Journal of Thrombosis and Thrombolysis

, Volume 41, Issue 3, pp 525–538 | Cite as

Occurrence and predictors of recurrence after a first episode of acute venous thromboembolism: population-based Worcester Venous Thromboembolism Study

  • Wei Huang
  • Robert J. Goldberg
  • Frederick A. Anderson
  • Alexander T. Cohen
  • Frederick A. Spencer


Venous thromboembolism (VTE) has multiple risk factors and tends to recur. Despite the benefits of anticoagulation, the prevalence of, and case-fatality rate associated with, recurrent VTE remains a concern after an acute episode; it is particularly high during the acute treatment phase. We sought to quantify the magnitude, identify predictors, and develop risk score calculator of recurrence within 3 years after first-time VTE. This was a population-based surveillance study among residents of central Massachusetts (MA), USA, diagnosed with an acute first-time pulmonary embolism and/or lower-extremity deep vein thrombosis from 1999 to 2009 in hospital and ambulatory settings in all 12 central MA hospitals. Medical records were reviewed and validated. The 2989 study patients were followed for 5836 person-years [mean follow-up 23.4 (median 30) months]. Mean age was 64.3 years, 44 % were men, and 94 % were white. The cumulative incidence rate of recurrent VTE within 3 years after an index VTE was 15 % overall, and 25, 13, and 13 % among patients with active cancer, provoked, or unprovoked VTE, respectively. Multivariable regression indicated that active cancer, varicose vein stripping, and inferior vena cava filter placement were independent predictors of recurrence during both 3-month and 3-year follow-up. A risk score calculator was developed based on the 3-month prognostic model. In conclusion, the rate of VTE recurrence over 3 years of follow-up remained high. The risk score calculator may assist clinicians at the index encounter in determining the frequency of clinical surveillance and appropriate outpatient treatment of VTE during the acute treatment phase.


Venous thrombosis Pulmonary embolism Recurrence Predictors Risk assessment Epidemiology 



National Heart, Lung, and Blood Institute (R01-HL70283), and National Institute of Aging (R01AG031083).

Author contributions

Gordon FitzGerald, PhD (Center for Outcomes Research), Arlene Ash, PhD, Catarina Kiefe, MD, PhD, David Hoaglin, PhD, and Allison Rosen, MD, ScD (Department of Quantitative Health Sciences) and Joel Gore, MD (Department of Medicine) at UMass Medical School for helpful comments. Editorial support for the final version of the manuscript was provided by Sophie Rushton-Smith, PhD (Center for Outcomes Research, University of Massachusetts Medical School, Worcester, MA, USA).

Compliance with ethical standards

Conflict of interest

Professor Anderson received research grants from Sanofi and The Medicines Company; he has served as a consultant to GlaxoSmithKline and Takeda Oncology on the design of outcomes studies. Dr. Cohen reports grants and personal fees from Bayer, Boehringer-Ingelheim, BMS, Daiichi, GSK, Johnson and Johnson, Pfizer, Portola, Sanofi and XO1, outside the submitted work. All other authors declare that they have no conflict of interest.


