and arterial thrombotic events.

Keywords

Venous thromboembolism - deep venous thrombosis - pulmonary embolism - anticoagulation - thrombophilia - residual thrombosis - ultrasonography
 

  • References

  • 1 Prandoni P, Lensing AWA, Cogo A. et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1-7.
    CrossrefPubMedSearch in Google Scholar
  • 2 Prandoni P, Noventa F, Ghirarduzzi A. et al. 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 1626 patients Haematologica 2007; 91: 199-205.
    PubMedSearch in Google Scholar
  • 3 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. N Engl J Med 1995; 332: 1661-1665.
    CrossrefPubMedSearch in Google Scholar
  • 4 Hansson PO, Sorbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis. Incidence and risk factors. Arch Intern Med 2000; 1260: 769-774.
    PubMedSearch in Google Scholar
  • 5 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: 523-526.
    CrossrefPubMedSearch in Google Scholar
  • 6 Holley AB, King CS, Jackson JL. et al. Different finite durations of anticoagulation and outcomes following idiopathic venous thromboembolism: a metaanalysis. Thrombosis 2010; 2010: 540386.
    PubMedSearch in Google Scholar
  • 7 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. Br Med J 2011; 342: d3036.
    CrossrefPubMedSearch in Google Scholar
  • 8 Kyrle PA, Minar E, Bialonczyk C. et al. The risk of recurrent venous thromboembolism in men and women. N Engl J Med 2004; 350: 2558-2563.
    CrossrefPubMedSearch in Google Scholar
  • 9 McRae S, Tran H, Schulman S. et al. Effect of patient’s sex on risk of recurrent venous thromboembolism: a meta-analysis. Lancet 2006; 368: 371-378.
    CrossrefPubMedSearch in Google Scholar
  • 10 Douketis J, Tosetto A, Marcucci M. et al. Risk of recurrence after venous thromboembolism in men and women: patient level meta-analysis. Br Med J 2011; 342: d813.
    CrossrefPubMedSearch in Google Scholar
  • 11 Lijfering WM, Veeger NJ, Middeldorp S. et al. A lower risk of recurrent venous thrombosis in women compared to men is explained by sex-specific risk factors at time of first venous thrombosis in thrombophilic families. Blood 2009; 114: 2031-2036.
    CrossrefPubMedSearch in Google Scholar
  • 12 Le Gal G, Kovacs MJ, Carrier M. et al. Risk of recurrent venous thromboembolism after a first oestrogen-associated episode. Data from the REVERSE cohort study. Thromb Haemost 2010; 104: 498-503.
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 Roach RE, Lijfering WM, Rosendaal FR, Cannegieter SC. le Cessie S. Sex difference in risk of second but not of first venous thrombosis: paradox explained. Circulation 2014; 129: 51-56.
    CrossrefPubMedSearch in Google Scholar
  • 14 Eischer L, Eichinger S, Kyrle PA. Age at first venous thromboembolism and risk of recurrence: a prospective cohort study. Medicine 2009; 88: 366-370.
    CrossrefPubMedSearch in Google Scholar
  • 15 Lόpez-Jiménez L, Montero M, González-Fajardo JA. et al. Venous thromboembolism in very elderly patients: findings from a prospective registry. Haematologica 2006; 91: 1046-1051.
    PubMedSearch in Google Scholar
  • 16 Eichinger S, Hron G, Bialonczyk C. et al. Overweight, obesity, and the risk of recurrent venous thromboembolism. Arch Intern Med 2008; 68: 1678-1683.
    PubMedSearch in Google Scholar
  • 17 Gándara E, Kovacs MJ, Kahn SR. et al. Non-O blood type influences the risk of recurrent venous thromboembolism. A cohort study. Thromb Haemost 2013; 110: 1172-1179.
    Thieme ConnectPubMedSearch in Google Scholar
  • 18 Kovacs MJ, Kahn SR, Wells PS. et al. Patients with a first symptomatic unprovoked DVT are at higher risk of recurrent VTE than patients with a first unprovoked PE. J Thromb Haemost 2010; 08: 1926-1932.
