Is Rivaroxaban Safe in Patients With Renal Dysfunction?

Direct oral anticoagulants (DOACs) are well known to reduce critical bleeding compared with warfarin, as shown in pivotal trials of the currently used four DOACs. Rivaroxaban had been recognized as having a relatively higher risk of bleeding than other DOACs because the ROCKET-AF trial showed a higher bleeding rate.¹⁾ This was partially explained by the fact that the ROCKET-AF trial was conducted on patients with higher CHA₂DS₂-VASc scores and more co-morbidities than other trials. Afterward, real-world registry studies of rivaroxaban, such as XANTUS, XANAP, XANAP KR, and XaMINA, were conducted. These studies’ bleeding rates were similar to or better than those of other DOAC trials.

Anticoagulation in patients with chronic kidney disease (CKD) should be considered more seriously because CKD patients tend to have a higher risk of bleeding because of coagulopathy and co-morbidities. DOACs are also recommended to patients with CKD, except stage 5, because of their efficacy and safety over warfarin.²⁾ These recommendations are primarily based on the subgroup analysis of pivotal trials, systematic reviews, or retrospective observational studies using national or regional electronic data. Prospective studies of DOACs used in CKD patients were barely conducted.

In this issue of Korean Circulation Journal, Oh et al.³⁾ present data from a multicenter prospective registry of patients taking rivaroxaban with renal dysfunction (creatinine clearance, 15–49 mL/min) to evaluate real-world safety and efficacy. This study included patients with relatively high thromboembolic risk (CHACDS₂-VASc score 3.3±1.4), reporting major bleeding occurred in 5.6%, non-major bleeding in 10.5%, systemic thromboembolic events in 1.4%, and all-cause death in 2% during 2-years of follow-up.

The risk of major bleeding from rivaroxaban in this study appears comparable to those of other DOACs. However, a direct comparison of a DOAC with another is generally not possible. Little research has been done on the head-to-head comparison of DOACs, studies used various measures of outcome, and the quality and characteristics of data from retrospective studies are not standardized. One edoxaban retrospective study with 2–7 months of follow-up duration showed the incidence rate of major bleeding was 5.5%/year in patients taking 30 mg of edoxaban.⁴⁾ Another retrospective study comparing all DOACs with warfarin while stratifying patients as renal function showed major bleeding incidence rates of 4.4%/100 patient-year in patients with estimated glomerular filtration rate <60 mL/min/1.73 m².⁵⁾ In the subgroup analysis of the RE-LY trial using dabigatran, patients with renal dysfunction taking 110 mg showed a major bleeding rate of 5.45%/year.⁶⁾ Overall, in terms of major bleeding in patients with renal impairment, rivaroxaban is tolerable, similar to other DOACs.

This study has limitations other than those noted by the authors in the text. It is a single-arm observational study without a control group to compare. And rivaroxaban 10 mg was used in 10.6% of patients. Although rivaroxaban 10 mg once daily was used as a low-dose rivaroxaban in the J-ROCKET trial, the global and Korean-approved dose is still 15 mg in patients with mild to moderate renal dysfunction. The mixed use of rivaroxaban dosage should be considered when we interpret this study.