Efficacy and Safety of Rivaroxaban: An Observationalmulticenter Cohort Study Reporting the Routine Use in Adolescents & Adults with DVT

Background: Antithrombotic therapy with Rivaroxaban [RIVA] is increasingly being administered for secondary TE prophylaxis in adults. The objective of the present study was to evaluate efficacy and safety of standard RIVA administered as routine medication in an outpatient cohort of pts with TE. Furthermore, on an explorative basis we investigated the influence of RIVA on coagulation factors and biomarkers, and the impact of RIVA monitoring during routine administration.

Methods: In 140 consecutively admitted whiteoutpts (15-82 yrs; male 56%) with TE and standard RIVA medication (2x 15 mg followed by 20 mg absolute) recruited between January 2013 and January 2014, a comprehensive monitoring of RIVA through (24h) and peak levels (2h, 4h; Xa-based chromogenic substrate S-2732; Haemochrom Diagnostica) alongwith anti-factor-Xa-activities [Xa; Xa-based assay, Haemochrom Diagnostica], selected coagulation factors and biomarkers (factors II, V, VIII, von-Willebrand-Ristocetin-cofactor [RICO], antithrombin [AT], protein C [PC], D-Dimer, prothrombin fragment F1+2 [F1+2], dRVVT-ratio) was performed during routine follow-up. Efficacy endpoints were defined as any TE or thrombus progression during treatment, safety endpoints were defined as significant bleeding requiring any medical intervention, such as dose reduction, withdrawal of RIVA or death related to therapy. Blood samples were taken during routine follow-up visits in the study centers on a monthly (RIVA start) to 3-months (maintenance) interval. Apart from descriptive analysis non-parametric statistics was performed. In addition, chi-square or Fisher’s exact test was applied.

Results: During the study period of 15 months in 140 pts 210 follow-up visits including analyses of 420 individual blood samples were performed. Median pt age was 49yrs, with no difference between males and females. Median (min-max) body weight [bw] per kg was 85 (50-151). Median (min-max) daily RIVA dose per kgbw was 0.2 mg (0.09-0.51).Due to a significant lower bw the median daily RIVA dose of 0.24 mg (0.1-0.51) in females was significantly higher compared to males with 0.20 mg (0.09-0.4; p<0.000). The RIVA dose was clearly correlated to Xa (p<0.0001; rho=0.945). Median (min-max) 24h RIVA levels were 19 ng/ml (0-182) corresponding to Xa activities of 0.1 IU/ml (0.1-1.5), 2h RIVA levels were 175 ng/ml (13-390) and 2h Xa levels 1.19 IU/ml (0.1-2.86). Finally, 4h levels revealed 169 ng/ml (26.8-427) for RIVA and 1.47 IU/ml (0.15-3.27) for Xa activities. During the study period in one out of 140 patients thrombosis progression was observed [0.71%]: Shortly after reduction to once daily 20 mg RIVA a 21-year-old woman developed severe TE progression with the need to switch from RIVA to Enoxaparin, since during RIVA induction (2x15 mg) gastrointestinal hemorrhage had occurred. A total of 11 clinical relevant bleeding episodes [7.86%] were diagnosed during the follow-up in 9 of 140 patients, 8 females, 1 male (gastrointestinal n=2, both-sided recurrent nose bruising n=2, large hematomas n=3, uterine hemorrhage n=4), with a median (min-max) age of 23 years (15-80). Median (min-max) RIVA dose per kgbw was significantly higher in bleeders compared to non-bleeders (0.28 mg [0.18-0.51] vs. 0.20 mg [0.09-0.40]; p=0.04) corresponding to a significantly enhanced RIVA through level (43.5 ng/ml [23-153] vs. 18.7ng/ml [0-182]; p< 0.000). In addition, in two females mild von-Willebrand-disease could not be ruled out, and in the 80-year-old male with recurrent bruising ASA co-medication was documented.When coagulation factors at RIVA through levels were compared with peak levels, significantly reductions were measured for FII, FV, FVIII, D-Dimer and F1+2 and, vice versa, elevated activities for AT, PC and RICO were found. dRVVT ratios were normal at baseline only. Of note, elevated AT levels measured via Xa-based assays during RIVA treatment mask inherited AT deficiency previously confirmed by sequencing (n=3).

Conclusion: In conclusion, data of this cohort study demonstrated that efficacy of RIVA in outpts with TE is good, however, the bleeding rate of 7.86% is too high. With respect to this safety endpoint we have demonstrated a dose - and a drug-level-dependency of RIVA standard therapy. We suggest that drug monitoring is mandatory in selected pts, especially in cases of bleeding-related co-mediations or concomitant bleeding disorders.