Impact of gender on safety and efficacy of Rivaroxaban in adolescents & young adults with venous thromboembolism

Background The objective of the present study was to evaluate safety and efficacy of Rivaroxaban (RIVA) being administered as a routine medication for patients with venous thromboembolism (VTE) in a multicenter outpatient cohort. Methods 212 consecutively admitted outpatients (14–<55 years) with VTE treated with standard RIVA were recruited between January 2013 and December 2015. Monitoring of RIVA trough levels along with anti-factor-Xa-activities, factor (F) VIII, Ristocetin-cofactor and von Willebrand factor antigen were performed. Safety endpoints were defined as significant bleeding requiring any medical intervention such as: dose reduction, withdrawal of RIVA or death related to therapy. Efficacy endpoints were defined as any re-VTE or thrombus progression during treatment. Findings Patients were followed over a median period of 16 months. The bleeding incidence rate per 100 patient-years was 17.8% in fertile/premenopausal women and 4.0% in men with an annualized re-VTE rate of 0.48% (women only). The median daily RIVA dose of 0.25 mg/kg in females was significantly higher compared to males with 0.21 mg/kg (p < 0.0001), clearly correlated to FXa-activities. In bleeders compared to non-bleeders median RIVA dose per kg/body weight was significantly higher (0.26 mg vs. 0.22 mg; p = 0.008). Multivariate analysis adjusted for gender, body mass index, RIVA dose and FVIII revealed an increased hazard of 3.4% in women to develop RIVA-induced bleeding. Additionally, a gradual decrease of FVIII per IU/ml was significantly associated with clinical relevant bleeding. Interpretation Our data demonstrated a high incidence of mucosal type bleeding in women on standard RIVA. This has clinical implications suggesting a need for RIVA monitoring in selected individuals that are at an increased bleeding risk. Funding The study was supported by grants from the pediatric/adolescent stroke foundation “Schlaganfall und Thrombosen im Kindesalter e.V.” and Interdisziplinäres Zentrum für Klinische Forschung (IZKF: CRA01-09), University of Münster. The explorative study part, e.g. the HrQoL assessment, was sponsored by an unrestricted grant donated by Biotest Ag (Langen, Germany).