Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Thrombosis Journal
Published in: Thrombosis Journal 1/2015

Open Access 01-12-2015 | Review

Should lifelong anticoagulation for unprovoked venous thromboembolism be revisited?

Authors: Otto Moodley, Hadi Goubran

Published in: Thrombosis Journal | Issue 1/2015

Login to get access

Abstract

Venous thromboembolism [VTE] is a common medical condition that has significant morbidity and mortality. Although stringent guidelines recommend lifelong anticoagulation for patients with unprovoked VTE, the optimal management strategy for their long term treatment remains controversial.
Whereas in cancer-associated VTE and second unprovoked VTE lifelong anticoagulation is universally accepted, a careful analysis of the benefit vs. risk of long-term anticoagulation following a first unprovoked VTE should be considered as case fatality rates [CFR] from VTE appear more pronounced in the first few months. The CFR from major bleeding remains constant throughout therapy. Therefore, the risk of bleeding may be underestimated over longer treatment periods relative to the morbidity of recurrent VTE which appears to peak in the first year. The current review highlights the balance between the recurrence risk and bleeding risks in the era of direct oral anticoagulants.
Vitamin K antagonists have been the standard of care for over 50 years bearing significant bleeding risks. The new oral anticoagulants [NOACs] have shown similar efficacy and perhaps a questionable improved safety profile when compared to warfarin.
Aspirin has historically not been a useful agent in the management of VTE. However, two recent trials [WARFASA and ASPIRE] showed a likely 20-30 % risk reduction when compared to placebo for recurrent VTE after initial anticoagulation. The risk of major hemorrhage was low in both trials.
With the emergence of NOACs and the increased utility of aspirin, there are multiple therapeutic options for long term management for VTE. Given comparable efficacy and improved safety of NOACs and aspirin, the risk benefit of anticoagulation is improving.
A risk stratification model may help identifying patients at high risk for recurrence necessitating a lifelong anticoagulation. This cohort should be separated from a low risk group that may benefit from clinical observation, aspirin or NOACs.
Prospective clinical trials are needed to support these clinical observations.
Literature
1.
White R. Four topics in venous thromboembolism: the epidemiology of venous thromboembolism. Circulation. 2003;107:I-4–8.CrossRef
2.
Zhu T, Martinez I, Emmerich J. Venous thromboembolism: mechanisms, treatment, and public awareness. Arterioscler Thromb Vasc Biol. 2009;29:298–310.CrossRefPubMed
3.
4.
Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, 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(2 Suppl):e419S–94S.PubMedCentralPubMed
5.
Zhu T, Martinez I, Emmerich J. Venous thromboembolism: risk factors for recurrence. Arterioscler Thromb Vasc Biol. 2009;29:298–310.CrossRefPubMed
6.
7.
Caprini JA, Tapson VF, Hyers TM, Waldo AL, Wittkowsky AK, Friedman R, et al. Treatment of venous thromboembolism: adherence to guidelines and impact of physician knowledge, attitudes, and beliefs. J Vasc Surg. 2005;42(4):726–33.CrossRefPubMed
8.
Konstantinides S, Goldhaber SZ. Pulmonary embolism risk assessment and management. Eur Heart J. 2012;33(24):3014–22.CrossRefPubMed
9.
10.
Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011;365:2002–12.CrossRefPubMed
11.
Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation. 2007;115:2689–96.CrossRefPubMed
12.
