Background. Residual vein obstruction (RVO), the persistence of venous thrombosis with time and often after anticoagulation, may indicate a systemic prothrombotic condition. Prior studies have shown varying efficacy in using RVO as a risk factor for future venous thromboembolic (VTE) recurrence. Methods. To assess whether positive RVO imaging predicts recurrent VTE events, we performed a meta-analysis on studies in which patients with documented VTEs, anticoagulated for a minimum of 4 weeks, had repeat sonography to assess RVO and were subsequently followed for recurrent events. Results. Thirteen studies met inclusion criteria: 3531 patient VTE events with 3474 evaluable results were analyzed. The presence of RVO was associated with recurrence in all VTE (OR 1.93; 95% CI: 1.29, 2.89) and secondary VTE (OR 2.78; 95% CI: 1.41, 5.5) but not for primary VTE (OR 1.35; 95% CI: 0.87, 2.08). When cancer patients were eliminated from the secondary VTE group, there was no longer a significant association of RVO with VTE recurrence (OR 1.73; 95% CI: 0.81, 3.67) while in the subset of cancer patients, presence of RVO was associated with an increase in VTE recurrence risk (OR 5.14; 95% CI: 1.59, 16.65, ). Conclusions. We conclude that the presence of RVO is associated with recurrence in secondary VTE but not in primary VTE and that association may be driven by the subset with cancer. 1. Background Venous thromboembolism (VTE) is a common disease and long-term anticoagulation is effective in the prevention of recurrent deep venous thrombosis (DVT) and pulmonary embolism (PE). But anticoagulation is associated with bleeding complications necessitating a continuous assessment of bleeding risk versus recurrent thrombosis risk. Recent guidelines suggest that primary (unprovoked) VTE should be anticoagulated for 3 months and be evaluated for lifelong anticoagulation, whereas only 3-month anticoagulation is recommended for secondary (provoked) VTE [1–5]. In order to predict who will recur at the end of 3 months after a period of anticoagulation, clinical decision rules and laboratory surrogate markers have been developed. Current markers, however, are poor in predicting individual recurrence risk and better surrogate tests are needed [6–10]. One such test is using the presence of residual vein obstruction (RVO), after completing the period of anticoagulation, as demonstrating increased recurrence risk. However, various investigators have used different definitions for RVO [11, 12] and different studies assessing the predictability of RVO have yielded different results.
References
[1]
C. Kearon, E. A. Akl, A. J. Comerota 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, vol. 141, supplement 2, pp. e419–e494, 2012.
[2]
“Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing,” 2012.
[3]
B. A. Hutten and M. H. Prins, “Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism,” Cochrane Database of Systematic Reviews, no. 3, p. CD001367, 2000.
[4]
V. Snow, A. Qaseem, P. Barry et al., “Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians,” Annals of Internal Medicine, vol. 146, no. 3, pp. 204–210, 2007.
[5]
F. Boutitie, L. Pinede, S. Schulman 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,” British Medical Journal, vol. 342, p. d3036, 2011.
[6]
P. A. Kyrle, F. R. Rosendaal, and S. Eichinger, “Risk assessment for recurrent venous thrombosis,” The Lancet, vol. 376, no. 9757, pp. 2032–2039, 2010.
[7]
P. A. Kyrle, E. Minar, M. Hirschl et al., “High plasma levels of factor VIII and the risk of recurrent venous thromboembolism,” The New England Journal of Medicine, vol. 343, no. 7, pp. 457–462, 2000.
[8]
B. Cosmi, C. Legnani, A. Tosetto 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, vol. 115, no. 3, pp. 481–488, 2010.
[9]
J. B. Segal, D. J. Brotman, A. J. Necochea 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,” Journal of the American Medical Association, vol. 301, no. 23, pp. 2472–2485, 2009.
