Residual Venous Obstruction as an Indicator of Clinical Outcomes following Deep Vein Thrombosis: A Management Study

Abstract

Background Residual venous obstruction (RVO) is considered a risk factor of recurrence and possibly other clinical outcomes following deep vein thrombosis (DVT). Current guidelines do not support an RVO-tailored duration of anticoagulant therapy; contemporary data of such management strategies are scarce. We aimed to evaluate an RVO-based management strategy and to assess associations of RVO with recurrence, post-thrombotic syndrome (PTS), arterial events and cancer. To gain further insight, D-dimer levels were measured 1 month after stopping anticoagulant therapy.

Methods Consecutive patients with symptomatic, proximal DVT were treated in a 2-year clinical care pathway (CCP) at Maastricht University Medical Center and were followed up to 5 years. RVO was assessed at the end of regular duration of anticoagulant therapy, which was extended once if RVO was detected. The study was approved by the medical ethics committee.

Result From a total of 825 patients, 804 patients (97.5%) completed the CCP and 755 (93.9%) were available for extended follow-up. Most patients (76.5%) stopped anticoagulant therapy. Incidence rates of recurrence, PTS, arterial events, and cancer were 4.4, 11.9, 1.7, and 1.8 per 100 patient-years, respectively. RVO was independently associated with PTS (hazard ratio [HR]: 1.66 [1.19–2.32]) and arterial events (HR: 2.07 [1.18–3.65]), but not with recurrence or cancer. High D-dimer was associated with recurrence (HR: 3.51 [2.24–5.48]).

Conclusion Our RVO-based management strategy might have attenuated the association of RVO with recurrence. In addition, RVO identified patients at increased risk of PTS and arterial events, which might be used to identify patients in need of alternative treatment strategies.

Keywords

cancer - deep vein thrombosis - post-thrombotic syndrome - residual venous obstruction - venous thromboembolism

Authors' Contribution

A.J.T.C-H. implemented the CCP. A.J.T.C-H. and B.M.M.K. collected the data. A.F.J.I. and A.P.R. drafted the analysis plan and conducted the statistical analysis under supervision of A.J.T.C-H. A.F.J.I. drafted the article. A.F.J.I., A.J.T.C-H., B.M.M.K., A.P.R., and H.T.C. critically revised the article. A.J.T.C-H. gave final approval of the version to be published.

