TY - JOUR
T1 - Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children
T2 - a randomised, controlled, phase 3 trial
AU - Male, C.
AU - Lensing, A.W.A.
AU - Palumbo, J.S.
AU - Kumar, R.
AU - Nurmeev, I.
AU - Hege, K.
AU - Bonnet, D.
AU - Connor, P.
AU - Hooimeijer, H.L.
AU - Torres, M.
AU - Chan, A.K.C.
AU - Kenet, G.
AU - Holzhauer, S.
AU - Santamaria, A.
AU - Amedro, P.
AU - Chalmers, E.
AU - Simioni, P.
AU - Bhat, R.V.
AU - Yee, D.L.
AU - Lvova, O.
AU - Beyer-Westendorf, J.
AU - Biss, T.T.
AU - Martinelli, I.
AU - Saracco, P.
AU - Peters, M.
AU - Kallay, K.
AU - Gauger, C.A.
AU - Massicotte, M.P.
AU - Young, G.
AU - Pap, A.F.
AU - Majumder, M.
AU - Smith, W.T.
AU - Heubach, J.F.
AU - Berkowitz, S.D.
AU - Thelen, K.
AU - Kubitza, D.
AU - Crowther, M.
AU - Prins, M.H.
AU - Monagle, P.
AU - EINSTEIN-Jr Phase 3 Investigators
N1 - Funding Information:
In children of all ages with various manifestations of venous thromboembolism, treatment with bodyweight-adjusted rivaroxaban, targeting the therapeutic exposure range of young adults, resulted in a low risk of recurrent venous thromboembolism and clinically relevant bleeding, similar to standard therapy. Moreover, treatment with rivaroxaban resulted in a greater reduction of thrombus mass as compared with standard therapy at repeat imaging. Study outcome rates and relative efficacy and safety of rivaroxaban were similar to findings from previous randomised trials evaluating rivaroxaban versus standard anticoagulants in adults with venous thromboembolism. The study could not be powered to independently show non-inferiority for efficacy of rivaroxaban in comparison to standard therapy in children; therefore, interpretation of the results relies in part on extrapolation of data obtained with rivaroxaban in adults. As a prerequisite for extrapolation according to FDA and European Medicines Agency paediatric guidelines, 27,28 on the basis of comparison of the results of this paediatric study with those of large randomised studies in adults, 9–11 we deduce a similar clinical course of venous thromboembolism, and similar relative treatment effects. The upper margin of the 95% CI of the HR for the main efficacy outcome of the comparison of rivaroxaban with standard anticoagulants was 1·41. In rivaroxaban treatment studies in adults, 9–11 a non-inferiority margin of 1·75 was accepted because this margin preserves at least 75% of the established treatment effect of standard anticoagulant therapy. 29 By use of this margin, or even the more stringent margin of 1·50 which was used in the venous thromboembolism treatment study with edoxaban, 30 bodyweight-adjusted rivaroxaban treatment could be considered to be non-inferior to standard anticoagulants in children. Certain features of the study require comment. First, we believe that the trial population is representative of the paediatric population with venous thromboembolism, since the broad range of manifestations of venous thromboembolism typically observed in paediatric practice were included and a short list of ineligibility criteria was applied. Approximately 90% of children had venous thromboembolism secondary to underlying disorders associated with hypercoagulable states such as cancer, trauma or surgery, major organ disease, thrombophilia and infection, while many had multiples of these risk factors. The proportion is distinctly different from the distribution of risk factors in adults in whom approximately half of the patients present with unprovoked venous thromboembolism, 31 but is consistent with the known epidemiology of thrombosis in children. 2–5,8,22 Second, the use of an open-label design is a potential weakness, but long-term administration of placebo injections and blood samples for sham laboratory monitoring in children randomised to rivaroxaban was considered to be neither ethical nor feasible. Hence, observer bias was limited by requiring objective tests when recurrent venous thromboembolism was suspected and by use of an independent adjudication committee unaware of study treatment assignment. Third, in adults, rivaroxaban is started without initial heparinisation and administered in a dose of 15 mg twice-daily for 3 weeks followed by 20 mg once-daily. Since many children with venous thromboembolism are referred from peripheral centres to more specialised centres and the process of obtaining informed consent in children is notoriously time consuming, most potentially eligible children had already received initial heparin treatment for several days. Therefore, we decided to deviate from the rivaroxaban regimen in adults and elected for an initial course of at least 5 days of heparinisation followed by rivaroxaban. What are the clinical implications of this study's observations? We think physicians will have the option to treat children with bodyweight-adjusted oral rivaroxaban regimens, administered as tablet or suspension, without requiring regular laboratory monitoring and dose adjustments. Such anticoagulant regimens, validated in the paediatric venous thromboembolism population, obviate the need for manipulation of adult dosage forms, and substantially reduce the number of injections needed for standard anticoagulation treatment and associated blood sampling. Thus, the paediatric rivaroxaban regimens represent an advantageous alternative treatment for children with venous thromboembolism. In summary, in children with acute venous thromboembolism, treatment with rivaroxaban in