Research in context
Evidence before this study
Venous thromboembolism in children is predominantly seen in children with severe underlying medical or surgical problems. Guidelines for treatment of paediatric venous thromboembolism rely on low level paediatric evidence or are extrapolated from adult evidence. We searched PubMed for the period Jan 1, 1990, to Jan 1, 2019, using the terms “anticoagulants”, “heparin”, “vitamin K antagonist”, “DOAC”, “children”, “pediatric”, “treatment”, “venous thromboembolism”, and “randomised study”. The single randomised trial which we identified was done in children with venous thromboembolism almost 20 years ago and was prematurely stopped after inclusion of only 76 children owing to slow enrolment. The trial compared intravenous unfractionated heparin followed by warfarin with subcutaneous administrations of the low molecular weight heparin reviparin followed by warfarin. Recurrent thromboembolism occurred in four (10%) of 40 children and major bleeding occurred in five (13%) of 40 children treated with unfractionated heparin and warfarin, compared with two (6%) of 36 and two (6%) of 36 children treated with reviparin and warfarin. Treatment of venous thrombosis in children is further limited by the absence of paediatric anticoagulant formulations, and the need for parenteral administration and for regular laboratory monitoring.
Fixed-dose treatment with the direct oral anticoagulant rivaroxaban is efficacious and safe for treatment of venous thromboembolism in adults. In the EINSTEIN-Jr phase 1 and 2 studies, bodyweight-adjusted rivaroxaban dose regimens with tablets or a newly developed oral suspension have been established for children aged between birth and 18 years matching the exposure range of young adults treated with rivaroxaban 20 mg once daily.
Added value of this study
The EINSTEIN-Jr phase 3 study is the first completed trial of a direct oral anticoagulant in children and the largest trial of anticoagulant treatment ever done in children. The results show that treatment of children with venous thromboembolism with bodyweight-adjusted rivaroxaban tablets or suspension resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding compared with standard anticoagulants.
Implications of all the available evidence
Study outcomes and relative efficacy and safety of rivaroxaban versus standard anticoagulants in children were similar to those observed in adult studies on rivaroxaban treatment. Given this similarity of clinical course of venous thromboembolism, and relative treatment effects, the results of the EINSTEIN-Jr studies can be interpreted in the context of the body of evidence from adults, which overall provides sufficient evidence to inform practical use of rivaroxaban in children. The availability of the rivaroxaban suspension formulation will obviate the need for long-term treatment of children with parenteral anticoagulants.