PracticeUpdate Oncology Best of 2018

EDITOR’S PICKS 19

Edoxaban for the Treatment of Cancer- Associated Venous Thromboembolism The New England Journal of Medicine

Take-home message • Patients with cancer and venous thromboembolism were randomized to treatment with either low-molecular-weight heparin for ≥5 days followed by oral edoxaban for ≥6 months or subcutaneous dalteparin daily for ≥6 months. The composite primary outcome of recurrent venous thromboembolism and major bleeding within 12 months occurred in 12.8% of the edoxaban group vs 13.5% in the dalteparin group, demonstrating noninferiority of treatment with edoxaban. Compared with treatment with dalteparin, treatment with edoxaban resulted in a lower rate of recurrent venous thromboembolism (7.9% vs 11.3%) but a higher rate of major bleeding (6.9% vs 4.0%). • For the treatment of venous thromboembolism in patients with cancer, oral therapy with edoxaban was noninferior to subcutaneous therapy with dalteparin.

COMMENT By Rakhi Naik MD, MHS C ancer-related venous thromboembolism (VTE) is a lead- ing cause of morbidity and mortality. Over the past decade, the optimal treatment of VTE in malignancy has been the subject of much debate, with current guidelines rec- ommending low molecular–weight heparin as the preferred agent for acute management. The recent increase in use of direct oral anticoagulants (DOACs) in clinical practice, however, has naturally led to questions about their efficacy in cancer-re- lated VTE. In this paper, the Hokusai VTE Cancer Investigators report the results of a large randomized controlled trial of low molecular–weight heparin x 5 days followed by oral edox- aban (60 mg daily) compared with subcutaneous dalteparin (200 IU/kg daily x 1 month followed by 150 IU/kg daily) in 1050 patients with malignancy-associated VTE. They found no dif- ference in the composite endpoint of recurrent VTE and major bleeding between the two treatments. However, they did note a higher rate of major bleeding in the edoxaban arm (6.9% vs 4.0%), due mainly to gastrointestinal (GI) bleeding in patients with GI cancers. In a clinical context, this study is important because it demon- strated that edoxaban can be used for treatment of acute VTE in cancer patients, and these findings may translate to other DOACs such as apixaban and rivaroxaban as well. However, this study does come with a few caveats. Certainly, not all can- cers are the same, both in their bleeding and clotting risks. Edoxaban clearly may be associated with an increased risk of bleeding, especially in cancers in high-risk locations. None- theless, as in all clinical contexts, the decision regarding the optimal choice of anticoagulant in an individual patient comes down to risk versus benefit. At least we now know that we can add an oral agent, edoxaban, to our treatment options for acute cancer-related VTE.

Abstract BACKGROUND Low-molecular-weight heparin is the standard treatment for cancer-associated venous thromboembolism. The role of treatment with direct oral anticoagulant agents is unclear. METHODS In this open-label, noninferiority trial, we randomly assigned patients with cancer who had acute symptomatic or incidental venous thromboembo- lism to receive either low-molecular-weight heparin for at least 5 days followed by oral edoxaban at a dose of 60 mg once daily (edoxaban group) or subcutaneous dalteparin at a dose of 200 IU per kilogram of body weight once daily for 1 month followed by dalteparin at a dose of 150 IU per kilogram once daily (dalteparin group). Treatment was given for at least 6 months and up to 12 months. The primary outcome was a composite of recurrent venous thromboembolism or major bleeding dur- ing the 12 months after randomization, regardless of treatment duration. RESULTS Of the 1050 patients who underwent randomization, 1046 were included in the modified intention-to-treat analysis. A primary-outcome event occurred in 67 of the 522 patients (12.8%) in the edoxaban group as compared with 71 of the 524 patients (13.5%) in the dalteparin group (hazard ratio, 0.97; 95% confidence interval [CI], 0.70 to 1.36; P=0.006 for noninferiority; P=0.87 for superiority). Recurrent venous thromboembolism occurred in 41 patients (7.9%) in the edoxaban group and in 59 patients (11.3%) in the dalteparin group (difference in risk, -3.4 percentage points; 95% CI, -7.0 to 0.2). Major bleeding occurred in 36 patients (6.9%) in the

Dr. Naik is Associate Director for Hematology with the Hematology/Oncology Fellowship Program

and Assistant Professor of Medicine in Hematology at Johns Hopkins Medicine, Baltimore, Maryland.

edoxaban group and in 21 patients (4.0%) in the dalteparin group (differ- ence in risk, 2.9 percentage points; 95% CI, 0.1 to 5.6). CONCLUSIONS Oral edoxaban was noninferior to subcutaneous dalteparin with respect to the composite outcome of recurrent venous thromboem- bolism or major bleeding. The rate of recurrent venous thromboembolism was lower but the rate of major bleeding was higher with edoxaban than with dalteparin. Edoxaban for the Treatment of Cancer-Associated Venous Thrombo- embolism. N Engl J Med 2017 Dec 12;[EPub Ahead of Print], GE Raskob,

N van Es, P Verhamme, et al. www.practiceupdate.com/c/61955

VOL. 2 • NO. 4 • 2018