Influence of Gender and Coagulation Factors on Efficacy and Safety of Rivaroxaban in Adolescents & Young Adults with Venous Thromboembolism

Background: Venous thromboembolism [TE] is a multifactorial disease and antithrombotic therapy with Rivaroxaban [RIVA] is increasingly being administered for TE treatment in adults.

Aim: The objective of the present study was to evaluate efficacy and safety of standard RIVA administered as routine medication in an outpatient cohort of patients with TE.

Methods: In 212 consecutively admitted outpatients (14-<55 years; male:female ratio 1.5:1) with TE on standard RIVA medication (2x 15 mg followed by 20 mg) recruited between January 2013 and December 2014, monitoring of RIVA through (24h) and peak levels (Xa-based chromogenic substrate S-2732; Haemochrom Diagnostica) along with anti-factor-Xa-activities [Xa; Xa-based assay, Haemochrom Diagnostica], selected coagulation factors and biomarkers (factors II, V, VIII, Ristocetin-cofactor [RICO] was performed. Efficacy endpoints were defined i) as any TE or thrombus progression during treatment [TP], safety endpoints were defined as ii) significant bleeding [B] requiring any medical intervention, such as dose reduction, withdrawal of RIVA or death related to therapy. Descriptive analysis non-parametric statistics, Chi-square test and logistic regression were performed.

Results: Patients were followed over a median of 12 months. The median daily RIVA dose of 0.25 mg (0.1-0.52) in females was significantly higher compared to males with 0.21 mg (0.09-0.4; p<0.000). RIVA dose was clearly correlated to Xa (p<0.0001; rho=0.945). During the study period two out of 212 patients developed TP [0.94%] and a total of 46 clinical relevant B episodes [21.7%] were diagnosed in 38 females (hypermenorrhagia n=21: necessitating hysterectomy in 2 cases) and 8 males. In bleeders compared to non-bleeders median (min-max) RIVA dose per kgbw was significantly higher (0.26 mg [0.16-0.52] vs. 0.22 mg [0.09-0.52]; p=0.008). Multivariate analysis adjusted for gender, body mass index, RIVA dose, through levels and coagulation factors revealed and increased odds [95% CI] of 3.9 [1.5-9.6] in women to develop B. In addition, a gradual decrease of RICO per IU/ml was significantly associated with clinical relevant B (p=0.04).

Conclusion: Along with good efficacy results our data demonstrate a high bleeding rate of 36.9% in women on standard RIVA. Lower RISTO activities in fertile/premenopausal women contributed significantly to B.