Efficacy of edoxaban for the treatment of gynecological cancer-associated venous thromboembolism: analysis of Japanese real-world data

Patients with cancer have a 4-to-7-fold increased risk for venous thromboembolism (VTE) compared with people without cancer [1, 2]. Management of cancer-associated venous thromboembolism (CAT) is extremely important because it can cause death and interrupt cancer treatment [3, 4]. Vitamin K antagonists (VKAs) and low-molecular-weight heparin (LMWH) are generally used to treat CAT [5]. However, direct oral anticoagulants (DOACs) were recently approved for the treatment of CAT based on the results of clinical trials that showed the non-inferiority of DOACs to LMWH in terms of efficacy and safety [6, 7, 8]. Therefore, the current guidelines for the management of CAT recommend the use of DOACs, as well as LMWH, for the management of CAT. Consequently, DOACs are being increasingly used for the treatment of CAT [9, 10, 11].

Regarding gynecological malignancies, it was reported that 25%–38% of patients with gynecological cancers have VTE; therefore, they are regarded as high-risk patients. In accordance with the aforementioned pan-cancer guidelines, the Society of Gynecological Oncology Clinical Statement strongly recommends that patients with gynecological CAT should receive long-term treatment (at least 3–6 months) using LMWH or DOACs [12]. However, this recommendation is based on the results of trials conducted primarily on mixed populations with different types of cancer and a small number of patients with gynecological cancer. Indeed, only 10.5% of the study population of the Hokusai VTE Cancer study, which showed the noninferiority of edoxaban to dalteparin, were patients with gynecological cancer [6]. Considering that there is relatively little evidence of the efficacy of DOACs for the treatment of gynecological malignancies, we reckon that it is important to verify the efficacy and safety of DOACs for the treatment of gynecological cancers using Japanese real-world data. Therefore, this retrospective study was conducted to investigate the efficacy and safety of edoxaban (Lixana^®; Daiichi Sankyo, Tokyo, Japan), which is the first DOAC approved in Japan and the most utilized for the treatment of gynecological CAT compared with VKA.

This study was approved by the Jikei University ethical review board of the institutes participating in this study (31-018 [9517]). Informed consent was obtained from the participants by providing an opt-out option on participating institutional websites. We reviewed the medical records of 371 patients with gynecological malignancies, including ovarian, uterine, and cervical cancers, who received edoxaban or VKA treatment for VTE at the participating 4 hospitals between January 2011 and December 2018. All patients had symptomatic or non-symptomatic pulmonary embolism (PE) and/or deep vein thrombosis (DVT). Patients with borderline ovarian malignancy or synchronous cancer were excluded. Patients were also excluded if they had a history of thrombosis.

After the diagnosis of cancer, the D-dimer (D-d) levels of all patients were routinely measured for CAT screening. The patients were subsequently followed-up by physicians depending on their symptoms and the occurrence of events, including tumor recurrence and surgery, during cancer management. If a patient’s D-d level exceeded 1.0 µg/mL regardless of symptoms and/or if a patient showed any symptoms related to CAT, such as pain, swelling, leg tenderness, unexplained shortness of breath, or chest pain, contrast-enhanced computed tomography (CT) and/or lower limb ultrasonography were performed for the diagnosis of VTE. After the diagnosis of VTE, follow-up examinations, which included contrast-enhanced CT or ultrasonography, were performed periodically.

The anticoagulant drug administered to each patient was selected by a physician. Edoxaban was approved by the Pharmaceutical and Medical Devices Agency of Japan in September 2014, whereas LMWH has not yet been approved; thus, VKA was the only option in Japan until September 2014. Each physician decided whether unfractionated heparin (UFH) should be administered as an initial anticoagulant prior to VKA or edoxaban. The UFH dose was adjusted to ensure that the patient’s activated partial thromboplastin time (APTT) was in the therapeutic range of 40–60 seconds. The dose of edoxaban was 30 mg/day for patients who weighed less than 60 kg and 60 mg/day for those who weighed more than 60 kg. Patients with renal dysfunction whose creatinine clearance was between 30 and 50 mL per minute were administered 30 mg/day of edoxaban. The initial VKA dose was determined by each physician and adjusted toward a target prothrombin time-international normalized ratio of 2.0 (range, 1.5–2.5).

The primary efficacy outcome was VTE recurrence, defined as new symptomatic or asymptomatic PE or DVT. The primary safety outcome was the occurrence of any clinically relevant adverse event. In accordance with the criteria provided by the International Society on Thrombosis and Haemostasis, major bleeding was defined as overt bleeding associated with a decrease in hemoglobin level of 2 g per deciliter or more, leading to transfusion of 2 or more units of blood [13]. Clinically relevant non-major bleeding was defined as any overt bleeding events during the therapeutic period that did not meet the criteria for major bleeding but resulted in medical attention, unappointed visits, discontinuation of anticoagulants, or a decrease in patients’ activities.

