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

Figures

• 

  Figure 1.. Flowchart of patient enrollment. BW, body weight; PC, plasma concentration.

• 

  Figure 2.. Distribution of trough (T) and peak plasma concentrations (PCs) in patients using (A) on-label 15 mg, off-label 10 mg, and on-label 10 mg rivaroxaban and (B) on-label 60 mg, off-label 60 mg (overdosing), off-label 30 mg, and on-label 30 mg edoxaban. Bleeding events (red circles) occurred in a total of 39 (10.0%) and 18 (5.4%) of patients using rivaroxaban and edoxaban, respectively. Red numbers and percentages in parentheses indicate the incidence of bleeding in each dosing group. In both the rivaroxaban and edoxaban groups, there were no differences in trough drug PCs between patients with and without bleeding events, except for 1 patient using off-label 60 mg edoxaban (overdose).

• 

  Figure 3.. Changes in peak plasma concentrations (PCs) with drug switching from rivaroxaban to edoxaban (n=86) or dose reduction to an off-label reduced dose (n=58) in identical patients with bleeding events and/or high PCs under rivaroxaban (R) and edoxaban (E) treatment. Peak PCs decreased not only with drug switching, but also with dose reduction. However, 4 patients (red lines) experienced bleeding events because of the off-label of edoxaban 60 mg (overdose). The boxes show the interquartile range, with the median value indicated by the horizontal line; whiskers show the range. In each box, the “X” and numbers next to the box indicate the mean values. BW, body weight.

• 

  Figure 4.. Peak plasma concentrations (PCs) and the incidence of bleeding in patients with a body weight of ≤60 kg and a creatinine clearance of >50 mL/min using rivaroxaban (Riv) on-label 15 mg (n=54) and edoxaban (Edox) on-label 30 mg (n=69). Rivaroxaban on-label 15 mg users (Group A1 in Table 3) had higher peak PCs (box plots) and a greater incidence rate of bleeding events (red), compared with patients using on-label edoxaban 30 mg (Group D1–2 in Table 3). The boxes show the interquartile range, with the median value indicated by the horizontal line; whiskers show the range. In each box, the “X” and numbers next to the box indicate the mean values.

• 

  Figure 5.. Relationship between prothrombin time (PT), measured using Thromborel® S, and plasma concentrations (PCs) in patients receiving rivaroxaban (Left) or edoxaban (Right). There was a good correlation between PT and PCs (r=0.883, P<0.0001) in the 280 samples from edoxaban users, but a poor correlation in rivaroxaban users. Using this correlation in edoxaban users, we determined a cut-off level of 21.7 s for peak PT (area under the curve [AUC] 0.857; Lower right) for predicting bleeding events in the 280 on-label users with PT data. CI, confidence interval.