Publikationsverlauf

Eingereicht: 09. September 2022

Angenommen: 14. März 2023

Accepted Manuscript online:
21. März 2023

Artikel online veröffentlicht:
12. April 2023

• References

• 1 Khan F, Tritschler T, Kahn SR, Rodger MA. Venous thromboembolism. Lancet 2021; 398 (10294): 64-77
• 2 O'Brien EC, Holmes DN, Thomas LE. et al. Prognostic significance of nuisance bleeding in anticoagulated patients with atrial fibrillation. Circulation 2018; 138 (09) 889-897
• 3 Prins MH, Guillemin I, Gilet H. et al. Scoring and psychometric validation of the Perception of Anticoagulant Treatment Questionnaire (PACT-Q). Health Qual Life Outcomes 2009; 7: 30
• 4 Stevens SM, Woller SC, Baumann Kreuziger L. et al. Executive summary: Antithrombotic therapy for VTE disease: Second update of the CHEST guideline and expert panel report. Chest 2021; 160 (06) 2247-2259
• 5 Kakkos SK, Gohel M, Baekgaard N. et al; Esvs Guidelines Committee. Editor's choice - European Society for Vascular Surgery (ESVS) 2021 clinical practice guidelines on the management of venous thrombosis. Eur J Vasc Endovasc Surg 2021; 61 (01) 9-82
• 6 Ortel TL, Neumann I, Ageno W. et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020; 4 (19) 4693-4738
• 7 McCormack T, Harrisingh MC, Horner D, Bewley S. Guideline Committee. Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing. BMJ 2020; 369: m1565
• 8 Prins MH, Lensing AWA, Prandoni P. et al. Risk of recurrent venous thromboembolism according to baseline risk factor profiles. Blood Adv 2018; 2 (07) 788-796
• 9 Ageno W, Samperiz A, Caballero R. et al; RIETE investigators. Duration of anticoagulation after venous thromboembolism in real world clinical practice. Thromb Res 2015; 135 (04) 666-672
• 10 Cate VT, Lensing AWA, Weitz JI. et al. Extended anticoagulant therapy in venous thromboembolism: a balanced, fractional factorial, clinical vignette-based study. Haematologica 2019; 104 (10) e474 –e477
• 11 Palareti G, Bignamini A, Cini M. et al; WHITE study group. Unprovoked or provoked venous thromboembolism: not the prevalent criterion to decide on anticoagulation extension in clinical practice of various countries-the prospective, international, observational WHITE study. Intern Emerg Med 2022; 17 (01) 71-82
• 12 Carrier M, Rodger MA, Wells PS, Righini M, LE Gal G. Residual vein obstruction to predict the risk of recurrent venous thromboembolism in patients with deep vein thrombosis: a systematic review and meta-analysis. J Thromb Haemost 2011; 9 (06) 1119-1125
• 13 Tan M, Mos ICM, Klok FA, Huisman MV. Residual venous thrombosis as predictive factor for recurrent venous thromboembolism in patients with proximal deep vein thrombosis: a systematic review. Br J Haematol 2011; 153 (02) 168-178
• 14 ten Cate-Hoek AJ, Henke PK, Wakefield TW. The post thrombotic syndrome: Ignore it and it will come back to bite you. Blood Rev 2016; 30 (02) 131-137
• 15 Appelen D, van Loo E, Prins MH. et al. Compression therapy for prevention of post-thrombotic syndrome. Cochrane Database Syst Rev Wiley 2017; 9 (09) CD004174
• 16 Becattini C, Vedovati MC, Ageno W, Dentali F, Agnelli G. Incidence of arterial cardiovascular events after venous thromboembolism: a systematic review and a meta-analysis. J Thromb Haemost 2010; 8 (05) 891-897
• 17 Carrier M, Le Gal G, Wells PS, Fergusson D, Ramsay T, Rodger MA. Systematic review: the Trousseau syndrome revisited: should we screen extensively for cancer in patients with venous thromboembolism?. Ann Intern Med 2008; 149 (05) 323-333
• 18 Dronkers CEA, Mol GC, Maraziti G. et al. Predicting post-thrombotic syndrome with ultrasonographic follow-up after deep vein thrombosis: a systematic review and meta-analysis. Thromb Haemost 2018; 118 (08) 1428-1438
• 19 Prandoni P, Lensing AWA, Prins MH. et al. The impact of residual thrombosis on the long-term outcome of patients with deep venous thrombosis treated with conventional anticoagulation. Semin Thromb Hemost 2015; 41 (02) 133-140
• 20 Prandoni P, Lensing AWA, Prins MH. et al. Elastic compression stockings for prevention of the post-thrombotic syndrome in patients with and without residual vein thrombosis and/or popliteal valve reflux. [Internet] Haematologica 2022; 107 (01) 303-306