Patients’ characteristics, including age, body weight, tumor type, International Federation of Gynecology and Obstetrics (FIGO) stage of tumor, histological diagnosis, symptoms, VTE site, timing of VTE diagnosis during the oncological clinical course, D-d value at the first diagnosis of VTE, VTE recurrence, all adverse events, induction of UFH therapy, duration of UFH therapy, and entire duration of anticoagulant therapy, were retrieved. Follow-up duration was calculated as the duration from the date of VTE diagnosis to the date of the last follow-up.

Statistical analyses were performed using EZR software version 1.37 (Saitama Medical Center, Jichii Medical University, Saitama, Japan) [14]. Continuous variables were compared using unpaired t-tests. Categorical variables are presented as absolute numbers and/or percentages and were compared using the χ² test. To compare the occurrence of adverse events between the 2 treatment groups, the time to VTE recurrence was analyzed using a Cox proportional-hazards model. Time-to-event curves were calculated using the Kaplan-Meier method. The significance level was set at p<0.05.

In this retrospective study, we demonstrated that edoxaban is effective and safe for the treatment of gynecological CAT using a large amount of patient data. To our knowledge, this is the first study to show the efficacy of edoxaban for the treatment of ovarian, endometrial, and cervical CAT through subgroup analysis of different tumor types. Additionally, this study showed that initiation of UFH therapy may not be necessary for patients without PE.

Based on the results of a series of clinical trials, including the Hokusai VTE Cancer (edoxaban vs. dalteparin, n=522 vs. 524), Caravaggio (apixaban vs. dalteparin, n=576 vs. 579), and SELECT-D (rivaroxaban vs. dalteparin, n=203 vs. 203) trials, and meta-analyses including these trials, DOACs are considered effective, safe, and useful for the treatment of CAT [6, 7, 8]. These trials showed that the rate of VTE recurrence in patients treated with DOACs ranges from 4% to 8% and that of major bleeding events ranges from 3% to 7%, which is not inferior to the rates for LMWH [16]. Indeed, some guidelines recommend using DOACs, as well as LMWH, for the treatment of CAT. The guidelines provided by the American Society of Clinical Oncology recommend edoxaban and rivaroxaban for the treatment of CAT, whereas those by the National Comprehensive Cancer Network recommend edoxaban, apixaban, and rivaroxaban [12]. Unfortunately, patients with gynecological cancer were a relatively minor cohort in the abovementioned trials. There were 110 (10.5%) cases of gynecological cancer in the Hokusai VTE Cancer trial, which included 1,050 cases in total, 119 (10.3%) in the Caravaggio trial, which included 1,155 cases in total, and 13 (3.2%) in the SELECT-D trial, which included 406 cases. Notably, subgroup analysis of different cancer types was performed in the Hokusai VTE Cancer trial [17]. In that trial, the outcomes of patients with gynecological cancer were analyzed, and the results showed that edoxaban is just as effective and safe as dalteparin. The authors reported that 3 (6.3%) patients treated with edoxaban and 9 (14.3%) treated with dalteparin experienced VTE recurrence, whereas 2 (4.2%) patients treated with edoxaban and 2 (3.2%) treated with dalteparin had on-treatment major bleeding. Unfortunately, subgroup analysis for gynecological malignancies was not performed in the other 2 trials.

Regarding other data on the use of DOACs for the treatment of gynecological CAT, Lee et al. [18] conducted a retrospective analysis of data on the use of rivaroxaban for the treatment of gynecological CAT. A total of 102 and 60 cases were included in the rivaroxaban and dalteparin groups, respectively, making it the largest study on the use of DOACs for gynecological CAT until the present study was performed. In that study, 6 (5.9%) patients treated with rivaroxaban and 4 (6.7%) treated with dalteparin experienced recurrent VTE, whereas major bleeding occurred in 8 (7.8%) and 3 (5.0%) patients treated with rivaroxaban and dalteparin, respectively. Likewise, Shimizu et al. [19] also performed a retrospective study that compared the outcome of DOACs and VKA for gynecological CAT. In the study, 54 and 53 patients were included in the DOACs and VKA groups, respectively, and 3 of the 53 patients (5.7%) in the VKA group developed recurrent VTE; there was no VTE recurrent patient in DOACs group, and only 1 patient (1.9%) in the DOACs group showed clinically relevant bleeding. In this study, 14 (6.6%) and 11 (5.2%) of the 211 patients who received edoxaban and 22 (13.8%) and 11 (6.9%) of the 160 patients who received VKA for the treatment of CAT experienced VTE recurrence and major bleeding, respectively. Cumulative recurrence of VTE was also equivalent between edoxaban and VKA. Accordingly, the outcome of edoxaban and VKA for gynecological CAT is equivalent in terms of efficacy and safety. Therefore, this study, which was performed on a larger scale than any previous prospective and retrospective studies, provides evidence that supports the existing data on the efficacy of DOACs for the treatment of gynecological CAT.

