Therapeutic monitoring of rivaroxaban in dogs using thromboelastography and prothrombin time

Abstract

Background: The chromogenic anti-Xa assay, the gold standard for monitoring the anti-Xa effect of rivaroxaban, is not available as a cage-side diagnostic test for use in a clinical setting.

Hypothesis/objectives: To evaluate clinical modalities for measuring the anticoagulant effects of rivaroxaban using a point-of-care prothrombin time (PT) and thromboelastography (TEG).

Animals: Six healthy Beagle dogs.

Methods: Prospective, experimental study. Four different doses of rivaroxaban (0.5, 1, 2, and 4 mg/kg) were administered PO to dogs. Single PO and 3 consecutive dosing regimens also were assessed. Plasma rivaroxaban concentration was determined using a chromogenic anti-Xa assay, point-of-care PT, and TEG analysis with 4 activators (RapidTEG, 1 : 100 tissue factor [TF100], 1 : 3700 tissue factor [TF3700], and kaolin), and results were compared. Spearman correlation coefficients were calculated between ratios (peak to baseline PT; peak reaction time [R] of TEG to baseline [R] of TEG) and anti-Xa concentration.

Results: Anti-Xa concentration had a significant correlation with point-of-care PT (R = 0.82, P < .001) and RapidTEG-TEG, TF100-TEG, and TF3700-TEG (R = 0.76, P < .001; R = 0.82, P < .001; and R = 0.83, P < .001, respectively).

Conclusions and clinical importance: Overall, a 1.5-1.9 × delay in PT and R values of TEG 3 hours after rivaroxaban administration is required to achieve therapeutic anti-Xa concentrations of rivaroxaban in canine plasma. The R values of TEG, specifically using tissue factors (RapidTEG, TF100, TF3700) and point-of-care PT for rivaroxaban can be used practically for therapeutic monitoring of rivaroxaban in dogs.

Keywords: TEG; anti-Xa; oral anticoagulant; point-of-care PT test.

Figure 1

Plasma anti‐Xa concentration in dogs with rivaroxaban administration. A, Plasma anti‐Xa concentration after 3 consecutive days of rivaroxaban administration at different doses (0.5 mg/kg [n = 3] and 1 mg/kg [n = 3]). In order to determine peak plasma concentration of anti‐Xa, only 2 different doses were challenged. Error bar shows 95% confidence intervals. B, Plasma anti‐Xa concentration after administration for 3 consecutive days to different subject with 0.5 (Dog A‐C) and 1 (Dog D‐F) mg/kg. The line represented individuals. C, Spearman correlation coefficient showing linear correlation between the dose and plasma anti‐Xa concentration at 3 hours time point with baseline values of 0 mg/kg dosage group (R = 0.84, P < .001). However, 3 hours plasma anti‐Xa concentrations of each dosage (0.5, 1, 2, and 4 mg/kg [n = 6]) of rivaroxaban were not significantly different among doses. D, Plasma anti‐Xa concentration after a single dose of rivaroxaban administered after 3 hours to dogs. The line represented individuals

Figure 2

Scatter plot shows a strong, positive linear association between plasma anti‐Xa concentration and ratio values (peak time result/baseline result). (A) Prothrombin time (PT) ratio, (B) RapidTEG‐TEG R ratio, (C) TF100‐TEG R ratio. Ratio values were calculated by dividing results at peak time (3 hours) to baseline. Scatter plot shows based on anti‐Xa concentration after 4 different dosages (0.5, 1, 2, and 4 mg/kg) of rivaroxaban. Therapeutic range of ratio values (dashed line) was calculated by using linear regression equation that corresponds to plasma anti‐Xa concentration of 140‐260 ng/mL, which is an effective thromboprophylactic anti‐Xa concentration range in humans. Thus, the dashed lines represent the targeted plasma anti‐Xa concentration and the corresponding PT ratio. TEG, thromboelastography