    CrossrefPubMedSearch in Google Scholar
  • 19 Baglin T, Douketis J, Tosetto A. et al. Does the clinical presentation and extent of venous thrombosis predict likelihood and type of recurrence?. A patient level meta-analysis J Thromb Haemost 2010; 08: 2436-2442.
    CrossrefPubMedSearch in Google Scholar
  • 20 Kearon C, Julian JA, Kovacs MJ. et al. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: Results from a randomized trial. Blood 2008; 112: 4432-4436.
    CrossrefPubMedSearch in Google Scholar
  • 21 De Stefano V, Simioni P, Rossi E. et al. The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants antithrombin, protein C and protein S. Haematologica. 2006; 91: 695-698.
    PubMedSearch in Google Scholar
  • 22 Di Minno MN, Dentali F, Lupoli R, Ageno W. Mild antithrombin deficiency and the risk of recurrent venous thromboembolism: a prospective cohort study. Circulation 2014; 129: 497-503.
    CrossrefPubMedSearch in Google Scholar
  • 23 Eichinger S, Stümpflen A, Hirschl M. et al. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism. Thromb Haemost 1998; 80: 566-569.
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 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: 457-462.
    CrossrefPubMedSearch in Google Scholar
  • 25 Eischer L, Gartner V, Schulman S, Kyrle PA, Eichinger S. 6 versus 30 months anticoagulation for recurrent venous thrombosis in patients with high factor VIII. Ann Hematol 2008; 88: 85-90.
    PubMedSearch in Google Scholar
  • 26 Weltermann A, Eichinger S, Bialonczyk C. et al. The risks of recurrent venous thromboembolism among patients with high factor IX levels. J Thromb Haemost 2003; 01: 28-32.
    CrossrefPubMedSearch in Google Scholar
  • 27 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. J Am Med Assoc 2009; 301: 2472-2485.
    CrossrefPubMedSearch in Google Scholar
  • 28 Lijfering WM, Middeldorp S, Veeger NJ. et al. Risk of recurrent venous thrombosis in homozygous carriers and double heterozygous carriers of factor V Leiden and prothrombin G20210A. Circulation 2010; 121: 1706-1712.
    CrossrefPubMedSearch in Google Scholar
  • 29 Zöller B, Ohlsson H, Sundquist J, Sundquist K. Familial risk of venous thromboembolism in first-, second-and third-degree relatives: a nationwide family study in Sweden. Thromb Haemost 2013; 109: 458-463.
    Thieme ConnectPubMedSearch in Google Scholar
  • 30 Hron G, Eichinger S, Weltermann A. et al. Family history for venous thromboembolism and the risk for recurrence. Am J Med 2006; 119: 50-53.
    CrossrefPubMedSearch in Google Scholar
  • 31 Gauthier K, Kovacs MJ, Wells PS, LE Gal G, Rodge M. Family history of venous thromboembolism (VTE) as a predictor for recurrent VTE in unprovoked VTE patients. J Thromb Haemost 2013; 11: 200-203.
    CrossrefPubMedSearch in Google Scholar
  • 32 Palareti G, Legnani C, Cosmi B. et al. Predictive value of D-Dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idioipathic event and in carriers of congenital thrombophilia. Circulation 2003; 108: 313-318.
    CrossrefPubMedSearch in Google Scholar
  • 33 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.
    Thieme ConnectPubMedSearch in Google Scholar
  • 34 Eichinger S, Minar E, Bialonczyk C. et al. D-dimer levels and risk of recurrent venous thromboembolism. J Am Med Assoc 2003; 290: 1071-1074.
    CrossrefPubMedSearch in Google Scholar
  • 35 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: 481-490.
    CrossrefPubMedSearch in Google Scholar
  • 36 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; 07: 611-618.
    CrossrefPubMedSearch in Google Scholar
  • 37 Stain M, Schönauer V, Minar E. et al. The post-thrombotic syndrome: risk factors and impact on the course of thrombotic disease. J Thromb Haemost 2005; 03: 2671-2676.
