Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism

Trial Oversight

The rationale and design of this randomized, open-label trial have been reported previously.¹³ A coordinating committee, in collaboration with the sponsor (Daiichi Sankyo), was responsible for the trial design, protocol, and oversight. The institutional review board at each participating center approved the protocol.

The sponsor was responsible for collection and maintenance of the data. An independent data and safety monitoring committee periodically reviewed trial outcomes. The sponsor performed the statistical analysis in collaboration with the writing committee, which included all the authors. The members of the writing committee wrote all drafts of the manuscript and made the decision to submit the manuscript for publication; they also verified the data and vouch for the completeness of the data, the accuracy of the analyses, and the fidelity of the trial to the protocol. The protocol and accompanying documents are available with the full text of this article at NEJM.org.

Patients

Adult patients with cancer were eligible for inclusion in the trial if they had acute symptomatic or incidentally detected deep-vein thrombosis involving the popliteal, femoral, or iliac vein or the inferior vena cava; acute symptomatic pulmonary embolism that was confirmed by means of diagnostic imaging; or incidentally detected pulmonary embolism involving segmental or more proximal pulmonary arteries. An independent clinical events committee, whose members were unaware of the treatment assignments, confirmed the qualifying diagnosis of venous thromboembolism. The protocol also required that the treating physician intended to administer low-molecular-weight heparin for at least 6 months.

Patients had to have cancer other than basal-cell or squamous-cell skin cancer that was active or had been diagnosed within the previous 2 years and was objectively confirmed. Active cancer was defined as cancer diagnosed within the previous 6 months; recurrent, regionally advanced, or metastatic cancer; cancer for which treatment had been administered within 6 months before randomization; or hematologic cancer that was not in complete remission. A single independent physician (the second author), who was unaware of the treatment assignments, reviewed the data for all the enrolled patients to confirm the diagnosis of cancer and to verify the status of cancer as active or inactive.

A list of the exclusion criteria is provided in the Supplementary Appendix, available at NEJM.org. All the patients provided written informed consent.

Randomization and Trial Treatment

Eligible patients were randomly assigned, in a 1:1 ratio, to receive either edoxaban or dalteparin. Randomization was performed with the use of an interactive Web-based system, with stratification according to whether risk factors for bleeding were present and whether the patient met the criteria to receive a lower dose of edoxaban. Risk factors for bleeding were surgery within the previous 2 weeks, the use of antiplatelet agents, a primary or metastatic brain tumor, regionally advanced or metastatic cancer, gastrointestinal or urothelial cancer that had been diagnosed within the previous 6 months, or treatment with bevacizumab within the previous 6 weeks.

Edoxaban was started after a course of therapeutic-dose low-molecular-weight heparin was given subcutaneously for at least 5 days. This lead-in low-molecular-weight heparin was not required to be dalteparin; the choice of heparin and therapeutic regimen were at the discretion of the treating physician. Edoxaban was administered orally at a fixed dose of 60 mg once daily, with or without food. It was administered at a lower dose (30 mg once daily) in patients with a creatinine clearance of 30 to 50 ml per minute or a body weight of 60 kg or less or in those receiving concomitant treatment with potent P-glycoprotein inhibitors.

Dalteparin was given subcutaneously at a dose of 200 IU per kilogram of body weight once daily for 30 days,⁴ with a maximum daily dose of 18,000 IU. Thereafter, dalteparin was given at a dose of 150 IU per kilogram once daily.⁴ If the platelet count declined to less than 100,000 per microliter during treatment, the dose of dalteparin was temporarily reduced.

In all the patients, treatment with edoxaban or dalteparin was to be continued for at least 6 months and up to 12 months. The duration beyond 6 months was determined by the treating physician.

Outcome Measures

The primary outcome was a composite of recurrent venous thromboembolism or major bleeding. Recurrent venous thromboembolism was defined as symptomatic new deep-vein thrombosis or pulmonary embolism, incidental new deep-vein thrombosis or pulmonary embolism involving segmental or more proximal pulmonary arteries, or fatal pulmonary embolism or unexplained death for which pulmonary embolism could not be ruled out as the cause. Incidental venous thromboembolism was defined as thromboembolism that was detected by means of imaging tests performed for reasons other than clinical suspicion of venous thromboembolism.¹⁴ In accordance with the criteria of the International Society on Thrombosis and Haemostasis (ISTH), major bleeding was defined as overt bleeding that was associated with a decrease in the hemoglobin level of 2 g per deciliter or more, led to a transfusion of 2 or more units of blood, occurred in a critical site, or contributed to death.¹⁵

Death was adjudicated to be caused by venous thromboembolism, bleeding, cancer, cardiovascular disease, or other causes. Pulmonary embolism was considered to be the cause of death if there was objective documentation that pulmonary embolism caused the death or if the death could not be attributed to a documented cause and pulmonary embolism could not be ruled out.

