A randomized, open-label trial of edoxaban in Japanese patients with severe renal impairment undergoing lower-limb orthopedic surgery

Takeshi Fuji, Satoru Fujita, Yohko Kawai, Yasuyuki Abe, Tetsuya Kimura, Masayuki Fukuzawa, Kenji Abe, Shintaro Tachibana, Takeshi Fuji, Satoru Fujita, Yohko Kawai, Yasuyuki Abe, Tetsuya Kimura, Masayuki Fukuzawa, Kenji Abe, Shintaro Tachibana

Abstract

Background: Edoxaban is an oral, direct, factor Xa inhibitor approved in Japan for thromboembolic prophylaxis after lower-limb orthopedic surgery (LLOS), but contraindicated in patients with severe renal impairment (SRI; creatinine clearance [CLCR] ≥15 to <30 mL/min).

Methods: This open-label study compared the safety of edoxaban 15 mg once daily in Japanese patients with SRI to that of edoxaban 30 mg in patients with mild renal impairment (MiRI; CLCR ≥50 to ≤80 mL/min; N = 30) undergoing LLOS. Patients with CLCR ≥20 to <30 mL/min were randomized to receive edoxaban 15 mg (N = 22) or subcutaneous fondaparinux 1.5 mg once daily (N = 21). All patients with CLCR ≥15 to <20 mL/min received edoxaban 15 mg (N = 7). Treatment was administered for 11 to 14 days.

Results: Major or clinically relevant non-major bleeding occurred in 6.7%, 3.4%, and 5.0% of patients in the MiRI edoxaban 30-mg, SRI edoxaban 15-mg, and SRI fondaparinux groups, respectively; there were no major bleeding events. No thromboembolic events occurred. At all time points assessed, edoxaban plasma concentrations and changes in coagulation biomarkers were similar between the SRI and MiRI groups.

Conclusions: These results suggest edoxaban 15 mg once daily is well tolerated in Japanese patients with SRI undergoing LLOS.

Trial registration: Clinicaltrials.gov Identifier: NCT01857583.

Keywords: Edoxaban; Orthopedic surgery; Renal impairment; Thromboprophylaxis.

Figures

Figure 1
Figure 1
Study design. CLCR = creatinine clearance; HFS = hip fracture surgery; MiRI = mild renal impairment; R = randomization; SRI = severe renal impairment; THA = total hip arthroplasty; TKA = total knee arthroplasty.
Figure 2
Figure 2
Patient disposition. CLCR = creatinine clearance; EDX = edoxaban; FPX = fondaparinux; MiRI = mild renal impairment; SRI = severe renal impairment. aOne patient randomized to FPX 1.5 mg discontinued prior to initiation of study treatment due to excessive bleeding from the surgical wound.
Figure 3
Figure 3
Mean plasma concentrations of edoxaban on day 7. Horizontal line = median; + = mean; error bars = minimum and maximum values within 1.5 interquartile range; • = outliers; SRI = severe renal impairment; MiRI = mild renal impairment.
Figure 4
Figure 4
Relationship between plasma edoxaban concentrations and A) PT; B) aPTT on day 7 and completion. aPTT = activated partial thromboplastin time; CLCR = creatinine clearance; EDX = edoxaban; MiRI = mild renal impairment; PT = prothrombin time; SRI = severe renal impairment.

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