  1. 1.
    Colman RW, Marder VJ, Clowes AW, George JN, Goldhaber SZ (2006) Hemostasis and thrombosis basic principles and clinical practice, vol 1, 5th edn. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  2. 2.
    Deitelzweig SB, Johnson BH, Lin J, Schulman KL (2011) Prevalence of clinical venous thromboembolism in the USA: current trends and future projections. Am J Hematol 86(2):217–220CrossRefPubMedGoogle Scholar
  3. 3.
    Heit JA (2005) Venous thromboembolism: disease burden, outcomes and risk factors. J Thromb Haemost 3(8):1611–1617CrossRefPubMedGoogle Scholar
  4. 4.
    Park B, Messina L, Dargon P, Huang W, Ciocca R, Anderson FA (2009) Recent trends in clinical outcomes and resource utilization for pulmonary embolism in the United States: findings from the nationwide inpatient sample. Chest 136(4):983–990CrossRefPubMedGoogle Scholar
  5. 5.
    Huang W, Goldberg RJ, Anderson FA, Kiefe CI, Spencer FA (2014) Secular trends in occurrence of acute venous thromboembolism: the Worcester venous thromboembolism study (1985 to 2009). Am J Med 127:829–839CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Guyatt GH, Akl EA, Crowther M, Schunemann HJ, Gutterman DD, Zelman Lewis S (2012) Introduction to the ninth edition: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141(2 Suppl):48S–52SCrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Heit JA, Silverstein MD, Mohr DN, Petterson TM, Lohse CM, O’Fallon WM, Melton LJ III (2001) The epidemiology of venous thromboembolism in the community. Thromb Haemost 86(1):452–463PubMedGoogle Scholar
  8. 8.
    Spencer FA, Gore JM, Lessard D, Douketis JD, Emery C, Goldberg RJ (2008) Patient outcomes after deep vein thrombosis and pulmonary embolism: the Worcester Venous Thromboembolism Study. Arch Intern Med 168(4):425–430CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    White RH (2003) The epidemiology of venous thromboembolism. Circulation 107(23 Suppl 1):I4–I8PubMedGoogle Scholar
  10. 10.
    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(6):761–768CrossRefPubMedGoogle Scholar
  11. 11.
    Prandoni P, Noventa F, Ghirarduzzi A, Pengo V, Bernardi E, Pesavento R, Iotti M, Tormene D, Simioni P, Pagnan A (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(2):199–205CrossRefPubMedGoogle Scholar
  12. 12.
    Carrier M, Le Gal G, Wells PS, Rodger MA (2010) Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med 152(9):578–589CrossRefPubMedGoogle Scholar
  13. 13.
    Agnelli G, Becattini C (2013) Risk assessment for recurrence and optimal agents for extended treatment of venous thromboembolism. Am Soc Hematol Educ Progr 2013:471–477CrossRefGoogle Scholar
  14. 14.
    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(14):1630–1636CrossRefPubMedGoogle Scholar
  15. 15.
    Louzada ML, Carrier M, Lazo-Langner A, Dao V, Kovacs MJ, Ramsay TO, Rodger MA, Zhang J, Lee AY, Meyer G, Wells PS (2012) Development of a clinical prediction rule for risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism. Circulation 126(4):448–454CrossRefPubMedGoogle Scholar
  16. 16.
    Martinez C, Cohen AT, Bamber L, Rietbrock S (2014) Epidemiology of first and recurrent venous thromboembolism: a population-based cohort study in patients without active cancer. Thromb Haemost 112(2):255–263CrossRefPubMedGoogle Scholar
  17. 17.
    Prandoni P, Lensing AW, Piccioli A, Bernardi E, Simioni P, Girolami B, Marchiori A, Sabbion P, Prins MH, Noventa F, Girolami A (2002) Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 100(10):3484–3488CrossRefPubMedGoogle Scholar
  18. 18.
    Rodger MA, Kahn SR, Wells PS, Anderson DA, Chagnon I, Le Gal G, Solymoss S, Crowther M, Perrier A, White R, Vickars L, Ramsay T, Betancourt MT, Kovacs MJ (2008) Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ 179(5):417–426CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Tosetto A, Iorio A, Marcucci M, Baglin T, Cushman M, Eichinger S, Palareti G, Poli D, Tait RC, Douketis J (2012) Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost 10(6):1019–1025CrossRefPubMedGoogle Scholar
