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.