This is the first completed randomized study on the use of a non-vitamin K antagonist oral anticoagulant (NOAC) in children and, in addition, the largest study on anticoagulant treatment in children. Up to now, only one single randomized trial assessed different anticoagulation regimes (comparison of unfractionated heparin (UFH) followed by warfarin with low molecular heparin (LMWH) followed by warfarin) in a small sample of 76 children with venous thromboembolism (VTE) 20 years ago. For the present study, 500 children aged 0-17 years were recruited from 107 pediatric hospitals in 28 countries from 2014 to 2018. In accordance with the respective phase 2 study, children aged 12-17 years were initially included in the present phase 3 study, followed by children aged 6-11 years, 2-5 years and, at last, children below the age of 2 years were included. In children aged below 0.5 years the gestational age at birth had to be at least 37 weeks, the bodyweight had to be at least 2600 g and the time of oral feeding had to be at least 10 days.
Included children were randomized in a 2:1 ratio to either open-label rivaroxaban or standard anticoagulation. Randomization was stratified according to age groups and VTE site. In general, the treatment period was 3 months, except in children below the age of 2 with catheter-related thrombosis, in whom it was 1 month. After diagnosis of VTE, included children initially received UFH, LMWH or fondaparinux for 5-9 days. After this run-in phase, children were randomized to rivaroxaban or standard anticoagulation treatment. Children who were randomized to rivaroxaban received a bodyweight-adjusted 20 mg-equivalent dose. Children with a body weight ≥ 30 kg received a once-daily bodyweight-adjusted 20 mg-equivalent dose, while children with a body weight 12 to (<)30 kg received a twice-daily dose and children with a body weight < 12 kg received a thrice-daily dose. Rivaroxaban was administered as tablets (in strengths of 5, 10, 15 or 20 mg) or suspension. In the standard treatment group, either heparin treatment was continued or a vitamin K antagonist was initiated. The primary efficacy endpoint was the recurrence of symptomatic VTE, the primary safety outcome was the occurrence of major or clinically relevant non-major bleeding. In addition, imaging studies were obtained for the documentation of resolution or progression of thrombotic burden.
Regarding the entity of VTE, in the lowest age group the majority of included children were diagnosed with catheter-related thrombosis, while the percentage proportion of non-catheter related thrombosis and the proportion of children with pulmonary embolism increased with increasing age. Referring to the efficacy endpoint, the EINSTEIN-Jr phase 3 study demonstrated that anticoagulation treatment with bodyweight-adjusted rivaroxaban resulted in a – in comparison with standard treatment – similarly low recurrence risk, a reduced thrombotic burden without increase in bleeding risk.
In summary, this study constitutes a landmark study in the field of anticoagulation treatment in children. Nevertheless, it should be acknowledged that the results of this study cannot be directly extrapolated to other indications of oral anticoagulation in children (besides VTE), nor to the use of other NOACs (other NOAC data are expected for publication in the future). Further, the suspension of rivaroxaban is not commercially available yet.
In any case, the management of anticoagulation in children is a critical task which clearly should be referred to specialized centers.
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