  20. 20.
    Spencer FA, Emery C, Lessard D, Anderson F, Emani S, Aragam J, Becker RC, Goldberg RJ (2006) The Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism. J Gen Intern Med 21(7):722–727CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Spencer FA, Lessard D, Emery C, Reed G, Goldberg RJ (2007) Venous thromboembolism in the outpatient setting. Arch Intern Med 167(14):1471–1475CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Anderson FA Jr, Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan NA, Jovanovic B, Forcier A, Dalen JE (1991) A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 151(5):933–938CrossRefPubMedGoogle Scholar
  23. 23.
    Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR (2005) Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA 293(19):2352–2361CrossRefPubMedGoogle Scholar
  24. 24.
    Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR, Turpie AG, Green D, Ginsberg JS, Wells P, MacKinnon B, Julian JA (1999) A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 340(12):901–907CrossRefPubMedGoogle Scholar
  25. 25.
    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 (2010) Risk of recurrent venous thromboembolism after a first oestrogen-associated episode. Data from the REVERSE cohort study. Thromb Haemost 104(3):498–503CrossRefPubMedGoogle Scholar
  26. 26.
    Agnelli G, Prandoni P, Santamaria MG, Bagatella P, Iorio A, Bazzan M, Moia M, Guazzaloca G, Bertoldi A, Tomasi C, Scannapieco G, Ageno W, Warfarin Optimal Duration Italian Trial Investigators (2001) Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med 345(3):165–169CrossRefPubMedGoogle Scholar
  27. 27.
    Spyropoulos AC (2009) Upper vs. lower extremity deep vein thrombosis: outcome definitions of venous thromboembolism for clinical predictor rules or risk factor analyses in hospitalized patients. J Thromb Haemost 7(6):1041–1042CrossRefPubMedGoogle Scholar
  28. 28.
    Spencer FA, Emery C, Lessard D, Goldberg RJ (2007) Upper extremity deep vein thrombosis: a community-based perspective. Am J Med 120(8):678–684CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Royston P, Altman D (1994) Regression using fractional polynomials of continuous covariates: parsimonious parametric modelling. Appl Stat 43(3):429–467CrossRefGoogle Scholar
  30. 30.
    Heit JA (2012) Predicting the risk of venous thromboembolism recurrence. Am J Hematol 87:S63–S67CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Hosmer DW, Lemeshow S, May S (2008) Applied Survival Analysis, 2nd edn. Wiley, Hoboken, NJCrossRefGoogle Scholar
  32. 32.
    Harrell FE Jr, Califf RM, Pryor DB, Lee KL, Rosati RA (1982) Evaluating the yield of medical tests. JAMA 247(18):2543–2546CrossRefPubMedGoogle Scholar
  33. 33.
    May S, Hosmer DW (2004) A cautionary note on the use of the Gronnesby and Borgan goodness-of-fit test for the Cox proportional hazards model. Lifetime Data Anal 10(3):283–291CrossRefPubMedGoogle Scholar
  34. 34.
    Spyropoulos AC, Anderson FA Jr, Fitzgerald G, Decousus H, Pini M, Chong BH, Zotz RB, Bergmann JF, Tapson V, Froehlich JB, Monreal M, Merli GJ, Pavanello R, Turpie AG, Nakamura M, Piovella F, Kakkar AK, Spencer FA (2011) Predictive and associative models to identify hospitalized medical patients at risk for venous thromboembolism. Chest 140(3):706–714CrossRefPubMedGoogle Scholar
  35. 35.
    Fox KA, Dabbous OH, Goldberg RJ, Pieper KS, Eagle KA, Werf F, Avezum A, Goodman SG, Flather MD, Anderson FA, Granger CB (2006) Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE). BMJ 333(7578):1091CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Eagle KA, Lim MJ, Dabbous OH, Pieper KS, Goldberg RJ, Van de Werf F, Goodman SG, Granger CB, Steg PG, Gore JM, Budaj A, Avezum A, Flather MD, Fox KA (2004) A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. JAMA 291(22):2727–2733CrossRefPubMedGoogle Scholar
  37. 37.