A list of prespecified secondary outcomes and the criteria for adjudication of all the outcomes are provided in the Supplementary Appendix. The clinical events committee adjudicated all the suspected outcome events and causes of death, as well as the severity of the major bleeding events, with the use of prespecified criteria.¹²

Surveillance and Follow-up

All the patients were followed for 12 months or until the end of the trial (minimum follow-up, 9 months). Patients underwent assessment, in the clinic or by telephone, on day 31 after randomization and at months 3, 6, 9, and 12. Patients were instructed to report symptoms that were suggestive of recurrent venous thromboembolism or bleeding. Appropriate diagnostic tests, laboratory tests, or both were required in patients with suspected outcome events. The following adverse events were reported: suspected outcome events, serious adverse events that were not related to the underlying cancer or its treatment, and combined elevations in aminotransferase and bilirubin levels.

Statistical Analysis

The trial hypothesis was that edoxaban would be noninferior to dalteparin with respect to the rate of primary-outcome events (recurrent venous thromboembolism or major bleeding), with an upper limit of the 95% confidence interval for the hazard ratio of less than 1.5 and a two-sided alpha level of 0.05. The margin of 1.5 was chosen as the maximum difference that may be potentially clinically acceptable because of the unmet need for an alternative to parenteral low-molecular-weight heparin and the advantages of oral therapy. Assuming equal effectiveness of edoxaban and dalteparin (i.e., a hazard ratio of 1.0) and a rate of primary-outcome events at 12 months of 20%, we estimated that a sample of approximately 1000 patients would be required to observe an expected total of 191 primary-outcome events and would give the trial 80% power to show the noninferiority of edoxaban. When the number of patients who were enrolled in the trial approached 1000, we set the date for the end of the trial such that the last patient enrolled would complete 9 months of follow-up.

The analysis of the primary outcome was performed in the modified intention-to-treat population, which included all the patients who had undergone randomization and received at least one dose of the assigned treatment. The primary analysis included any primary-outcome events that had occurred from randomization through the end of 12 months or the end of the trial (overall trial period), regardless of the duration of treatment for each patient. The time to the first primary-outcome event was analyzed with the use of a Cox proportional-hazards model to compare the hazards between treatment groups. The stratification factors were used as covariates. Time-to-event curves were calculated with the use of the Kaplan–Meier method. Analyses of secondary safety outcomes were performed in the safety population, which was the same as the modified intention-to-treat population.

Two sensitivity analyses were planned for the primary outcome. The first was an analysis of primary-outcome events that occurred during the first 6 months, which was the minimum intended duration of the assigned treatment and corresponds with the treatment duration used in previous trials.^4,5 The second was an analysis of outcomes that occurred during treatment (i.e., during or within 3 days after discontinuation of the assigned treatment) in the per-protocol population. This population excluded patients who had not received at least one dose of edoxaban or dalteparin after randomization and patients in whom the qualifying diagnosis of venous thromboembolism had not been confirmed.

Patients and Treatment

Figure 1. Figure 1. Randomization and Follow-up.

The modified intention-to-treat and safety populations included all the patients who had undergone randomization and received at least one dose of the assigned treatment. Of the 303 patients in the edoxaban group and the 316 in the dalteparin group who completed the overall trial period, 72 and 69 patients, respectively, had their follow-up truncated to between 9 and 12 months because they were enrolled less than 12 months before the end of the trial.

Table 1. Table 1. Demographic and Clinical Characteristics of the Patients at Baseline.

From July 2015 through December 2016, a total of 1050 patients were enrolled at 114 centers in 13 countries (Figure 1). The baseline characteristics of the patients were similar in the two trial groups (Table 1). The types of cancer and the categories of anticancer drugs given during the course of the trial are shown in Tables S1 and S2, respectively, in the Supplementary Appendix. The median duration of the assigned treatment was 211 days (interquartile range, 76 to 357) in the edoxaban group and 184 days (interquartile range, 85 to 341) in the dalteparin group (P=0.01). Details about the duration of the assigned treatment and reasons for discontinuation are provided in Table S3 in the Supplementary Appendix. The counts of pills and syringes indicated that 447 patients (85.6%) in the edoxaban group and 465 patients (88.7%) in the dalteparin group had received at least 80% of the prescribed treatment before permanent discontinuation.

Primary Outcome

Table 2. Table 2. Clinical Outcomes during the Overall Trial Period.

Figure 2. Figure 2. Kaplan–Meier Cumulative Event Rates for the Primary Outcome.

The primary outcome was a composite of recurrent venous thromboembolism or major bleeding. The inset shows the same data on an enlarged y axis.

The primary outcome of recurrent venous thromboembolism or major bleeding occurred in 67 of the 522 patients (12.8%) in the edoxaban group and in 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) (Table 2). The time to the occurrence of primary-outcome events is shown in Figure 2. Characteristics of the primary-outcome events are shown in Table S4 in the Supplementary Appendix.

