Introduction
Venous thromboembolism (VTE), comprising pulmonary embolism (PE) and deep vein thrombosis (DVT), is a prevalent vascular disease with a lifetime risk of around 8% among adults in the United States, gaining increasing awareness [
1]. The mainstay for the treatment of VTE is anticoagulation therapy, incorporating medications such as heparin, vitamin K antagonists (VKA), and direct oral anticoagulants (DOACs) [
2]. DOACs are increasingly replacing VKAs due to comparable efficacy and a lower risk of complications such as bleeding, as evidenced by several studies [
3–
6]. Additionally, DOACs offer several advantages over VKAs, including predictable pharmacokinetics that reduce the need for routine monitoring and allow for fixed-dose administration, coupled with fewer dietary interactions [
7].
However, VKAs have not been entirely replaced, especially in cases involving end-stage kidney disease (ESKD), where the safety of DOACs is not fully established since they are excreted through the kidneys [
8]. Considering the annual increase in ESKD patients and the significantly higher VTE risk in this population compared to the general population, VTE in ESKD patients emerges as a major health issue [
9]. Nevertheless, there is a dearth of research focusing on the safety of using DOACs in ESKD patients with VTE.
Therefore, in this study, our aim is to investigate the differences in major complications arising from the use of DOACs in patients undergoing hemodialysis compared to those with chronic kidney disease (CKD) not undergoing hemodialysis using national claim data.
Discussion
VTE, encompassing both PE and DVT, stands as a prevalent vascular disease with a documented increase in prevalence over time [
10]. Historically, VKAs were the cornerstone of treatment. However, the past decade has witnessed a significant shift towards DOACs, characterized by their advantageous features such as the absence of the need for laboratory monitoring and dose adjustment [
11]. Notably, due to the substantial renal elimination of DOACs, patients with a creatinine clearance (CrCl) of less than 30 mL/min, were advised to use VKAs [
12]. The four DOACs—dabigatran, rivaroxaban, edoxaban, and apixaban—demonstrate renal excretion rates of 80%, 66%, 50%, and 27%, respectively [
7]. Nevertheless, in practice, DOACs are being employed even in ESKD patients with a CrCl of less than 15 mL/min [
13]. Our study also revealed an increasing trend in the prescription of DOACs among CKD patients irrespective of whether they are receiving dialysis. However, there is a noticeable gap in the existing literature concerning the efficacy and safety of DOACs in ESKD patients undergoing dialysis [
8]. Consequently, our primary emphasis was on examining the safety aspect of DOACs within this population.
While our study indeed concentrates on safety outcomes, it is crucial to acknowledge that efficacy, particularly measured by recurrent VTE, plays a vital role in assessing the benefits of DOAC use in CKD patients. Bauersachs et al. [
14] demonstrated that rivaroxaban effectively prevents recurrent VTE across all renal function categories when compared to enoxaparin/VKA (P
interaction = 0.72), with recurrence rates varying from 1.8% to 4.8% in patients with different levels of renal impairment. Similarly, Goldhaber et al. [
15] found that dabigatran demonstrated better efficacy, indicated by the rates of VTE and VTE-related death, compared to warfarin in patients with renal insufficiency (CrCl 50 to <80 mL/min: 1.9% with dabigatran vs. 1.6% with VKA; CrCl 30 to <50 mL/min: 0% with dabigatran vs. 4.1% with VKA). However, research on the efficacy of DOACs for VTE in ESKD patients undergoing dialysis is limited, with only retrospective studies available. Reed et al. [
16] reported no significant difference in efficacy between apixaban and warfarin in ESKD patients undergoing dialysis (4.4% vs. 28.6%, p = 0.99) [
16]. While existing research suggests that DOACs appear to be non-inferior to VKAs, the limited number of studies poses challenges in drawing definitive conclusions.
The primary focus of our study was the safety outcome, typically defined as major bleeding or clinically relevant nonmajor bleeding. This is a crucial consideration in the use of DOACs in CKD patients, given their higher bleeding risk compared to the general population [
17]. Although DOACs are excreted renally to some extent, leading to reduced clearance and increased exposure in CKD patients [
7], most studies have consistently demonstrated that DOACs are similar to or even safer than VKAs in terms of safety, regardless of the stage of CKD. In a study by Bauersachs et al. [
14], HRs for major bleeding with rivaroxaban-enoxaparin/VKA were 0.79 (95% CI, 0.46–1.36) for normal renal function, 0.44 (95% CI, 0.24–0.84) for mild renal impairment, and 0.23 (95% CI, 0.06–0.81) for moderate renal impairment (P
interaction = 0.034). Similarly, in a study by Goldhaber et al. [
15], there was no significant difference in safety outcomes between dabigatran and VKA in patients with moderate renal impairment (in subgroup aged <75 years: dabigatran 10.0% vs. VKA 12.9%; in subgroup aged ≥75 years: dabigatran 11.8% vs. VKA 9.6%). Examining safety outcomes in ESKD patients on dialysis, the apixaban group exhibited fewer overall bleeding events (18.9% vs. 42.0%, p = 0.01) and major bleeding events (5.4% vs. 22%, p = 0.01) compared to the warfarin group [
16]. In our study, we did not specifically focus on differences between medications but rather observed bleeding complications associated with DOAC use in CKD patients comparing those receiving dialysis with those who were not. Importantly, there was no significant difference in complication rates between the two groups.
Fig. 2 suggests that both gastrointestinal and intracranial bleeding may appear higher in the HD group, but this difference is primarily driven by higher mortality in patients on dialysis, and it is not statistically significant. Therefore, there is no compelling reason to completely abandon the use of DOACs in CKD patients on dialysis.
Despite these findings, our study has several limitations. Firstly, it was retrospective, and the number of patients was limited. Secondly, the NHIS data, designed for reimbursement rather than research, lacks detailed clinical information. For instance, we were unable to differentiate the stages of CKD, making it impossible to gauge the severity of CKD in the control group, necessitating caution in interpreting the study results. We were also unable to differentiate between the types of DOACs due to NHIS data policy, preventing us from analyzing the risks associated with each specific medication.
In addition, our study was limited in evaluating the efficacy of VTE treatment in this population. Thus, our focus was on presenting safety outcomes related to DOACs rather than assessing efficacy. The nature of our dataset also restricts our findings to CKD patients, making a direct safety comparison with the general population unfeasible [
18]. Consequently, our results do not imply that the safety of using DOACs in dialysis patients is comparable to that in the general population. Nevertheless, these comparisons can offer more targeted and specific information for these distinct patient populations, allowing for a nuanced understanding of the safety profile of DOACs within the CKD spectrum. Additionally, we believe our study possesses strengths owing to the comprehensive coverage of medical practices in Korea provided by the NHIS database. This minimizes the likelihood of missing claims and patient loss, enhancing the robustness of our findings.