bodyweight-adjusted 20 mg-equivalent dose regimens resulted in a similar low risk of recurrent venous thromboembolism and improved clot resolution without increased bleeding, as compared with standard anticoagulation. Study outcomes and relative efficacy and safety of rivaroxaban in children were similar to those observed in adults. Contributors CM, AWAL, AKCC, GK, MPM, GY, and PM designed the study. All authors contributed to data collection, data analysis, and data interpretation. All authors contributed to the writing of the manuscript, approved the final version, and agree to be accountable for all aspects of the report. Declaration of interests CM reports receiving personal fees and fees, paid to his institution, from Bayer, Bristol-Myers-Squibb, Pfizer and fees, paid to his institution, from Boehringer Ingelheim. AWAL being employed by Bayer. RK receiving personal fees from Bayer, CSL Behring, and Kedrion. DB receiving personal fees and grant support from Actelion Pharmaceuticals, Bayer, Eli Lilly, BMS, and Novartis and grant support from AbbVie. PC receiving personal fees from Onyx Health Limited. AKCC receiving personal fees from Bayer and fees, paid to his institution, from Bayer, Pfizer, Daiichi Sankyo, and Bristol-Myers-Squibb. GK receiving personal fees from Bayer, Boehringer Ingelheim, and Daiichi Sankyo and fees, paid to her institution from Pfizer. SH receiving personal fees and fees, paid to her institution, from Bayer, Pfizer, and Daiichi Sankyo. AS receiving personal fees from Bayer, Pfizer, Daiichi Sankyo and Boehringer Ingelheim. PA receiving personal fees and fees, paid to his institution, from Abbvie and Bayer, and fees paid to his institution from Actelion, Novartis, and Daiichi Sankyo. EC receiving personal fees from Boehringer Ingelheim and Bristol Myers-Squibb, and fees, paid to her institution from Bayer, Pfizer, and Daiichi Sankyo. DLY receiving fees, paid to his institution, from Bayer, Pfizer, and Bristol-Myers Squibb. OL receiving personal fees from Bayer, Pfizer, Boehringer Ingelheim, and Novartis, and fees, paid to her institution, from Bayer. JB-W receiving personal fees and fees, paid to his institution, from Bayer, Daiichi Sankyo, DOASENSE and Portola and fees, paid to his institution, from Pfizer. TTB receiving fees from Boehringer Ingelheim and Bayer, and grant support from Leo Pharma. IM receiving fees from Sanofi and Bayer. MP receiving grant support from Pfizer and Sobi. MPM receiving personal fees from Bayer. GY receiving personal fees from GlaxoSmithKline and Portola and personal fees and fees, paid to his institution, from Bayer and Daiichi Sankyo. AFP, MM, WTS, SDB, KT, DK being employed by Bayer. JFH was employed by Bayer. MC receiving grant support from and serving on a data and safety monitoring board for Bayer, receiving advisory board fees from Shionogi, Octapharma, Bristol-Myers Squibb Canada, and Asahi Kasei, receiving educational funding from Alexion Pharmaceuticals, Pfizer, CSL Behring, and Diagnostica Stago, receiving grant support, paid to his institution, from Leo Pharma, serving on a data and safety monitoring board for Daiichi Sankyo, owning stock in Alnylam Pharmaceuticals, and receiving educational funding and advisory board fees from Servier Canada. MHP receiving personal fees from Bayer. No other potential conflict of interest relevant to this article was reported.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/1/1
Y1 - 2020/1/1
N2 - Background Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism.Methods In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboeinbolisin who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant nonmajor bleeding (assessed in participants who received >= 1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov , number NCT02234843 and has been completed.Findings From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HRJ 0.40, 95% CI 0.11-1.41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0.012). Major or clinically relevant non-major bleeding in participants who received >= 1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1.58, 95% CI 0- 51-6- 27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths.Interpretation In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. Copyright (C) 2019 Elsevier Ltd. All rights reserved.
AB - Background Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism.Methods In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboeinbolisin who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant nonmajor bleeding (assessed in participants who received >= 1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov , number NCT02234843 and has been completed.Findings From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HRJ 0.40, 95% CI 0.11-1.41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0.012). Major or clinically relevant non-major bleeding in participants who received >= 1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1.58, 95% CI 0- 51-6- 27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths.Interpretation In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. Copyright (C) 2019 Elsevier Ltd. All rights reserved.
KW - definition
KW - disease
KW - oral rivaroxaban
KW - thrombosis
KW - DEFINITION
KW - ORAL RIVAROXABAN
KW - THROMBOSIS
KW - DISEASE
U2 - 10.1016/S2352-3026(19)30219-4
DO - 10.1016/S2352-3026(19)30219-4
M3 - Article
SN - 2352-3026
VL - 7
SP - E18-E27
JO - The Lancet Haematology
JF - The Lancet Haematology
IS - 1
ER -