The results of the two prespecified sensitivity analyses were similar to the results of the primary analysis and also met the criteria for noninferiority (Tables S5 and S6 in the Supplementary Appendix). In the analysis of events that occurred during the first 6 months, a primary-outcome event occurred in 55 patients (10.5%) in the edoxaban group and in 56 patients (10.7%) in the dalteparin group (hazard ratio, 1.01; 95% CI, 0.69 to 1.46; P=0.02 for noninferiority). In the analysis of events that occurred during treatment in the per-protocol population, a primary-outcome event occurred in 51 of 490 patients (10.4%) in the edoxaban group and in 53 of 508 patients (10.4%) in the dalteparin group (hazard ratio, 0.99; 95% CI, 0.68 to 1.46; P=0.02 for noninferiority).

Secondary Outcomes

The secondary outcomes are shown in Table 2. 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]; hazard ratio, 0.71 [95% CI, 0.48 to 1.06; P=0.09]). Major bleeding occurred in 36 patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin group (difference in risk, 2.9 percentage points [95% CI, 0.1 to 5.6]; hazard ratio, 1.77 [95% CI, 1.03 to 3.04; P=0.04]).

Figure 3. Figure 3. Kaplan–Meier Cumulative Event Rates for Secondary Outcomes.

Shown are cumulative event rates for recurrent venous thromboembolism (Panel A) and major bleeding (Panel B). The insets show the same data on an enlarged y axis.

The time to the occurrence of recurrent venous thromboembolism and major bleeding during the overall trial period is shown in Figure 3. Sensitivity analyses for the secondary outcomes are shown in Tables S5 and S6, data on bleeding events that occurred during treatment in the safety population are shown in Table S7, and data on event-free survival are shown in Figure S1 — all in the Supplementary Appendix.

Death occurred in 206 patients (39.5%) in the edoxaban group and in 192 patients (36.6%) in the dalteparin group. The causes of death are shown in Table S8 in the Supplementary Appendix. The majority of deaths were related to cancer; six deaths in each group were related to either venous thromboembolism or bleeding.

Subgroup Analyses

Subgroup analyses for the primary outcome, and for recurrent venous thromboembolism and major bleeding separately, are shown in Figures S2 through S5 in the Supplementary Appendix. There were no statistically significant interactions between subgroup and treatment, except for the subgroups defined according to whether the patient had gastrointestinal cancer at the time of randomization. Patients with gastrointestinal cancer were more likely to have an increase in the risk of bleeding during treatment with edoxaban than with dalteparin (P=0.02 for interaction in the safety population).

Adverse Events

The adverse events reported in the trial are shown in Tables S9, S10, and S11 in the Supplementary Appendix. The most common adverse events were progression of neoplasm and pneumonia; for each of these events, the rate was similar in the two treatment groups.

The Hokusai VTE Cancer trial, which involved patients with predominantly advanced cancer and acute symptomatic or incidental venous thromboembolism, showed that treatment with a fixed once-daily dose of oral edoxaban for up to 12 months was noninferior to treatment with subcutaneous dalteparin with respect to the composite outcome of recurrent venous thromboembolism or major bleeding. The rate of recurrent venous thromboembolism was numerically lower with edoxaban than with dalteparin (7.9% and 11.3%, respectively; hazard ratio, 0.71; 95% CI, 0.48 to 1.06; P=0.09) because of the lower rate of recurrent symptomatic deep-vein thrombosis with edoxaban (Table 2). The 8.8% rate of recurrent venous thromboembolism at 6 months in the dalteparin group in this trial is consistent with rates reported with dalteparin in previous studies involving patients with cancer.^4,16

The rate of major bleeding was significantly higher with edoxaban than with dalteparin (6.9% and 4.0%, respectively; hazard ratio, 1.77; 95% CI, 1.03 to 3.04; P=0.04). This difference was mainly due to the higher rate of upper gastrointestinal bleeding with edoxaban. This finding is consistent with results of previous studies of direct oral anticoagulants.¹¹ The increase in upper gastrointestinal major bleeding occurred mainly in patients who had entered the trial with gastrointestinal cancer. However, the frequency of severe major bleeding (category 3 or 4; see Table 2) was similar with edoxaban and dalteparin. The 3.2% rate of major bleeding at 6 months in the dalteparin group in this trial is lower than previously reported rates with dalteparin.^4,16

Our trial has some limitations. First, the use of an open-label design is a potential weakness, but long-term administration of placebo injections was not considered to be appropriate. To mitigate potential bias, all events were adjudicated by a committee whose members were unaware of the treatment assignments. Second, the number of primary-outcome events was lower than expected; despite this limitation, noninferiority was established. Third, the median duration of the assigned treatment was shorter with dalteparin than with edoxaban, which may have influenced the relative efficacy of the two treatments. However, this difference was primarily due to the inconvenience of the use of subcutaneous dalteparin as compared with oral edoxaban, thus demonstrating the desirability of oral therapy in this context. In addition, the sensitivity analysis of events that occurred during treatment in the per-protocol population confirmed the results of the primary analysis. Finally, the trial included a broad spectrum of patients with cancer who had received a wide array of cytotoxic and biologic therapies, but the sample size limits our ability to make definitive conclusions about outcomes associated with individual tumor types.

In conclusion, in this trial involving patients with cancer-associated venous thromboembolism, edoxaban was noninferior to dalteparin with respect to the composite outcome of recurrent venous thromboembolism or major bleeding.