Safety and Efficacy Re-Evaluation of Edoxaban and Rivaroxaban Dosing With Plasma Concentration Monitoring in Non-Valvular Atrial Fibrillation: With Observations of On-Label and Off-Label Dosing

Abstract

Background: Off-label dosing of direct oral anticoagulants (DOAC) as a treatment for non-valvular atrial fibrillation (NVAF) is problematic. Here, we investigated the status of rivaroxaban and edoxaban dosing by monitoring plasma concentrations (PCs). Methods and Results:We monitored drug PCs in 391 and 333 outpatients receiving rivaroxaban and edoxaban, respectively, for NVAF. Drug doses were adjusted if the PC was above the cut-off value (rivaroxaban: 404 ng/mL; edoxaban: 402 ng/mL), determined from receiver operating characteristic curves for predicting bleeding events. On-label standard dosing was reduced to off-label underdosing due to high PCs above the cut-off more often for rivaroxaban (28.1%) than edoxaban (12.6%; P<0.001). Over a median follow-up of 13 months for rivaroxaban and 10 months for edoxaban, the annual incidence of bleeding events was higher with rivaroxaban than with edoxaban (4.88 vs. 3.73 patient-years; P<0.05), although no thromboembolic events occurred in either group. Furthermore, for patients with creatinine clearance >50 mL/min and body weight ≤60 kg, there was a greater incidence of bleeding events with rivaroxaban on-label 15 mg dosing than with edoxaban on-label 30 mg dosing (22.2% vs 2.9%; P<0.01). Conclusions:Monitoring the PCs of rivaroxaban and edoxaban in NVAF patients enables dose adjustments to reduce bleeding risk. The incidence of bleeding under drug PC monitoring was less in the edoxaban than rivaroxaban group.

Letter by Suwa et al Regarding Article, “Safety of Switching From a Vitamin K Antagonist to a Non–Vitamin K Antagonist Oral Anticoagulant in Frail Older Patients With Atrial Fibrillation: Results of the FRAIL-AF Randomized Controlled Trial”

“…We indicated that rivaroxaban had a high incidence of bleeding events, and plasma concentration in peak samplings measured with anti-FXa chromogenic assay showed higher levels in rivaroxaban compared with edoxaban dosing. 2 We had the same results when switching from rivaroxaban to edoxaban in the same patients, including elderly participants. 2 As mentioned previously, plasma concentration–directed dose adjustment has been shown to be helpful in controlling outcomes and prevented unnecessary bleeding events in NOAC dosing, even off-label dosing.…”

“…2 We had the same results when switching from rivaroxaban to edoxaban in the same patients, including elderly participants. 2 As mentioned previously, plasma concentration–directed dose adjustment has been shown to be helpful in controlling outcomes and prevented unnecessary bleeding events in NOAC dosing, even off-label dosing. 2,3 When using oral anticoagulants, many bleeding and thromboembolic events occurred.…”

“…2 As mentioned previously, plasma concentration–directed dose adjustment has been shown to be helpful in controlling outcomes and prevented unnecessary bleeding events in NOAC dosing, even off-label dosing. 2,3 When using oral anticoagulants, many bleeding and thromboembolic events occurred. If possible, we must differentiate whether these events are drug-induced, or not.…”

“…In our report, we indicate that plasma concentration monitoring can differentiate whether bleeding events are drug-induced in NOAC or not. 2 Reevaluation using plasma level measurement may challenge the results reported by Joosten et al 1 that VKA treatment is superior to NOAC in terms of bleeding complications. Furthermore, NOAC monitoring will clarify safety differences among NOACs.…”