Heart, Lung and Circulation

Factor Xa Inhibition for the Treatment of Venous Thromboembolism Associated With Cancer: A Meta-Analysis of the Randomised Controlled Trials

Published:December 09, 2021DOI:


      Venous thromboembolism (VTE) is a common cause of morbidity and mortality in cancer patients. Until recently, guidelines recommended the use of low-molecular weight heparin (LMWH) as standard of care for VTE in patients with cancer. Despite the proven efficacy of direct oral anticoagulants (DOACs) for treatment of VTE, there is equipoise supporting their use in cancer patients.


      A systematic review of PubMed, Medline and EMBASE identified four randomised controlled trials (RCTs) in patients with cancer and VTE comparing a factor Xa inhibitor (FXaI) to LMWH. A meta-analysis was performed with a primary outcome of VTE recurrence and key secondary outcomes of major bleeding, clinically relevant non-major bleeding (CRNMB) and gastrointestinal (GI) bleeding.


      Four RCTs with 2,907 patients were included. 1,451 patients were randomised to FXaI and 1,456 to LMWH. VTE recurrence was lower in the FXaI group (RR 0.62, 95%CI 0.44–0.87; p=0.01; I2=24.90), with an absolute risk difference of -4% equating to a number needed to treat of 25 for prevention of recurrent VTE with FXaI. No significant difference in major bleeding was noted between groups (RR 1.33, 95%CI 0.84–2.11; p=0.23). Rates of GI bleeding (RR 1.87, 95%CI 1.06–3.29; p=0.03) and CRNMB (RR 1.57, 95%CI 1.11–2.23; p=0.01) were greater with FXaIs.


      In patients with cancer and VTE, the rate of VTE recurrence was significantly lower with FXaI than with LMWH without an increased risk of major bleeding. Our data supports the use of FXaIs as the standard of care for the treatment of VTE in this population.


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        • Farge D.
        • Frere C.
        • Connors J.M.
        • Ay C.
        • Khorana A.A.
        • Munoz A.
        • et al.
        2019 International Clinical Practice Guidelines for the Treatment and Prophylaxis of Venous Thromboembolism in Patients Wth Cancer.
        Lancet Oncol. 2019; 20: e566-e581
        • Heit J.A.
        • Spencer F.A.
        • White R.H.
        The epidemiology of venous thromboembolism.
        J Thromb Thrombolysis. 2016; 41: 3-14
        • Lee A.Y.
        • Levine M.N.
        • Baker R.I.
        • Bowden C.
        • Kakkar A.K.
        • Prins M.
        • et al.
        Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.
        N Engl J Med. 2003; 349: 146-153
        • Agnelli G.
        • Buller H.R.
        • Cohen A.
        • Curto M.
        • Gallus A.S.
        • Johnson M.
        • et al.
        Oral apixaban for the treatment of acute venous thromboembolism.
        N Engl J Med. 2013; 369: 799-808
        • Prins M.H.
        • Lensing A.W.
        • Brighton T.A.
        • Lyons R.M.
        • Rehm J.
        • Trajanovic M.
        • et al.
        Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials.
        Lancet Haematol. 2014; 1: e37-e46
        • Goldhaber S.Z.
        • Schellong S.
        • Kakkar A.
        • Eriksson H.
        • Feuring M.
        • Kreuzer J.
        • et al.
        Treatment of acute pulmonary embolism with dabigatran versus warfarin. A pooled analysis of data from RE-COVER and RE-COVER II.
        Thromb Haemost. 2016; 116: 714-721
        • Büller H.R.
        • Décousus H.
        • Grosso M.A.
        • Mercuri M.
        • Middeldorp S.
        • Prins M.H.
        • et al.
        Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.
        N Engl J Med. 2013; 369: 1406-1415
        • Raskob G.E.
        • van Es N.
        • Verhamme P.
        • Carrier M.
        • Di Nisio M.
        • Garcia D.
        • et al.
        Edoxaban for the treatment of cancer-associated venous thromboembolism.
        N Engl J Med. 2018; 378: 615-624
        • Young A.M.
        • Marshall A.
        • Thirlwall J.
        • Chapman O.
        • Lokare A.
        • Hill C.
        • et al.
        Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D).
        J Clin Oncol. 2018; 36: 2017-2023
        • Agnelli G.
        • Becattini C.
        • Meyer G.
        • Munoz A.
        • Huisman M.V.
        • Connors J.M.
        • et al.
        Apixaban for the treatment of venous thromboembolism associated with cancer.
        N Engl J Med. 2020;
        • McBane 2nd, R.D.
        • Wysokinski W.E.
        • Le-Rademacher J.G.
        • Zemla T.
        • Ashrani A.
        • Tafur A.
        • et al.
        Apixaban and dalteparin in active malignancy-associated venous thromboembolism: the ADAM VTE trial.
        J Thromb Haemost. 2020; 18: 411-421
        • Lyman G.H.
        • Carrier M.
        • Ay C.
        • Di Nisio M.
        • Hicks L.K.
        • Khorana A.A.
        • et al.
        American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer.
        Blood Adv. 2021; 5: 927-974
        • Higgins J.P.
        • Altman D.G.
        • Gotzsche P.C.
        • Juni P.
        • Moher D.
        • Oxman A.D.
        • et al.
        The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
        BMJ. 2011; 343: d5928
        • Higgins J.P.
        • Thompson S.G.
        Quantifying heterogeneity in a meta-analysis.
        Stat Med. 2002; 21: 1539-1558
        • Mai V.
        • Tanguay V.F.
        • Guay C.A.
        • Bertoletti L.
        • Magnan S.
        • Turgeon A.F.
        • et al.
        DOAC compared to LMWH in the treatment of cancer related-venous thromboembolism: a systematic review and meta-analysis.
        J Thromb Thrombolysis. 2020;
        • Key N.S.
        • Khorana A.A.
        • Kuderer N.M.
        • Bohlke K.
        • Lee A.Y.Y.
        • Arcelus J.I.
        • et al.
        Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update.
        J Clin Oncol. 2020; 38: 496-520
        • Dong S.
        • Zhang Y.
        • Li Y.
        • Miao Y.
        • Zhao R.
        • Zhai S.
        Direct Oral Anticoagulant for the treatment of VTE in cancer patients: a systematic review and meta-analysis.
        Ann Pharmacother. 2021; 55: 430-439
        • Giustozzi M.
        • Agnelli G.
        • Del Toro-Cervera J.
        • Klok F.A.
        • Rosovsky R.P.
        • Martin A.C.
        • et al.
        Direct oral anticoagulants for the treatment of acute venous thromboembolism associated with cancer: a systematic review and meta-analysis.
        Thromb Haemost. 2020; 120: 1128-1136
        • Ueyama H.
        • Miyashita H.
        • Takagi H.
        • Cruz C.
        • Burger A.
        • Briasoulis A.
        • et al.
        Network meta-analysis of anticoagulation strategies for venous thromboembolism in patients with cancer.
        J Thromb Thrombolysis. 2021; 51: 102-111
        • Steinberg B.A.
        • Gao H.
        • Shrader P.
        • Pieper K.
        • Thomas L.
        • Camm A.J.
        • et al.
        International trends in clinical characteristics and oral anticoagulation treatment for patients with atrial fibrillation: results from the GARFIELD-AF, ORBIT-AF I, and ORBIT-AF II registries.
        Am Heart J. 2017; 194: 132-140