Previously reported data on the efficacy of DOACs for the treatment of gynecological CAT do not include analysis according to tumor types within gynecological malignancies, probably because of the small number of cases included in previous studies. In the Hokusai VTE Cancer trial, only 19, 15, and 10 cases of ovarian, endometrial, and cervical cancer, respectively, were included in the edoxaban group, whereas 33, 22, and 4 cases were included in the dalteparin group. It is important to consider that different cancers are associated with different degrees of risks for VTE because of factors such as patient’s characteristics, histological type of the tumor, tumor stage, and treatment regimen [20, 21, 22, 23, 24]. The risk for VTE recurrence is also affected by tumor features [25]. A previous study showed that the VTE risk was approximately 14-fold higher in patients with gynecologic cancer than without cancer, indicating DVT and PE incidence, ranging from 17% to 40% and 1% to 2.6%, respectively [26, 27, 28]. In detail, ovarian cancer, especially the clear cell carcinoma type, is reported to be associated with a higher risk for VTE than other types of gynecological malignancies. The patients have adenocarcinoma, a high rate of advanced disease, and are at high-risk of tumor recurrence, thereby requiring highly invasive surgery and chemotherapy [23, 29, 30, 31]. We could see some difference in response to anticoagulants between tumors in our results. The curve of cumulative VTE of the edoxaban group runs higher than VKA in ovarian cancer, whereas VKA run higher than edoxaban, and these differences may reflect tumor-specific features.

In addition, the risk of bleeding during anticoagulant therapy is influenced by the tumor site of origin, tumor stage, chemotherapy agents, radiation therapy, and surgery [32, 33]. In this context, we believe that the data of each type of gynecological malignancy would be useful in deciding on the anticoagulant to be administered. To our knowledge, this is the first study to demonstrate that ovarian, endometrial, and cervical CAT can be safely and effectively treated using edoxaban. However, there were 2 cases of intraperitoneal hemorrhage and one case of gastrointestinal bleeding due to ovarian cancer carcinomatosis and one case of intestinal bleeding due to radiation colitis in a patient with cervical cancer. These outcomes are tumor-specific features. Carcinomatosis is a common feature of ovarian cancer, whereas irradiation is the standard of care for locally advanced cervical cancer. Whether treatment with DOACs, including edoxaban, is associated with an increased risk of bleeding compared with LMWH or VKA therapy is still unclear. Thus, the possible risks of tumor-specific bleeding need to be considered during therapy especially carcinomatosis of ovarian cancer (Table S1) [6, 16].

We also investigated the necessity of UFH induction prior to administration of edoxaban because we noted that it had been omitted in many cases in the present study, despite its recommendation by the FDA (Fig. 2, Table 4, Fig. S2). This is probably because initiation of UFH requires in-hospital management with close monitoring of APTT, making it inconvenient in most cases. However, the study data showed that omission of initial UFH therapy did not cause significant increase in the progression of VTE (Table 4, Fig. 2). However, the backgrounds of the patients in the UFH and single-drug subgroups are different. Compared with the UFH subgroup, the single-drug subgroup had more patients without PE. Nakamura et al. [34] reported similar results in a prospective observational study of the use of edoxaban for the treatment of VTE in a Japanese cohort, approximately 25% of whom were patients with cancer. In that study, 44% of the patients who did not undergo initial UFH treatment did not show increased VTE recurrence. However, most patients with PE or proximal DVT in the study underwent initial UFH therapy. Therefore, the authors concluded that initial UFH is necessary, particularly for PE and proximal DVT. Collectively, we believe that single-drug therapy without initial UFH therapy may be useful for the treatment of patients without severe VTE, such as PE. However, further investigation is needed to provide solid evidence regarding the efficacy and safety of omitting initial UFH therapy for the treatment of patients without severe VTE.

This study has several limitations. First, the retrospective design prevented the elimination of potential confounding biases in the analysis, such as bias in the selection of the treatment method used in each case. Second, we compared the efficacy of edoxaban with that of VKA instead of LMWH. Evidence shows that LMWH is superior to VKA for the treatment of CAT. Unfortunately, LMWH for VTE is not approved in Japan; therefore, it was impossible to compare edoxaban with LMWH in the present study.

In conclusion, this study confirmed that edoxaban is effective and safe for the treatment of gynecological CAT. This result was consistent across types of gynecological cancer.

Table S1

Details of major bleeding events

Fig. S1

Annual shift in the proportion of patients who received VKA and edoxaban anticoagulants.

Fig. S2

Proportion of patients who received initial UFH during the study period.