• 21 Prandoni P, Lensing AWA, Prins MH. et al. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 2002; 137 (12) 955-960
• 22 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 (05) 515-522
• 23 Nagler M, Ten Cate H, Prins MH, Ten Cate-Hoek AJ. Risk factors for recurrence in deep vein thrombosis patients following a tailored anticoagulant treatment incorporating residual vein obstruction. Res Pract Thromb Haemost 2018; 2 (02) 299-309
• 24 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 (01) 172-179
• 25 Tan M, Bornais C, Rodger M. Interobserver reliability of compression ultrasound for residual thrombosis after first unprovoked deep vein thrombosis. J Thromb Haemost 2012; 10 (09) 1775-1782
• 26 Hassen S, Barrellier MT, Seinturier C. et al. High percentage of non-diagnostic compression ultrasonography results and the diagnosis of ipsilateral recurrent proximal deep vein thrombosis: a rebuttal. J Thromb Haemost 2011; 9 (02) 414-418
• 27 Compare 2 Proportions: 2-Sample, 2-Sided Equality [Internet] Statpages.info. 2023 [cited 2023 Aug 2]. Accessed March 30, 2023 at: https://statpages.info/#Power
• 28 Palareti G, Cosmi B, Legnani C. et al; DULCIS (D-dimer and ULtrasonography in Combination Italian Study) Investigators. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood 2014; 124 (02) 196-203
• 29 Prandoni P, Vedovetto V, Ciammaichella M. et al; Morgagni Investigators. Residual vein thrombosis and serial D-dimer for the long-term management of patients with deep venous thrombosis. Thromb Res 2017; 154: 35-41
• 30 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 Duration of Anticoagulation based on Compression UltraSonography (DACUS) study. Blood 2008; 112 (03) 511-515
• 31 Prandoni P, Prins MH, Lensing AWA. et al; AESOPUS Investigators. Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. Ann Intern Med 2009; 150 (09) 577-585
• 32 Meissner MH, Zierler BK, Bergelin RO, Chandler WL, Strandness Jr DE. Coagulation, fibrinolysis, and recanalization after acute deep venous thrombosis. J Vasc Surg 2002; 35 (02) 278-285
• 33 Mukhopadhyay S, Johnson TA, Duru N. et al. Fibrinolysis and inflammation in venous thrombus resolution. Front Immunol 2019; 10: 1348
• 34 Bouman AC, Smits JJM, Ten Cate H, Ten Cate-Hoek AJ. Markers of coagulation, fibrinolysis and inflammation in relation to post-thrombotic syndrome. J Thromb Haemost 2012; 10 (08) 1532-1538
• 35 Prandoni P. Is there a link between venous and arterial thrombosis? A reappraisal. Intern Emerg Med 2020; 15 (01) 33-36
• 36 Robertson L, Yeoh SE, Ramli A. Secondary prevention of recurrent venous thromboembolism after initial oral anticoagulation therapy in patients with unprovoked venous thromboembolism. Cochrane Database Syst Rev 2017; 12 (12) CD011088
• 37 Noumegni SR, Le Mao R, de Moreuil C. et al. Anticoagulation for VTE: Impact on the risk of major adverse cardiovascular events. Chest 2022; 162 (05) 1147-1162
• 38 Becattini C, Vedovati MC. Time to use direct oral anticoagulants to prevent recurrences and major acute cardiovascular events after VTE?. Chest 2022; 162 (05) 959-960
• 39 Nicklas JM, Gordon AE, Henke PK. Resolution of deep venous thrombosis: Proposed immune paradigms. Int J Mol Sci 2020; 21 (06) 2080
• 40 Bradbury C, Fletcher K, Sun Y. et al. A randomised controlled trial of extended anticoagulation treatment versus standard treatment for the prevention of recurrent venous thromboembolism (VTE) and post-thrombotic syndrome in patients being treated for a first episode of unprovoked VTE (the ExACT study). Br J Haematol 2020; 188 (06) 962-975
• 41 Schulman S, Lindmarker P, Holmström M. et al. Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. J Thromb Haemost 2006; 4 (04) 734-742
• 42 Bouman AC, Atalay S, Ten Cate H, Ten Wolde M, Ten Cate-Hoek AJ. Biomarkers for post-thrombotic syndrome. J Vasc Surg Venous Lymphat Disord 2014; 2 (01) 79-88.e3
• 43 Prandoni P, Ciammaichella M, Mumoli N. et al; Veritas Investigators. An association between residual vein thrombosis and subclinical atherosclerosis: cross-sectional study. Thromb Res 2017; 157: 16-19