A Randomized, Open-Label, Blinded Outcome Assessment Trial Evaluating the Efficacy and Safety of LMWH/Edoxaban Versus Dalteparin for Venous Thromboembolism Associated with Cancer: Hokusai VTE-Cancer Study

On behalf of the Hokusai VTE Cancer Investigators

The treatment of cancer-associated venous thromboembolism (VTE) is challenging because these patients are at increased risk of both recurrent VTE and major bleeding. Low-molecular-weight heparin (LMWH) treatment is standard care for these patients, but requires daily subcutaneous injections. Guidelines recommend LMWH treatment for 6 months, but the risk-benefit beyond this time is uncertain. Direct oral anticoagulants are used for the treatment of VTE in patients without cancer, but their role in patients with cancer- associated VTE is uncertain. In this randomized, open-label non-inferiority trial, cancer patients with acute symptomatic or incidental VTE were assigned to receive LMWH for a minimum of 5 days followed by the oral factor Xa inhibitor edoxaban at a dose of 60 mg once daily (or 30 mg once daily in patients with a creatinine clearance of 30 to 50 ml per minute or a body weight below 60 kg), or subcutaneous dalteparin 200 units per kg once daily for one month followed by 150 units per kg thereafter. Patients received these regimens for up to 12 months. The primary outcome was the composite of the first recurrent VTE or major bleeding event during follow-up for 12 months. Secondary outcomes included recurrent VTE and major bleeding analyzed separately, and survival free of recurrent VTE or major bleeding. The study hypothesis was that edoxaban would be noninferior to dalteparin for the primary outcome with an upper 95% confidence interval [CI] for the hazard ratio below 1.5, and a two-sided alpha of 0.05. All outcomes were independently adjudicated by a committee without knowledge of treatment allocation. This committee also assessed the clinical severity of major bleeding events using categorical criteria defined a priori (categories 1 to 4). From July 2015 through December 2016 a total of 1050 patients were enrolled at 114 centers in 13 countries; 525 were randomized to edoxaban and 525 to dalteparin. At entry, pulmonary embolism with or without deep-vein thrombosis was present in 657 patients (63%) while the remainder had isolated deep-vein thrombosis. Of the 1050 patents, 706 (67%) had symptomatic VTE and the rest were incidental. Active cancer at entry was present in 97% of the patients and 53% had metastatic disease. 1046 patients were included in the modified-intention-to-treat analysis. The primary outcome occurred in 67 of 522 patients (12.8%) in the edoxaban group compared with 71 of 524 patients (13.5%) in the dalteparin group (hazard ratio with edoxaban, 0.97; 95% CI, 0.70 to 1.36; P = 0.0056 for noninferiority) for a risk difference (edoxaban minus dalteparin) of - 0.7% (95% CI, - 4.8 to 3.4). The difference in risk for recurrent VTE was -3.8 % (95% CI, -7.1 to -0.4), whereas the corresponding difference in risk for major bleeding was 3.1% (95% CI, 0.5 to 5.7). The frequencies of severe major bleeding events (categories 3 and 4) were similar during treatment with edoxaban or dalteparin (12 patients in each group respectively). Survival at 12 months free of recurrent VTE and major bleeding in the edoxaban and dalteparin groups was similar (55.0% and 56.5% respectively). Oral edoxaban for up to 12 months is noninferior to subcutaneous dalteparin for the treatment of cancer-associated VTE.