In this challenging ExCAVE study, which evaluated the 3-month safety and efficacy of edoxaban without prior heparin administration in patients with GIC at high risk of bleeding, the incidence rates of MB or CRNMB, thrombus exacerbation or recurrence by either the central review or the investigator’s assessment, and all-cause death were 11% (n = 6), 9% (n = 5), and 6% (n = 3), respectively. On the other hand, in the analysis of events that occurred during the first 6 months in the Hokusai VTE Cancer study, which included patients who were given heparin administration before edoxaban initiation, the incidence rates of MB or CRNMB, VTE recurrence, and death were 16, 7, and 27%, respectively .
The Hokusai VTE Cancer study evaluated the safety and efficacy of edoxaban at 6 months; therefore, its results cannot be directly compared with the present study. However, a subset analysis on supplement data of the Hokusai VTE Cancer study found that the event-free survival rate at 3 months was 78% (407/522). In the present study, the rate of event-free survival, defined as the absence of bleeding, thrombus recurrence, and death, was 85% (45/53), suggesting that omitting heparin pretreatment may yield results comparable to those previously reported. The observation period in this study was 3 months, and the long-term safety of this strategy was not verified. However, no severe adverse events were observed during the observation period.
Edoxaban is the only fixed dose orally disintegrating DOAC tablet that can be taken once daily without scheduled titration. In addition, dose reduction criteria have been established for this drug to reduce the risk of bleeding, and the dose can be easily adjusted according to patients’ body weight and renal function. However, a single-drug approach using edoxaban without prior heparin administration is currently deprecated [6,7,8,9, 14]. In the Hokusai-VTE study, a 5-day course of initial treatment with heparin (enoxaparin or UFH), a global standard that was demonstrated as useful at the time, was incorporated into the study design. Since that study, prior administration of heparin has been recommended for treatment with edoxaban and the package insert for edoxaban states that edoxaban should be administered after appropriate initial treatment with a parenteral anticoagulant such as UFH. It is beneficial for patients to have edoxaban as an additional dose-adjustable DOAC option available without prior heparin administration for asymptomatic thrombosis.
Although several reports have discussed the efficacy and safety of DOACs for CAT [17,18,19], few studies focused on incidental asymptomatic CAT. For example, in the Sapporo CAT study, our previously reported observational study of CAT, only 43% of patients were treated for asymptomatic thrombosis . Conversely, Gary et al. reported that asymptomatic venous thrombotic events were associated with poor survival . However, inpatient treatment for asymptomatic thrombosis is excessive because heparin administration requires hospitalization, which imposes a heavy burden on patients in terms of cost. It has also been reported that rivaroxaban and edoxaban are less expensive than LMWH for the treatment of CAT, and DOACs are effective options as anticoagulant therapies for asymptomatic CAT even from the viewpoint of cost .
Generally, compared to the risk profile of dalteparin, edoxaban  and rivaroxaban  carry higher risks of MB in patients with GIC, and these DOACs should be used with caution in patients with unresected intraluminal tumors. By contrast, apixaban has been reported to have a bleeding rate equivalent to that of dalteparin in the treatment of CAT in patients with GIC . Moreover, a report indicated that apixaban has the most favorable safety profile (MB risk) in a head-to-head comparison of three DOACs (dabigatran, apixaban, and rivaroxaban) . However, no clinical trials have directly compared the safety profiles of DOACs in the treatment of CAT, and the safest DOAC for patients with CAT and GIC is unclear. Even when using apixaban, care should be taken when in patients with CAT and active GIC. That is, appropriate dose adjustment for at-risk patients is of paramount importance in bleeding risk management when using DOACs. In fact, more than half of the patients in this trial had at least one DAF, and all such patients underwent adequate dose adjustment to 30 mg.
Although no statistically significant difference was observed in this study, the frequency of bleeding events was slightly higher in the dose-adjusted group, suggesting that the frequency of bleeding might have increased further without dose reduction in patients with risk factors for bleeding, such as low body weight or low CrCl. In addition, in the present study, it is also important to note that PE occurred in one patient who did not undergo dose adjustment. In this patient, a dose of 60 mg should have been administered, but the dose was reduced to 30 mg at the attending physician’s discretion, indicating that the inappropriate dose reduction could be detrimental to the patients. The incidence of under-dosing of DOACs was investigated in the RIETE registry, which enrolled patients with VTE receiving DOACs . In that study, 17% of patients receiving rivaroxaban and 50% of those receiving apixaban received a lower than recommended dose, far exceeding the rate in the present study (5.7%). Low inappropriate doses during initial therapy represent an essential advantage for edoxaban, for which the dose-setting criteria are clear.
The results of large-scale randomized controlled trials of apixaban  and rivaroxaban  as primary prophylactic treatments for CAT have been reported in recent years, but clinical studies on the prophylactic efficacy of edoxaban for CAT have not yet been conducted. The reason may be that prior heparin administration is recommended before edoxaban administration, and if heparin pretreatment is not required, edoxaban can also be considered as an option for prophylactic treatment. It has been reported that 75% of MB events associated with DOACs occur in patients with unresected GI tumors . In other words, edoxaban can be used in cases in which the primary lesion was surgically removed. In addition, edoxaban, which is an orally disintegrating formulation, can be an easy-to-use drug for CAT prevention, especially during the postoperative period, even in cases of GIC in which the feeding condition is poor because of loss of appetite after surgery.
This study has notable limitations. First, this was a single-arm, prospective, interventional study without a control arm. Evaluating whether heparin administration could be omitted would require the inclusion of patients receiving prior heparin administration as a control arm. However, this approach was challenging in the present study because participants with asymptomatic CAT were less likely to accept heparin pretreatment, which required hospitalization. In Japan, LMWH, which is used as standard treatment for CAT in Europe and the United States, cannot be used due to insurance coverage. Therefore, it was not possible to compare LMWH and edoxaban in a randomized controlled trial setting in Japan. Second, the sample size was small, as the number of enrolled patients was approximately half of the target. One reason for the slow patient accrual was that this was a challenging clinical study targeting GIC, which carries a high risk of bleeding, and the COVID-19 pandemic may have also affected patient recruitment. However, as mentioned previously, the obtained results were similar to the accuracy assumed for evaluating the primary outcome, and it is considered that the results have specific implications. Third, the observation period was short (3 months), and the long-term effects have not been evaluated. Given that the purpose of the present study was to evaluate feasibility only at the early stage of the introduction of edoxaban without heparin, we used 3 months, not 6 months, as the time of evaluation. The protocol allowed each attending physician to decide whether to continue treatment or change the drug after 3 months. Further consideration of the long-term impact of this strategy is warranted. Fourth, the concordance rate was low between the thrombosis assessments performed by the investigators and the central review panel. Specifically, the difference between the investigator’s assessment and the central review tended to be more conspicuous for the determination of thrombus disappearance and improvement compared with the decision of exacerbation or no change in the thrombus. In most clinical studies using anticoagulants, the recurrence of thrombosis is often the endpoint and few studies have evaluated the state of thrombosis included in the present study. It should be noted that the discordance between the local and central evaluations may occur in studies where the disappearance of thrombus is defined as the endpoint to evaluate the efficacy of treatment for thrombosis.