EINSTEIN-Jr clinical trials of Rivaroxaban in children

EINSTEIN-Jr clinical trials of Rivaroxaban in children

Rivaroxaban is useful for treatment of venous thromboembolism in adults and is associated with lower risk of bleeding compared to standard anticoagulants. EINSTEIN-Jr phase 2 used bodyweight adjusted rivaroxaban for children with venous thromboembolism [1]. It was a single arm multicenter study three age groups – children younger than 6 months, those in age group 6 months to 5 years and in children and adolescents between 6-17 years. Studies were done at 54 sites across Australia, Europe, Israel, Japan and North America. The study was in children with confirmed venous thromboembolism who have been treated for at least 2 months low molecular weight heparin, fondaparinux or vitamin K antagonist. In children with catheter related venous thromboembolism the cut off for previous treatment was 6 weeks. 89 children (96%) completed study treatment. None of the children had major bleed. 4% had clinically relevant non-major bleed. There was no symptomatic recurrent venous thromboembolism. In 75 patients repeat imaging showed resolution of thrombus burden. 43 had improved and 8 were unchanged. No patient deteriorated in this study.

EINSTEIN-Jr phase 3 was a multicenter, open label randomized study in children and adolescents up to the age of 17 years [2]. The study was conducted across 107 pediatric hospitals in 28 countries. Children with acute venous thromboembolism on heparin were assigned to either body weight adjusted rivaroxaban or standard anticoagulants. Symptomatic recurrent venous thromboembolism occurred in 1% of the 335 children in rivaroxaban group and 3% of the 165 receiving standard anticoagulants. Improved effect of rivaroxaban was noted on repeat imaging compared with standard anticoagulants. 3% of the children had non-major clinically relevant bleeding on rivaroxaban. Two major and one non-major bleeding episodes occurred in those on standard anticoagulants (2%). There were no treatment related deaths. Treatment with rivaroxaban resulted in low recurrence and reduced thrombotic burden, without an increase in bleeding, compared to standard anticoagulants. Thus the safety and efficacy of rivaroxaban in children was similar to that in adults [3].

References

1. Monagle P, Lensing AWA, Thelen K, Martinelli I, Male C, Santamaría A, Samochatova E, Kumar R, Holzhauer S, Saracco P, Simioni P, Robertson J, Grangl G, Halton J, Connor P, Young G, Molinari AC, Nowak-Göttl U, Kenet G, Kapsa S, Willmann S, Pap AF, Becka M, Twomey T, Beyer-Westendorf J, Prins MH, Kubitza D; EINSTEIN-Jr Phase 2 Investigators. Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies. Lancet Haematol. 2019 Oct;6(10):e500-e509. doi: 10.1016/S2352-3026(19)30161-9. Epub 2019 Aug 13. PMID: 31420317.
2. Male C, Lensing AWA, Palumbo JS, Kumar R, Nurmeev I, Hege K, Bonnet D, Connor P, Hooimeijer HL, Torres M, Chan AKC, Kenet G, Holzhauer S, Santamaría A, Amedro P, Chalmers E, Simioni P, Bhat RV, Yee DL, Lvova O, Beyer-Westendorf J, Biss TT, Martinelli I, Saracco P, Peters M, Kállay K, Gauger CA, Massicotte MP, Young G, Pap AF, Majumder M, Smith WT, Heubach JF, Berkowitz SD, Thelen K, Kubitza D, Crowther M, Prins MH, Monagle P; EINSTEIN-Jr Phase 3 Investigators. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial. Lancet Haematol. 2020 Jan;7(1):e18-e27. doi: 10.1016/S2352-3026(19)30219-4. Epub 2019 Nov 5. PMID: 31699660.
3. O’Brien SH. Can paediatricians move directly to direct oral anticoagulants? Lancet Haematol. 2020 Jan;7(1):e2-e3. doi: 10.1016/S2352-3026(19)30204-2. Epub 2019 Nov 5. PMID: 31699659.