[10]
J.-L. P. Brouwer, W. M. Lijfering, M. K. T. Kate, H. C. Kluin-Nelemans, N. J. G. M. Veeger, and J. Van Der Meer, “High long-term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C or antithrombin,” Thrombosis and Haemostasis, vol. 101, no. 1, pp. 93–99, 2009.
[11]
P. Prandoni, A. W. A. Lensing, M. H. Prins et al., “Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism,” Annals of Internal Medicine, vol. 137, no. 12, pp. 955–960, 2002.
[12]
S. Siragusa, A. Malato, R. Anastasio et al., “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, vol. 112, no. 3, pp. 511–515, 2008.
[13]
B. Cosmi, C. Legnani, A. Iorio et al., “Residual venous obstruction, alone and in combination with D-Dimer, as a risk factor for recurrence after anticoagulation withdrawal following a first idiopathic deep vein thrombosis in the prolong study,” European Journal of Vascular and Endovascular Surgery, vol. 39, no. 3, pp. 356–365, 2010.
[14]
S. Siragusa, A. Malato, G. Saccullo et al., “Residual vein thrombosis for assessing duration of anticoagulation after unprovoked deep vein thrombosis of the lower limbs: the extended DACUS study,” American Journal of Hematology, vol. 86, no. 11, pp. 914–917, 2011.
[15]
B. Cosmi, C. Legnani, M. Cini, G. Guazzaloca, and G. Palareti, “D-dimer levels in combination with residual venous obstruction and the risk of recurrence after anticoagulation withdrawal for a first idiopathic deep vein thrombosis,” Thrombosis and Haemostasis, vol. 94, no. 5, pp. 969–974, 2005.
[16]
G. Le Gal, M. Carrier, M. J. Kovacs et al., “Residual vein obstruction as a predictor for recurrent thromboembolic events after a first unprovoked episode: data from the REVERSE cohort study,” Journal of Thrombosis and Haemostasis, vol. 9, no. 6, pp. 1126–1132, 2011.
[17]
P. Prandoni, M. H. Prins, A. W. A. Lensing et al., “Annals of internal medicine, residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis, a randomized trial,” Annals of Internal Medicine, vol. 150, no. 9, pp. 577–585, 2009.
[18]
B. Cosmi, C. Legnani, M. Cini, G. Guazzaloca, and G. Palareti, “The role of D-dimer and residual venous obstruction in recurrence of venous thromboembolism after anticoagulation withdrawal in cancer patients,” Haematologica, vol. 90, no. 5, pp. 713–715, 2005.
[19]
B. Cosmi, C. Legnani, M. Cini, G. Guazzaloca, and G. Palareti, “D-dimer and residual vein obstruction as risk factors for recurrence during and after anticoagulation withdrawal in patients with a first episode of provoked deep-vein thrombosis,” Thrombosis and Haemostasis, vol. 105, no. 5, pp. 837–845, 2011.
[20]
C. Kearon, M. Gent, J. Hirsh et al., “A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism,” The New England Journal of Medicine, vol. 340, no. 12, pp. 901–907, 1999.
[21]
C. Kearon, J. S. Ginsberg, D. R. Anderson et al., “Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor,” Journal of Thrombosis and Haemostasis, vol. 2, no. 5, pp. 743–749, 2004.
[22]
D. Poli, E. Antonucci, G. Ciuti, R. Abbate, and D. Prisco, “Combination of D-dimer, F1+2 and residual vein obstruction as predictors of VTE recurrence in patients with first VTE episode after OAT withdrawal,” Journal of Thrombosis and Haemostasis, vol. 6, no. 4, pp. 708–710, 2008.
[23]
L. Young, P. Ockelford, D. Milne, V. Rolfe-Vyson, S. Mckelvie, and P. Harper, “Post-treatment residual thrombus increases the risk of recurrent deep vein thrombosis and mortality,” Journal of Thrombosis and Haemostasis, vol. 4, no. 9, pp. 1919–1924, 2006.
