Edoxaban, Rivaroxaban, or Apixaban for Cancer-Associated Venous Thromboembolism in the Real World: Insights from the COMMAND VTE Registry-2

Abstract

Background Real-world data on clinical characteristics and outcomes related to the use of different direct oral anticoagulants (DOACs) for cancer-associated venous thromboembolism (VTE) is lacking.

Methods The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive patients with acute symptomatic VTE from 31 centers in Japan from January 2015 to August 2020. Our study population comprised 1,197 patients with active cancer who were divided into the edoxaban (N = 643, 54%), rivaroxaban (N = 297, 25%), and apixaban (N = 257, 22%) groups.

Results The cumulative 5-year incidence of recurrent VTE (9.3, 10.2, and 8.5%, respectively, p = 0.82) and all-cause death (67.5, 66.8, and 63.8%, respectively, p = 0.22) did not differ among the groups. Despite adjusting for confounders, the risks of recurrent VTE and all-cause death did not differ significantly among the groups. The cumulative 5-year incidence of major and clinically relevant bleeding was significantly lower in the rivaroxaban group than those in the other groups (22.6, 14.0, and 22.8%, p = 0.04; and 37.6, 26.8, and 38.3%, p = 0.01, respectively). After adjusting for confounders, in the rivaroxaban group, the risk for major bleeding was numerically lower (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.40–1.01) and that of clinically relevant all bleeding was significantly lower (HR: 0.67, 95% CI: 0.48–0.92) than those in the edoxaban group.

Conclusion The risks of recurrent VTE and all-cause death did not differ significantly among the different DOACs ; however, the risk of bleeding events could differ, with a potentially lower risk of bleeding with rivaroxaban.

Keywords

venous thromboembolism - cancer-associated VTE - DOACs

Authors' Contribution

D.S.: writing—original draft, investigation, funding acquisition, conceptualization. Y.Y.: writing—review and editing, project administration, conceptualization. T.M.: formal analysis. R.C., Y.N., K.K., N.I., Y.K., S.I., K.K., M.I., T.T., S.T., M.O., T.T., K.O., J.S., Y.O., T.I., S.U., P.-M.C., K.T., N.K., S.H., K.D., H.M., Y.T., K.M., K.T., H.N., W.S., T.D., R.N.: investigation. Takeshi Kimura: writing—review and editing, supervision, project administration, conceptualization. K.T.: supervision.

Publication History

Received: 28 March 2024

Accepted: 28 April 2024

Accepted Manuscript online:
29 April 2024

Article published online:
24 May 2024

• References

• 1 Walker AJ, Card TR, West J, Crooks C, Grainge MJ. Incidence of venous thromboembolism in patients with cancer - a cohort study using linked United Kingdom databases. Eur J Cancer 2013; 49 (06) 1404-1413
• 2 Elyamany G, Alzahrani AM, Bukhary E. Cancer-associated thrombosis: an overview. Clin Med Insights Oncol 2014; 8: 129-137
• 3 Girardi L, Wang TF, Ageno W, Carrier M. Updates in the incidence, pathogenesis, and management of cancer and venous thromboembolism. Arterioscler Thromb Vasc Biol 2023; 43 (06) 824-831
• 4 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
• 5 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
• 6 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
• 7 Schrag D, Uno H, Rosovsky R. et al; CANVAS Investigators. Direct oral anticoagulants vs low-molecular-weight heparin and recurrent VTE in patients with cancer: a randomized clinical trial. JAMA 2023; 329 (22) 1924-1933
• 8 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
• 9 Zeng J, Zhang X, Lip GYH. et al. Efficacy and safety of direct oral anticoagulants for risk of cancer-associated venous thromboembolism. Clin Appl Thromb Hemost 2019; 25: 1076029619853629
• 10 Camilli M, Lombardi M, Vescovo GM. et al. Efficacy and safety of novel oral anticoagulants versus low molecular weight heparin in cancer patients with venous thromboembolism: a systematic review and meta-analysis. Crit Rev Oncol Hematol 2020; 154: 103074
• 11 Sabatino J, De Rosa S, Polimeni A, Sorrentino S, Indolfi C. direct oral anticoagulants in patients with active cancer: a systematic review and meta-analysis. JACC Cardiooncol 2020; 2 (03) 428-440
• 12 Riaz IB, Fuentes HE, Naqvi SAA. et al. Direct oral anticoagulants compared with dalteparin for treatment of cancer-associated thrombosis: a living, interactive systematic review and network meta-analysis. Mayo Clin Proc 2022; 97 (02) 308-324
• 13 Wu S, Lv M, Chen J. et al. Direct oral anticoagulants for venous thromboembolism in cancer patients: a systematic review and network meta-analysis. Support Care Cancer 2022; 30 (12) 10407-10420
• 14 Ning H, Yang N, Ding Y. et al. Efficacy and safety of direct oral anticoagulants for the treatment of cancer-associated venous thromboembolism: a systematic review and Bayesian network meta-analysis. Med Clín (Barc) 2023; 160 (06) 245-252
• 15 Fujisaki T, Sueta D, Yamamoto E. et al. Comparing anticoagulation strategies for venous thromboembolism associated with active cancer: a systematic review and meta-analysis. JACC Cardiooncol 2024; 6 (01) 99-113
• 16 Kaneda K, Yamashita Y, Morimoto T. et al; COMMAND VTE Registry-2 Investigators. Anticoagulation strategies and long-term recurrence in patients with venous thromboembolism in the era of direct oral anticoagulants. Eur J Intern Med 2023; 118: 59-72
• 17 Chatani R, Yamashita Y, Morimoto T. et al; COMMAND VTE Registry-2 Investigators. Cancer-associated venous thromboembolism in the direct oral anticoagulants era: insight from the COMMAND VTE Registry-2. Thromb Res 2024; 234: 86-93
• 18 Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999; 353 (9162) 1386-1389
• 19 Büller HR, Décousus H, Grosso MA. et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
• 20 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
• 21 Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13 (11) 2119-2126
• 22 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
• 23 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