    Granger CB, Goldberg RJ, Dabbous O, Pieper KS, Eagle KA, Cannon CP, Van De Werf F, Avezum A, Goodman SG, Flather MD, Fox KA (2003) Predictors of hospital mortality in the global registry of acute coronary events. Arch Intern Med 163(19):2345–2353CrossRefPubMedGoogle Scholar
  38. 38.
    Huang W, Anderson FA, Spencer FA, Gallus A, Goldberg RJ (2013) Risk-assessment models for predicting venous thromboembolism among hospitalized non-surgical patients: a systematic review. J Thromb Thrombolysis 35(1):67–80CrossRefPubMedGoogle Scholar
  39. 39.
    Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY (2008) Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ 336(7655):1227–1231CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Spencer FA, Gurwitz JH, Schulman S, Linkins LA, Crowther MA, Ginsberg JS, Lee AY, Saczynski JS, Anand S, Lessard D, Emery C, Huang W, Goldberg RJ (2014) Venous thromboembolism in older adults: a community-based study. Am J Med 127(6):530–537CrossRefPubMedGoogle Scholar
  41. 41.
    Douketis JD, Foster GA, Crowther MA, Prins MH, Ginsberg JS (2000) Clinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. Arch Intern Med 160(22):3431–3436CrossRefPubMedGoogle Scholar
  42. 42.
    Heit JA, Lahr BD, Petterson TM, Bailey KR, Ashrani AA, Melton LJ III (2011) Heparin and warfarin anticoagulation intensity as predictors of recurrence after deep vein thrombosis or pulmonary embolism: a population-based cohort study. Blood 118(18):4992–4999CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Heit JA, Lahr BD, Ashrani AA, Petterson TM, Bailey KR (2015) Predictors of venous thromboembolism recurrence, adjusted for treatments and interim exposures: a population-based case-cohort study. Thromb Res 136:298–307CrossRefPubMedGoogle Scholar
  44. 44.
    Wiener RS, Schwartz LM, Woloshin S (2011) Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med 171(9):831–837CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Anderson FA Jr, Spencer FA (2003) Risk factors for venous thromboembolism. Circulation 107(23 Suppl 1):I9–I16PubMedGoogle Scholar
  46. 46.
    Spencer FA, Bates SM, Goldberg RJ, Lessard D, Emery C, Glushchenko A, Gore JM, White RH (2010) A population-based study of inferior vena cava filters in patients with acute venous thromboembolism. Arch Intern Med 170(16):1456–1462CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    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(9383):523–526CrossRefPubMedGoogle Scholar
  48. 48.
    Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ III (1998) Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 158(6):585–593CrossRefPubMedGoogle Scholar
  49. 49.
    White RH, Zhou H, Romano PS (1998) Length of hospital stay for treatment of deep venous thrombosis and the incidence of recurrent thromboembolism. Arch Intern Med 158(9):1005–1010CrossRefPubMedGoogle Scholar
  50. 50.
    Verso M, Agnelli G, Ageno W, Imberti D, Moia M, Palareti G, Pistelli R, Cantone V (2012) Long-term death and recurrence in patients with acute venous thromboembolism: the MASTER registry. Thromb Res 130(3):369–373CrossRefPubMedGoogle Scholar
  51. 51.
    Poli D, Palareti G (2013) Assessing recurrence risk following acute venous thromboembolism: use of algorithms. Curr Opin Pulm Med 19(5):407–412CrossRefPubMedGoogle Scholar
  52. 52.
    Altman DG, Vergouwe Y, Royston P, Moons KG (2009) Prognosis and prognostic research: validating a prognostic model. BMJ 338:b605CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Wei Huang
    • 1
  • Robert J. Goldberg
    • 2
  • Frederick A. Anderson
    • 1
  • Alexander T. Cohen
    • 3
  • Frederick A. Spencer
    • 4
  1. 1.Department of Surgery, Center for Outcomes ResearchUniversity of Massachusetts Medical SchoolWorcesterUSA
  2. 2.Department of Quantitative Health ScienceUniversity of Massachusetts Medical SchoolWorcesterUSA
  3. 3.Haematological Medicine, Guy’s and St Thomas’ HospitalsKing’s CollegeLondonUK
  4. 4.Department of MedicineMcMaster UniversityHamiltonCanada

Personalised recommendations