Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial

Christoph Male*, Anthonie W.A. Lensing, EINSTEIN-Jr Phase 3 Investigators, Joseph S. Palumbo, Riten Kumar, Ildar Nurmeev, Kerry Hege, Damien Bonnet, Philip Connor, Hélène L. Hooimeijer, Marcela Torres, Anthony K.C. Chan, Gili Kenet, Susanne Holzhauer, Amparo Santamaría, Pascal Amedro, Elizabeth Chalmers, Paolo Simioni, Rukhmi V. Bhat, Donald L. YeeOlga Lvova, Jan Beyer-Westendorf, Tina T. Biss, Ida Martinelli, Paola Saracco, Marjolein Peters, Krisztián Kállay, Cynthia A. Gauger, M. Patricia Massicotte, Guy Young, Akos F. Pap, Madhurima Majumder, William T. Smith, Jürgen F. Heubach, Scott D. Berkowitz, Kirstin Thelen, Dagmar Kubitza, Mark Crowther, Martin H. Prins, Paul Monagle, Angelo C. Molinari, Ulrike Nowak Göttl, Juan Chain, Jeremy Robertson, Katharina Thom, Werner Streif, Rudolf Schwarz, Klaus Schmitt, Gernot Grangl, An Van Damme, Philip Maes

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

193 Citations (Scopus)

Abstract

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 thromboembolism 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 non-major 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 [HR] 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. Funding: Bayer AG and Janssen Research & Development.

Original languageEnglish
Pages (from-to)e18-e27
JournalThe Lancet Haematology
Volume7
Issue number1
DOIs
Publication statusPublished - Jan 2020
Externally publishedYes

Bibliographical note

Funding Information:
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

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