    CrossrefPubMedSearch in Google Scholar
  • 38 Prandoni P, Lensing AW, Prins MH. et al. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 2002; 137: 955-960.
    CrossrefPubMedSearch in Google Scholar
  • 39 Piovella F, Crippa L, Barone M. et al. 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: 515-522.
    PubMedSearch in Google Scholar
  • 40 Tan M, Mos IC, Klok FA. et al. Residual venous thrombosis as predictive factor for recurrent venous thromboembolim in patients with proximal deep vein thrombosis: a sytematic review. Br J Haematol 2011; 153: 168-178.
    CrossrefPubMedSearch in Google Scholar
  • 41 Donadini MP, Ageno W, Antonucci E. et al. Prognostic significance of residual venous obstruction in patients with treated unprovoked deep vein thrombosis. A patient-level meta-analysis. Thromb Haemost 2014; 111: 172-179.
    Thieme ConnectPubMedSearch in Google Scholar
  • 42 Prandoni P, Lensing AWA, Prins MH. et al. Residual vein thrombosis as a strong predictor of recurrent thromboembolism and post-thrombotic syndrome. J Thromb Haemost 2013; 11 (Suppl. 02) AS 19.2.
    PubMedSearch in Google Scholar
  • 43 Golpe R, de Llano LA, Castro-Añόn O. et al. Long-term outcome of patients with persistent vascular obstruction on computed tomography pulmonary angiography 6 months after acute pulmonary embolism. Acta Radiol 2012; 53: 728-731.
    CrossrefPubMedSearch in Google Scholar
  • 44 Pesavento R, Filippi L, Pagnan A. et al. Unexpectedly high recanalization rate in patients with pulmonary embolism treated with anticoagulants alone. Am J Resp Crit Care Med. 2014. Epub ahead of print.
    Search in Google Scholar
  • 45 Rodger MA, Kahn SR, Wells PS. et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ 2008; 179: 417-426.
    CrossrefPubMedSearch in Google Scholar
  • 46 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. Circulation 2010; 121: 1630-1636.
    CrossrefPubMedSearch in Google Scholar
  • 47 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: 1019-1025.
    CrossrefPubMedSearch in Google Scholar
  • 48 Kyrle PA, Eichinger S. Clinical scores to predict recurrence risk of venous thromboembolism. Thromb Haemost. 2012; 108: 1061-1064.
    PubMedSearch in Google Scholar
  • 49 Kearon C, Akl EA, Comerota AJ. et al. 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 (Suppl. 02) e419S-e494S.
    CrossrefPubMedSearch in Google Scholar
  • 50 Kearon C, Ginsberg JS, Anderson DR. et al. 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; 02: 743-749.
    CrossrefPubMedSearch in Google Scholar
  • 51 Carrier M, Le Gal G, 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: 578-589.
    CrossrefPubMedSearch in Google Scholar
  • 52 Lecumberri R, Alfonso A, Jiménez D. et al. Dynamics of case-fatalilty rates of recurrent thromboembolism and major bleeding in patients treated for venous thromboembolism. Thromb Haemost 2013; 110: 834-843.
    Thieme ConnectPubMedSearch in Google Scholar
  • 53 Spencer FA, Gore JM, Lessard D, Douketis JD, Emery C, Goldberg RJ. Patient outcomes after deep vein thrombosis and pulmonary embolism: the Worcester Venous Thromboembolism Study. Arch Intern Med 2008; 168: 425-430.
    CrossrefPubMedSearch in Google Scholar
  • 54 Prandoni P, Santos JT, Sánchez-Cantalejo E. et al. Major bleeding as a predictor of mortality in patients with venous thromboembolism. J Thromb Haemost 2010; 08: 2475-2477.
    PubMedSearch in Google Scholar
  • 55 Palareti G, Cosmi B, Legnani C. et al. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006; 355: 1780-1789.
    CrossrefPubMedSearch in Google Scholar
  • 56 Cosmi B, Legnani C, Tosetto A. et al. 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: 481-488.
    CrossrefPubMedSearch in Google Scholar
  • 57 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: 577-585.