Chen SY, Wu N, Gulseth M, LaMori J, Bookhart BK, Boulanger L, et al. One-year adherence to warfarin treatment for venous thromboembolism in high-risk patients and its association with long-term risk of recurrent events. J Manag Care Pharm. 2013;19(4):291–301.CrossRefPubMed
13.
Halperin JL, Malhotra JK. Implications of New oral anticoagulants for stroke prophylaxis in elderly patients with atrial fibrillation. Annals of long-term care. 2014;22(5):15–6.
14.
van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103:1116–27.CrossRefPubMed
15.
Perzborn E, Roehrig S, Straub A, Kubitza D, Misselwitz F. The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat Rev Drug Discov. 2011;10:61–75.CrossRefPubMed
16.
Wong PC, Pinto DJ, Zhang D. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J Thromb Thrombolysis. 2011;31:478–92.PubMedCentralCrossRefPubMed
17.
18.
Prandoni P, Barbar S, Milan M, Vedovetto V, Pesavento R. The risk of recurrent thromboembolic disorders in patients with unprovoked venous thromboembolism: new scenarios and opportunities. Eur J Intern Med. 2014;25(1):25–30.CrossRefPubMed
19.
Martinez C, Cohen AT, Bamber L, Rietbrock S. Epidemiology of first and recurrent venous thromboembolism: a population-based cohort study in patients without active cancer. Thromb Haemost. 2014;112(2):255–63.CrossRefPubMed
20.
Tagalakis V, Kondal D, Ji Y, Boivin JF, Moride Y, Ciampi A, et al. Men had a higher risk of recurrent venous thromboembolism than women: a large population study. Gend Med. 2012;9(1):33–43.CrossRefPubMed
21.
Ljungqvist M, Sonnevi K, Bergendal A, Holmström M, Kieler H, Lärfars G. Risk factors for recurrent venous thromboembolism in young and middle-aged women. Thromb Res. 2014;133(5):762–7.CrossRefPubMed
22.
Nakamura M, Miyata T, Ozeki Y, Takayama M, Komori K, Yamada N, et al. Current venous thromboembolism management and outcomes in Japan. Circ J. 2014;78(3):708–17.CrossRefPubMed
23.
Middeldorp S, Prins MH, Hutten BA. Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism. Cochrane Database Syst Rev. 2014;8:CD001367.PubMed
24.
Galanaud JP, Sevestre MA, Genty C, Kahn SR, Pernod G, Rolland C, et al. Incidence and predictors of venous thromboembolism recurrence after a first isolated distal deep vein thrombosis. J Thromb Haemost. 2014;12(4):436–43.CrossRefPubMed
25.
Spencer FA, Gore JM, Lessard D, Emery C, Pacifico L, Reed G, et al. Venous thromboembolism in the elderly. A community-based perspective. Thromb Haemost. 2008;100(5):780–8.PubMedCentralPubMed
26.
Hirschl M, Kundi M. New oral anticoagulants in the treatment of acute venous thromboembolism - a systematic review with indirect comparisons. Vasa. 2014;43(5):353–64.CrossRefPubMed
27.
Sánchez Muñoz-Torrero JF, Lorenzo-Hernández A, Trujillo-Santos J, Fernández-Capitán C, Zamorano J, Monreal M. Natural history of venous thromboembolism in patients from the Mediterranean region. A systematic review. Rev Clin Esp. 2014;214(4):184–91.CrossRefPubMed
28.
Lindh JD, Holm L, Dahl ML, Alfredsson L, Rane A. Incidence and predictors of severe bleeding during warfarin treatment. J Thromb Thrombolysis. 2008;25(2):151–9. Epub 2007 May 20.CrossRefPubMed
29.
Khan F, Datta YH Risk of bleeding during long-term anticoagulation with warfarin: a tertiary care center experience. Blood Coagul Fibrinolysis. 2014 Aug 23. [Epub ahead of print].
30.
Hollowell J, Ruigómez A, Johansson S, Wallander MA, García-Rodríguez LA. The incidence of bleeding complications associated with warfarin treatment in general practice in the United Kingdom. Br J Gen Pract. 2003;53(489):312–4.PubMedCentralPubMed
31.
32.
Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51.CrossRefPubMed
33.
