Direct Oral Anticoagulants for the Treatment of Acute Venous Thromboembolism Associated with Cancer: A Systematic Review and Meta-AnalysisFunding None.
31 March 2020
23 April 2020
04 May 2020 (online)
Background International guidelines have endorsed the use of edoxaban or rivaroxaban as an alternative to low-molecular-weight heparin (LMWH) for the treatment of acute venous thromboembolism (VTE) in cancer patients. Recently, a large randomized controlled trial of apixaban versus dalteparin in patients with cancer was completed. We performed an updated meta-analysis to assess the efficacy and safety of direct oral anticoagulants (DOACs) versus LMWH in patients with cancer-associated VTE.
Methods MEDLINE, EMBASE, and CENTRAL (Cochrane Controlled Trials Registry) were systematically searched up to March 30, 2020 for randomized controlled trials comparing DOACs versus LMWH for the treatment of VTE in patients with cancer. The two coprimary outcomes were recurrent VTE and major bleeding at 6 months. Data were pooled by the Mantel–Haenszel method and compared by relative risk ratios (RRs) and 95% confidence intervals (CIs).
Results Four randomized controlled studies (2,894 patients) comparing apixaban, edoxaban, or rivaroxaban with dalteparin were included in the meta-analysis. Recurrent VTE occurred in 75 of 1,446 patients (5.2%) treated with oral factor Xa inhibitors and in 119 of 1,448 patients (8.2%) treated with LMWH (RR 0.62; 95% CI 0.43–0.91; I 2, 30%). Major bleeding occurred in 62 (4.3%) and 48 (3.3%) patients receiving oral factor Xa inhibitors or LMWH, respectively (RR 1.31; 95% CI 0.83–2.08; I 2, 23%).
Conclusion In patients with cancer-associated VTE, oral factor Xa inhibitors reduced the risk of recurrent VTE without a significantly higher likelihood of major bleeding at 6 months compared with LMWH.
Keywordsdirect oral anticoagulants - oral factor Xa inhibitors - cancer - dalteparin - meta-analysis - venous thromboembolism
- 1 Cohen AT, Katholing A, Rietbrock S, Bamber L, Martinez C. Epidemiology of first and recurrent venous thromboembolism in patients with active cancer. A population-based cohort study. Thromb Haemost 2017; 117 (01) 57-65
- 2 Kourlaba G, Relakis J, Mylonas C. , et al. The humanistic and economic burden of venous thromboembolism in cancer patients: a systematic review. Blood Coagul Fibrinolysis 2015; 26 (01) 13-31
- 3 Prandoni P, Lensing AW, Piccioli A. , et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100 (10) 3484-3488
- 4 Chee CE, Ashrani AA, Marks RS. , et al. Predictors of venous thromboembolism recurrence and bleeding among active cancer patients: a population-based cohort study. Blood 2014; 123 (25) 3972-3978
- 5 Giustozzi M, Curcio A, Weijs B. Variation in the association between antineoplastic therapies and venous thromboembolism in patients with active cancer. Thromb Haemost 2020;120(5):847–856
- 6 Konstantinides SV, Meyer G, Becattini C. , et al; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41 (04) 543-603
- 7 Raskob GE, van Es N, Verhamme P. , et al; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018; 378 (07) 615-624
- 8 Young AM, Marshall A, Thirlwall J. , 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 (20) 2017-2023
- 9 Streiff MB, Holmstrom B, Angelini D. , et al. NCCN guidelines insights: cancer-associated venous thromboembolic disease, version 2.2018. J Natl Compr Canc Netw 2018; 16 (11) 1289-1303
- 10 Khorana AA, Noble S, Lee AYY. , et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost 2018; 16 (09) 1891-1894
- 11 Farge D, Frere C, Connors JM. , et al; International Initiative on Thrombosis and Cancer (ITAC) advisory panel. 2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol 2019; 20 (10) e566-e581
- 12 Key NS, Khorana AA, Kuderer NM. , et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol 2020; 38 (05) 496-520
- 13 McBane II RD, Wysokinski WE, Le-Rademacher JG. , et al. Apixaban and dalteparin in active malignancy-associated venous thromboembolism: the ADAM VTE trial. J Thromb Haemost 2020; 18 (02) 411-421
- 14 Agnelli G, Becattini C, Meyer G. , et al; Caravaggio Investigators. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 2020; 382 (17) 1599-1607
- 15 Higgins JP, Altman DG, Gøtzsche PC. , et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928
- 16 Liberati A, Altman DG, Tetzlaff J. , et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009; 339: b2700
- 17 McGinn T, Wyer PC, Newman TB, Keitz S, Leipzig R, For GG. ; Evidence-Based Medicine Teaching Tips Working Group. Tips for learners of evidence-based medicine: 3. Measures of observer variability (kappa statistic). CMAJ 2004; 171 (11) 1369-1373
- 18 Brignardello-Petersen R, Bonner A, Alexander PE. , et al; GRADE Working Group. Advances in the GRADE approach to rate the certainty in estimates from a network meta-analysis. J Clin Epidemiol 2018; 93: 36-44
- 19 Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21 (11) 1539-1558
- 20 Cochran WG. The combination of estimates from different experiments. Biometrics 1954; 10: 101-129
- 21 Leeflang MM, Deeks JJ, Rutjes AW, Reitsma JB, Bossuyt PM. Bivariate meta-analysis of predictive values of diagnostic tests can be an alternative to bivariate meta-analysis of sensitivity and specificity. J Clin Epidemiol 2012; 65 (10) 1088-1097
- 22 van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 2014; 124 (12) 1968-1975
- 23 Guideline on clinical investigation of medicinal products for the treatment of venous thromboembolic disease. Available at: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guideline-clinical-investigation-medicinal-products-treatment-venous-thromboembolic-disease_en.pdf . Accessed March 25, 2020
- 24 Lee AYY. Anticoagulant therapy for venous thromboembolism in cancer. N Engl J Med 2020; 382 (17) 1650-1652
- 25 van der Hulle T, Kooiman J, den Exter PL, Dekkers OM, Klok FA, Huisman MV. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2014; 12 (03) 320-328
- 26 Lee AY, Bauersachs R, Janas MS. , et al; CATCH Investigators. CATCH: a randomised clinical trial comparing long-term tinzaparin versus warfarin for treatment of acute venous thromboembolism in cancer patients. BMC Cancer 2013; 13: 284
- 27 Fuentes HE, McBane II RD, Wysokinski WE. , et al. Direct oral factor Xa inhibitors for the treatment of acute cancer-associated venous thromboembolism: a systematic review and network meta-analysis. Mayo Clin Proc 2019; 94 (12) 2444-2454
- 28 Mai V, Tanguay VF, Guay CA. , et al. DOAC compared to LMWH in the treatment of cancer related-venous thromboembolism: a systematic review and meta-analysis. J Thromb Thrombolysis 2020; DOI: 0.1007/s11239-020-02055-1.
- 29 Dong Y, Wang Y, Ma RL. , et al. Efficacy and safety of direct oral anticoagulants versus low-molecular-weight heparin in patients with cancer: a systematic review and meta-analysis. J Thromb Thrombolysis 2019; 48 (03) 400-412