Rivaroxaban is safe and effective for paediatric venous thromboembolism

New data from the randomised phase 3 EINSTEIN-Jr study support the use of rivaroxaban, either as tablet or in liquid suspension, for children with venous thromboembolism (VTE), using an age- and weight-adjusted algorithm. These data will likely form the basis for an official indication in the near future.

VTE among paediatric patients differs substantially from adults in many aspects, including aetiology, anatomical location, frequency, and recovery. This different natural history of VTE in children, coupled with metabolic variation based on age and body weight, complicate the anticoagulant options available in daily practice. No formulations of direct oral anticoagulants —either liquid (for small children) or tablet— are currently available for children with VTE; this unmet need drove the current study.

Prof. Guy Young (Children's Hospital Los Angeles, USA) reported the dose-exposure versus response of rivaroxaban used in EINSTEIN-Jr [1]. Age-adjusted and body weight-adjusted dosing of rivaroxaban was incorporated to achieve a similar exposure as that observed in adults treated for VTE with 20 mg rivaroxaban.

Children were randomised 2:1 to weight-based rivaroxaban doses or standard treatment with heparin or vitamin K antagonists. The main study period was 3 months for the majority of children or 1 month for children under 2 years with clear catheter-related VTE, followed by open-label treatment for up to 12 additional months. A total of 316 children received rivaroxaban in tablet form (n=121) or liquid formulation (n=195). Dosing/scheduling was stratified by body weight: children weighing ≥30 kg received daily dosing, children weighing 12-29 kg received twice-daily dosing, and children weighing <12 kg received 3 doses daily. In order to span the broad 2.6-50 kg range among the children in the trial, 12 separate doses were used. Age was also a factor in the algorithm used: groups were 0-6 months (n=13), 6-23 months (n=21), 2-5 years (n=44), 6-11 years (n=65), and 12-17 years (n=173).

The principal safety outcome was major bleeding and clinically relevant non-major bleeding. No major bleeding events were reported, although 10 patients experienced clinically relevant non-major bleeding and another 111 patients had minor bleeding events. Imaging outcomes at 3 months were classified as healthy/no disease evident (n=124), improved (n=125), no relevant change (n=16), deteriorated (n=1), or unclear (n=48).

Three standard pharmacokinetic measures were used to confirm dosing: area under the 24-hour curve for blood levels (24-hour AUC), peak concentration, and trough concentration. In total, 25 patients had measures out of the target ranges. Only 5 of those exceeded the maximum for any of the 3 measures at any time, so excessive exposure was not significant. No patient had a trough concentration below the target range. Notably, only 1 patient with values outside of target had a suboptimal clinical outcome (24-hour AUC below target, no clinical improvement). There were no differences observed between the tablet and liquid formulations.

In conclusion, weight-adjusted dosing of rivaroxaban in children with VTE was well tolerated and demonstrated anti-coagulant activity.

1. Young G, et al. Abstract 164, ASH 2019, 7-10 December, Orlando, USA.

Posted on 5 March 202030 March 2021