Castellucci LA, Cameron C, Le Gal G, Rodger MA, Coyle D, Wells PS, et al. Clinical and safety outcomes associated with treatment of acute venous thromboembolism: a systematic review and meta-analysis. JAMA. 2014;312(11):1122–35.CrossRefPubMed
34.
Beyer-Westendorf J, Förster K, Pannach S, Ebertz F, Gelbricht V, Thieme C, et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood. 2014;124(6):955–62.PubMedCentralCrossRefPubMed
35.
Holster L, Valkhoff V, Kuipers E, Tjwa E. New oral anticoagulants increase risk of gastrointestinal bleeding: a systemiatic review and meta-analysis. Gastroenterology. 2013;45:105–12.CrossRef
36.
Rodger M, Carrier M, Gandara E, Le Gal G. Unprovoked venous thromboembolism: Short term or indefinite anticoagulation? Balancing long-term risk and benefit. Blood Rev. 2010;24(4–5):171–8.CrossRefPubMed
37.
Lecumberri R, Alfonso A, Jiménez D, Fernández Capitán C, Prandoni P, Wells PS, et al. Dynamics of case-fatalilty rates of recurrent thromboembolism and major bleeding in patients treated for venous thromboembolism. Thromb Haemost. 2013;110(4):834–43.CrossRefPubMed
38.
Andresen MS, Sandven I, Brunborg C, Njaastad AM, Strekerud F, Abdelnoor M, et al. Mortality and recurrence after treatment of VTE: long term follow-up of patients with good life-expectancy. Thromb Res. 2011;127(6):540–6.CrossRefPubMed
39.
de Jong PG, Coppens M, Middeldorp S. Duration of anticoagulant therapy for venous thromboembolism: balancing benefits and harms on the long term. Br J Haematol. 2012;158(4):433–41.CrossRefPubMed
40.
Kyrle PA. Predicting recurrent venous thromboembolism in cancer: is it possible? Thromb Res. 2014;133 Suppl 2:S17–22.CrossRefPubMed
41.
van Hylckama Vlieg A, Flinterman LE, Bare LA, Cannegieter SC, Reitsma PH, Arellano AR, Tong CH, Devlin JJ, Rosendaal FR. Genetic Variations Associated with Recurrent Venous Thrombosis. Circ Cardiovasc Genet. 2014. [Epub ahead of print].
42.
Donadini MP, Ageno W, Antonucci E, Cosmi B, Kovacs MJ, Le Gal G, 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(1):172–9. doi:10.​1160/​TH13-04-0336. Epub 2013 Oct 24.CrossRefPubMed
43.
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(6):1119–25.CrossRefPubMed
44.
Janakiram M, Sullivan M, Shcherba M, Guo S, Billett HH. A systematic review of the utility of residual vein obstruction studies in primary and secondary venous thrombosis. Thrombosis. 2013;2013:247913.PubMedCentralCrossRefPubMed
45.
LE Gal G, Carrier M, Kovacs MJ, Betancourt MT, Kahn SR, Wells PS, et al. Residual vein obstruction as a predictor for recurrent thromboembolic events after a first unprovoked episode: data from the REVERSE cohort study. J Thromb Haemost. 2011;9(6):1126–32.CrossRefPubMed
46.
Cosmi B, Legnani C, Iorio A, Pengo V, Ghirarduzzi A, Testa S, 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. Eur J Vasc Endovasc Surg. 2010;39(3):356–65.CrossRefPubMed
47.
Cosmi B, Legnani C, Cini M, Guazzaloca G, Palareti G. The role of D-dimer and residual venous obstruction in recurrence of venous thromboembolism after anticoagulation withdrawal in cancer patients. Haematologica. 2005;90(5):713–5.PubMed
48.
Poli D, Cenci C, Antonucci E, Grifoni E, Arcangeli C, Prisco D, et al. Risk of recurrence in patients with pulmonary embolism: predictive role of D-dimer and of residual perfusion defects on lung scintigraphy. Thromb Haemost. 2013;109(2):181–6.CrossRefPubMed
49.
50.
Mannucci PM, Franchini M. The real value of thrombophilia markers in identifying patients at high risk of venous thromboembolism. Expert Rev Hematol. 2014 Sep 18:1–9. [Epub ahead of print].
51.
Wu O, Robertson L, Twaddle S, Lowe GD, Clark P, Greaves M, et al. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Health Technol Assess. 2006;10(11):1–110.CrossRefPubMed