    CrossrefPubMedSearch in Google Scholar
  • 58 Siragusa S, Malato A, Anastasio R. et al. Residual vein thrombosis to establish duration of anticoagulation after a first episode of deep vein thrombosis: the “DACUS” study. Blood 2008; 112: 511-515.
    CrossrefPubMedSearch in Google Scholar
  • 59 Palareti G, Cosmi B, Legnani C. et al. D-dimer and residual thrombosis to guide the duration of anticoagulation in patients with venous thromboembolism. A management study. Blood 2014; 124: 196-203.
    CrossrefPubMedSearch in Google Scholar
  • 60 Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342-2352.
    CrossrefPubMedSearch in Google Scholar
  • 61 Schulman S, Kakkar AK, Goldhaber SZ. et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129: 764-772.
    CrossrefPubMedSearch in Google Scholar
  • 62 The Einstein Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
    CrossrefPubMedSearch in Google Scholar
  • 63 The Einstein Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287-1297.
    CrossrefPubMedSearch in Google Scholar
  • 64 Agnelli G, Buller HR, Cohen A. et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 368: 699-708.
    CrossrefPubMedSearch in Google Scholar
  • 65 The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369: 1406-1415.
    CrossrefPubMedSearch in Google Scholar
  • 66 Schulman S, Kearon C, Kakkar AK. et al. Extended Use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368: 709-718.
    CrossrefPubMedSearch in Google Scholar
  • 67 Agnelli G, Buller HR, Cohen A. et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368: 699-708.
    CrossrefPubMedSearch in Google Scholar
  • 68 Becattini C, Agnelli G. Schenone et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012; 366: 1959-1967.
    CrossrefPubMedSearch in Google Scholar
  • 69 Brighton TA, Eikelboom JW, Mann K. et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 2012; 367: 1979-1987.
    CrossrefPubMedSearch in Google Scholar
  • 70 Warkentin TE. Aspirin for dual prevention of venous and arterial thrombosis. N Engl J Med 2012; 367: 2039-2041.
    CrossrefPubMedSearch in Google Scholar
  • 71 Warkentin AE, Donadini MP, Spencer FA, Lim W, Crowther M. Bleeding risk in randomized controlled trials comparing warfarin and aspirin: a systematic review and meta-analysis. J Thromb Haemost 2012; 10: 512-520.
    CrossrefPubMedSearch in Google Scholar
  • 72 Milan M, Noventa F, Ghirarduzzi A. et al. Aspirin and recurrent venous thromboembolism in patients with symptomatic atherosclerosis. Retrospective cohort study. J Thromb Haemost 2012; 10: 2205-2206.
    CrossrefPubMedSearch in Google Scholar
  • 73 Sørensen HT, Horvath-Puho E, Søgaard KK. et al. Arterial cardiovascular events, statins, low dose aspirin and subsequent risk of venous thromboembolism: a population-based case-control study. J Thromb Haemost 2009; 07: 521-528.
    CrossrefPubMedSearch in Google Scholar
  • 74 Agarwal V, Phung OJ, Tongbram V, Bhardwaj A, Coleman CI. Statin use and the prevention of venous thromboembolism: a meta-analysis. Int J Clin Pract 2010; 64: 1375-1383.
    CrossrefPubMedSearch in Google Scholar
  • 75 Biere-Rafi S, Hutten BA, Squizzato A. et al. Statin treatment and the risk of recurrent pulmonary embolism. Eur Heart J 2013; 34: 1800-1806.
    CrossrefPubMedSearch in Google Scholar
  • 76 Nguyen CD, Andersson C, Jensen TB. et al. Statin treatment and risk of recurrent venous thromboembolism: a nationwide cohort study. Br Med J Open 2013; 03: e003135.
    PubMedSearch in Google Scholar
  • 77 Schmidt M, Cannegieter SC, Johannesdottir SA, Dekkers OM, Horváth-Puhό E, Sørensen HT. Statin use and venous thromboembolism recurrence: a combined nationwide cohort and nested case-control study. J Thromb Haemost. 2014. Epub ahead of print.
    Search in Google Scholar