Discussion
The main finding of this study is that weight (≤ 60 kg) and cancer were associated with bleeding complications under appropriate edoxaban dosage regimen. Patients with weights of less than or equal to 60 kg and cancer had around a 3.4-fold increased risk of bleeding complications compared to heavier patients (>60 kg) and those without cancer. In the subgroup analysis with high-risk patients who took low-dose edoxaban (15 mg and 30 mg), weights of less than or equal to 60 kg was remained a significant factor for bleeding outcomes than those who weigh more than 60 kg.
Edoxaban is implicated in the reduction of stroke and systemic embolism risks in nonvalvular AF and treatment of DVT and PE [5]. According to the 2019 AHA/ACC/HRS Guideline for the Management of AF, edoxaban has been added to the list of DOACs used for stroke prevention and is recommended over warfarin except in patients with moderate to severe mitral stenosis or prosthetic heart valves [1]. Several studies have shown that edoxaban was not inferior to warfarin regarding the prevention of stroke or systemic embolization and was associated with significantly lower rates of bleeding and death from cardiovascular causes [6-9]. Yet, although edoxaban is the preferred oral anticoagulant over warfarin, it still can increase the risk of bleeding and can cause serious or even potentially fatal bleeding. Hence, risk factors should be carefully considered when administering edoxaban.
It has been reported that Asians exhibit more bleeding risks than other ethnicities; a study showed that death from hemorrhagic stroke was more common in Asian patients compared to others [14]. Reports of bleeding complications with antithrombotic agents also consistently revealed that Asians experienced more bleeding complications than other ethnic groups. A meta-analysis showed that DOAC-associated intracranial hemorrhage (ICH) was significantly higher in the Asian population [15]. In addition, in the case of warfarin treatment, a retrospective cohort study using AF patients showed that the incidence for ICH in Asians was 4.06-times higher than in Caucasians [16]. For antiplatelet therapy, a meta-analysis showed that bleeding events occurred twice as frequently in Asians than in the non-Asian group [17].
Most dosage studies of oral anticoagulants have primarily involved Caucasians; therefore, current edoxaban dosage regimens may have been predominantly derived from data on white patients. This study showed that standard dosage regimens of edoxaban induced complications in Asian individuals, which may stem from ethnicity-dependent profiles. The U.S. Savaysa package insert suggested that DVT/PE patients with CrCl 15 to 50 mL/min, weights of less than or equal to 60 kg, or who are taking certain concomitant P-gp inhibitors are recommended to take 30 mg once daily [5]. Also, for patients with nonvalvular AF, CrCl 15-50 mL/min was the sole criterion for dose reduction [5]. In contrast, the Korean package insert suggests that patients with AF, in addition to DVT/PE, should reduce edoxaban dose under two more criteria, namely lower weight (≤ 60 kg) and P-gp inhibitor concomitant usage, alongside CrCl 15-50 mL/min. [12]. Thus it may be stated that considering high bleeding risks of Asian populations, the Korean dose recommendation is much more conservative.
In this study, subgroup analyses showed that 27 patients still experienced bleeding complications despite dosage adjustments. It has been previously established that the incidence of bleeding events during edoxaban administration shows a dose-dependent trend [18]. Moreover, Yamashita et al. reported body weight-dependent differences in the incidence of bleeding risks, suggesting that weight is an important factor to consider in assessing the risk of bleeding while taking edoxaban [18]. Hence, for ethnic groups that are known to be more prone to bleeding complications, modification of anticoagulation intensity may be considered. Since the current results showed that lower weight was a significant risk factor for bleeding outcome even in patients using low-dose edoxaban, more strict dosage guidelines for patients with lower weights could be beneficial or perhaps necessary.
This study revealed that cancer was significantly associated with bleeding complications for patients with edoxaban therapy. Cancer patients with anticoagulation are more prone to bleeding outcomes compared to those without cancer. A study showed that cancer patients on anticoagulation therapy had approximately 2.2-fold higher bleeding complications than those without malignancies [19]. Another retrospective analysis concluded that the incidence of bleeding complications for cancer patients was higher than in patients without cancer. Hutten et al. showed that patients with cancer, compared with nonmalignant patients, had a statistically significantly increased overall incidence (100 patient-years) of recurrence (27.1 vs 9.0, respectively) as well as bleeding (13.3 vs 2.1, respectively) [20]. Our study was also consistent with the findings that patients with cancer showed a 3.4-fold increased risk of bleeding complications than those without cancer.
It is possible that bleeding is caused by the cancer itself, as tumor invasion, abnormal tumor vasculature or tumor regression can increase risk of bleeding [21]. Furthermore, anti-tumor treatment including chemotherapy and anti-inflammatory drugs can exacerbate bleeding outcomes. Finally, cancer patients with thrombocytopenia from malignancies or chemotherapy may result in bleeding complications [21]. In this context, cancer should be considered for dosage adjustment when administering edoxaban. Moreover, more frequent monitoring in this high-risk group may be recommended.
The limitations of our study are that it was conducted in a single center and designed retrospectively. Another shortcoming is a lack of information on detailed mechanisms and genetic polymorphisms. Nevertheless, this study revealed potential risk factors for bleeding complications in Asian patients undergoing edoxaban therapy. In addition, this study provided preliminary data to modify current dosage regimen to reduce the risk of bleeding outcomes; these factors can be applied for developing individualized drug therapy with edoxaban.