[24]
S. Siragusa, A. Malato, D. Mascheroni, et al., “The optimal duration of anticoagulant therapy in patients with Cancer-related deep vein thrombosis: the advantage of using residual vein thrombosis (The Cancer-DACUS Study),” 2010.
[25]
P. Prandoni, A. W. A. Lensing, A. Cogo et al., “The long-term clinical course of acute deep venous thrombosis,” Annals of Internal Medicine, vol. 125, no. 1, pp. 1–7, 1996.
[26]
P.-O. Hansson, J. S？rbo, and H. Eriksson, “Recurrent venous thromboembolism after deep vein thrombosis: Incidence and risk factors,” Archives of Internal Medicine, vol. 160, no. 6, pp. 769–774, 2000.
[27]
P. Prandoni, S. Villalta, P. Bagatella et al., “The clinical course of deep-vein thrombosis. Prospective long-term follow-up of 528 symptomatic patients,” Haematologica, vol. 82, no. 4, pp. 423–428, 1997.
[28]
N. Labropoulos, J. Jen, H. Jen, A. P. Gasparis, and A. K. Tassiopoulos, “Recurrent deep vein thrombosis: long-term incidence and natural history,” Annals of Surgery, vol. 251, no. 4, pp. 749–753, 2010.
[29]
P. Prandoni, F. Noventa, A. Ghirarduzzi 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 1,626 patients,” Haematologica, vol. 92, no. 2, pp. 199–205, 2007.
[30]
C. S. Landefeld and R. J. Beyth, “Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention,” American Journal of Medicine, vol. 95, no. 3, pp. 315–328, 1993.
[31]
M. Carrier, G. Le Gal, P. S. Wells, and M. A. Rodger, “Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism,” Annals of Internal Medicine, vol. 152, no. 9, pp. 578–589, 2010.
[32]
F. Piovella, L. Crippa, M. Barone et al., “Normalization rates of compression ultrasonography in patients with a first episode of deep vein thrombosis of the lower limbs: association with DVT recurrence and new thrombosis,” Haematologica, vol. 87, no. 5, pp. 515–522, 2002.
[33]
W. Ageno, L. Steidl, E. Piantanida et al., “Predictors of residual venous obstruction after deep vein thrombosis of the lower limbs: a prospective cohort study,” Thrombosis Research, vol. 108, no. 4, pp. 203–207, 2002.
[34]
M. Galli, W. Ageno, A. Squizzato et al., “Residual venous obstruction in patients with a single episode of deep vein thrombosis and in patients with recurrent deep vein thrombosis,” Thrombosis and Haemostasis, vol. 94, no. 1, pp. 93–95, 2005.
[35]
L. A. Killewich, R. F. Macko, K. Cox et al., “Regression of proximal deep venous thrombosis is associated with fibrinolytic enhancement,” Journal of Vascular Surgery, vol. 26, no. 5, pp. 861–868, 1997.
[36]
M. M. Bern and N. McCarthy, “Failure to lyse venous thrombi because of elevated plasminogen activator inhibitor 1 (PAI-1) and 4G polymorphism of its promotor genome (The PAI-1/4G syndrome),” Clinical and Applied Thrombosis/Hemostasis, vol. 16, no. 5, pp. 574–578, 2010.
[37]
M. Carrier, M. A. Rodger, P. S. Wells, M. Righini, and G. Le Gal, “Residual vein obstruction to predict the risk of recurrent venous thromboembolism in patients with deep vein thrombosis: a systematic review and meta-analysis,” Journal of Thrombosis and Haemostasis, vol. 9, no. 6, pp. 1119–1125, 2011.
[38]
M. Tan, I. C. M. Mos, F. A. Klok, and M. V. Huisman, “Residual venous thrombosis as predictive factor for recurrent venous thromboembolim in patients with proximal deep vein thrombosis: a sytematic review,” British Journal of Haematology, vol. 153, no. 2, pp. 168–178, 2011.