52.
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(1):7–12.PubMed
53.
Palareti G, Legnani C, Cosmi B, Valdré L, Lunghi B, Bernardi F, et al. Predictive value of D-dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idiopathic event and in carriers of congenital thrombophilia. Circulation. 2003;108(3):313–8.CrossRefPubMed
54.
Eichinger S, Minar E, Bialonczyk C, Hirschl M, Quehenberger P, Schneider B, et al. D-dimer levels and risk of recurrent venous thromboembolism. JAMA. 2003;290(8):1071–4.CrossRefPubMed
55.
Palareti G, Cosmi B, Legnani C, Antonucci E, De Micheli V, Ghirarduzzi A, et al. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood. 2014;124(2):196–203.CrossRefPubMed
56.
Kearon C, Spencer FA, O’Keeffe D, Parpia S, Schulman S, Baglin T, et al. D-Dimer testing to select patients with a first unprovoked venous thromboembolism who can stop anticoagulant therapy. Ann Intern Med. 2015;162:27–34.CrossRefPubMed
57.
Lind M, Boman K, Johansson L, Nilsson TK, Järvholm LS, Jansson JH. D-dimer predicts major bleeding, cardiovascular events and all-cause mortality during warfarin treatment. Clin Biochem. 2014;47(7–8):570.CrossRefPubMed
58.
Rodger MA, Kahn SR, Wells PS, et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ. 2008;179:417–26.PubMedCentralCrossRefPubMed
59.
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;366:1019–25.CrossRef
60.
Eichinger S, Heinze G, Jandeck LM, Kyrle PA. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model. Circulation. 2010;121(14):1630–6.CrossRefPubMed
61.
Kyrle PA, Eischer L. Predicting the risk of recurrent venous thromboembolism. The Austrian study on recurrent venous thromboembolism (AUREC). Hamostaseologie. 2013;33(3):201–9.CrossRefPubMed
62.
Becattini C, Agnelli G, Schenone A, Eichinger S, Bucherini E, Silingardi M, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012;366(21):1959–67.CrossRefPubMed
63.
Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Ockelford P, et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012;367(21):1979–87.CrossRefPubMed
64.
Simes J, Becattini C, Agnelli G, Eikelboom JW, Kirby AC, Mister R, et al. Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE Collaboration. Circulation. 2014;130(13):1062–71.CrossRefPubMed
Metadata
Title
Should lifelong anticoagulation for unprovoked venous thromboembolism be revisited?
Authors
Otto Moodley
Hadi Goubran
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Thrombosis Journal / Issue 1/2015
Electronic ISSN: 1477-9560
DOI
https://doi.org/10.1186/s12959-015-0063-z

Other articles of this Issue 1/2015

Thrombosis Journal 1/2015 Go to the issue

Case report

The role of soluble fibrin during anticoagulant therapy: a case report

Original basic research

Original approach for thrombolytic therapy in patients with Ilio-femoral deep vein thrombosis : 2 years follow-up

Original clinical investigation

Family history of venous thromboembolism is a risk factor for venous thromboembolism in combined oral contraceptive users: a nationwide case-control study

Original clinical investigation

Safety and efficacy of switching from low molecular weight heparin to dabigatran in patients undergoing elective total hip or knee replacement surgery

Case report

Unsuccessful percutaneous mechanical thrombectomy in fibrin-rich high-risk pulmonary thromboembolism

Original basic research

Cost-effectiveness analysis of treatment of venous thromboembolism with rivaroxaban compared with combined low molecular weight heparin/vitamin K antagonist

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits