Introduction

The ONCO DVT (Edoxaban for 12 Months Versus 3 Months in Patients With Cancer With Isolated Distal Deep Vein Thrombosis; NCT03895502) study showed the potential benefit of extended anticoagulation therapy with edoxaban in patients with cancer-associated isolated distal deep vein thrombosis (IDDVT), whereas it also suggested a potential signal for an increased risk of bleeding with a 12-month compared with a 3-month edoxaban treatment duration.¹ Therefore, we conducted a post hoc analysis on an exploratory basis to compare the net clinical benefit (NCB) of a 12-month compared with a 3-month edoxaban treatment duration.

The ONCO DVT study was a multicenter, open-label, randomized controlled trial in which patients with active cancer who were newly diagnosed with IDDVT were randomly assigned (1:1) to the 12-month or 3-month edoxaban treatment group.¹ The study was conducted in accordance with the amended Declaration of Helsinki and approved by the Institutional Review Boards of Kyoto University and all other participating centers. The endpoints measured included thrombotic (symptomatic or asymptomatic recurrent venous thromboembolism [VTE]) and bleeding (major bleeding or all clinically relevant bleeding) events at 12 months.¹ There were no VTE-related deaths in either group. The bleeding events were defined according to the International Society on Thrombosis and Haemostasis criteria. All clinically relevant bleeding included major and clinically relevant nonmajor bleeding.

First, we assessed the net adverse clinical events (NACEs), which were defined as a simple combination of the thrombotic and bleeding events, in each treatment group. If both thrombotic and bleeding events occurred, the first event was considered NACE. We defined NACE 1 as a composite endpoint of symptomatic recurrent VTE or major bleeding at 12 months. In addition, to assess the broader spectrum of events, we defined NACE 2 as a composite endpoint of symptomatic or asymptomatic recurrent VTE or all clinically relevant bleeding at 12 months. We compared the incidence rates (events per 100 person-years) of NACEs between the 2 treatment groups in the intention-to-treat population and calculated the incidence rate ratios (IRRs) with the corresponding 95% CIs using the Poisson regression models to offset the duration of follow-up to obtain the incidence rate per person-year at risk. We also performed subgroup analyses with interaction tests. Second, we assessed the NCB of 12 months compared with 3 months of edoxaban, which was defined as the sum of the differences in the incidence of thrombotic and bleeding events between the 2 treatment groups and was calculated as follows: incidence of thrombotic events (3-month group − 12-month group) + incidence of bleeding events (3-month group − 12-month group) × bleeding weight.^2,3 The bleeding weights were defined as the clinical importance of bleeding events relative to thrombotic events. We set the bleeding weight as 1.0 in the base case analyses. NCB 1 and NCB 2 corresponded to NACE 1 and NACE 2, respectively. Given the lack of established bleeding weights, we calculated the NCB with the bleeding weights set at 0.5 and 2.^2,3

Of the 601 eligible patients, 296 were in the 12-month group, and 305 were in the 3-month group. All-cause deaths occurred in 66 patients (22.3%) in the 12-month group and 77 (25.3%) in the 3-month group. The median (range) length of follow-up was 316 days (range, 11-365 days) in the 12-month group and 314 days (range, 10-365 days) in the 3-month group. With a bleeding weight of 1.0, the incidence rates of NACE 1 were 12.3 (95% CI: 8.6-17.5) events per 100 person-years in the 12-month group and 17.0 (95% CI: 12.5-22.9) in the 3-month group (IRR: 0.73; 95% CI: 0.46-1.17). The NCB 1 was 3.6% (95% CI: −1.5% to 8.8%). The incidence rates of NACE 2 were 31.2 (95% CI: 24.6-39.5) events per 100 person-years in the 12-month group and 42.6 (95% CI: 34.8-52.0) in the 3-month group (IRR: 0.75; 95% CI: 0.55-1.02). The NCB 2 was 7.8% (95% CI: 0.8%-14.9%).

The effect of the 12-month vs the 3-month group for NACE 1 was almost consistent across the subgroups, except for those with metastases. The 12-month group had a lower risk of NACE 1 than the 3-month group among the patients with metastases (IRR: 0.41; 95% CI: 0.18-0.91) but not among those without metastases (IRR: 1.15; 95% CI: 0.62-2.12) with a significant interaction (P = 0.045). As the bleeding weights increased from 0.5 to 2, the NCB 1 became attenuated from 4.8% (95% CI: 0.5%-9.0%) to 0.7% (95% CI: −5.7% to 7.1%) (Figure 1A), and the NCB 2 became attenuated from 10.1% (95% CI: 3.7%-16.4%) to 3.1% (95% CI: −4.8% to 11.0%) (Figure 1B).

This study suggested that 12 months of edoxaban was favorable regarding NACEs compared with 3 months of edoxaban; however, the NCB of 12 months of edoxaban became attenuated as the bleeding weights increased. Further studies are required to evaluate the case fatality rate of each event and its impact on cancer treatment.

This study showed a differential effect on NACEs in the subgroup of metastases. For patients with VTE and metastases, the current guidelines recommend prolonged anticoagulation therapy beyond 6 months because of a high risk of VTE recurrence, but supporting evidence is scarce.⁴ This study indicates a potential NCB of 12-months compared with 3-months of edoxaban treatment in those with metastases.

This study had limitations. First, this was not a prespecified analysis but rather a post hoc exploratory analysis, and the results should be interpreted cautiously as hypothesis generating. In particular, such a weighting was somewhat arbitrary, but our estimated NCB may provide a useful anchoring point in the debate on the duration of anticoagulation therapy for patients with cancer-associated IDDVT. Second, this study shared the following limitations of the ONCO DVT study: the open-label design, high proportion of patients with asymptomatic IDDVT, relatively low protocol adherence to the edoxaban treatment, and racial and practice differences.¹ Third, using NACE simply as a combination of each event does not account for the differential clinical importance of each event.

In conclusion, the NCB of the 12-month compared with the 3-month edoxaban treatment duration was not significant, although the 12-month treatment group had a numerically lower incidence of NACEs than the 3-month treatment group.

Footnotes