Christoph Male1, Anthonie W A Lensing2, Joseph S Palumbo3, Riten Kumar4, Ildar Nurmeev5, Kerry Hege6, Damien Bonnet7, Philip Connor8, Hélène L Hooimeijer9, Marcela Torres10, Anthony K C Chan11, Gili Kenet12, Susanne Holzhauer13, Amparo Santamaría14, Pascal Amedro15, Elizabeth Chalmers16, Paolo Simioni17, Rukhmi V Bhat18, Donald L Yee19, Olga Lvova20, Jan Beyer-Westendorf21, Tina T Biss22, Ida Martinelli23, Paola Saracco24, Marjolein Peters25, Krisztián Kállay26, Cynthia A Gauger27, M Patricia Massicotte28, Guy Young29, Akos F Pap2, Madhurima Majumder30, William T Smith30, Jürgen F Heubach2, Scott D Berkowitz30, Kirstin Thelen2, Dagmar Kubitza2, Mark Crowther31, Martin H Prins32, Paul Monagle33. 1. Department of Paediatrics, Medical University of Vienna, Vienna, Austria. Electronic address: christoph.male@meduniwien.ac.at. 2. Bayer AG, Wuppertal, Germany. 3. Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. 4. Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA. 5. Kazan State Medical University, Russia. 6. Riley Hospital for Children at IU Health, Indianapolis, IN, USA. 7. M3C-Necker Enfants malades, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 8. The Noah's Ark Children's Hospital for Wales, Cardiff, UK. 9. Department of Hematology and Oncology, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, Netherlands. 10. Department of Hematology and Oncology, Cook Children's Medical Center, Fort Worth, TX, USA. 11. McMaster Children's Hospital, Hamilton, ON, Canada. 12. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, The Israeli National Hemophilia Center and Thrombosis Unit, and The Amalia Biron Thrombosis Research Institute, Sheba Medical Center, Tel Hashomer, Israel. 13. Charité University Medicine, Department of Paediatric Haematology and Oncology, Berlin, Germany. 14. Haemostasis and Thrombosis Unit, Department of Haematology, University Hospital Vall d'Hebron, Barcelona, Spain. 15. Paediatric and Congenital Cardiology Department, M3C Regional Reference Centre, Montpellier University Hospital, PhyMedExp, INSERM, CNRS, Montpellier, France. 16. Royal Hospital for Children, Glasgow, UK. 17. Thrombotic and Haemorrhagic Diseases Unit, Department of Medicine (DIMED), Padua University Hospital, Padua, Italy. 18. Ann & Robert H Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, IL, USA. 19. Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA. 20. Ural Federal University and Ural State Medical University, Yekaterinburg, Russia. 21. Department of Medicine I, Division of Haematology and Haemostaseology, University Hospital "Carl Gustav Carus" Dresden, and King's Thrombosis Service, Department of Haematology, King's College London, UK. 22. Department of Haematology, The Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle Upon Tyne, UK. 23. Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, A Bianchi Bonomi Haemophilia and Thrombosis Centre, Milan, Italy. 24. University Hospital Città della Salute e della Scienza, Turin, Italy. 25. Department of Paediatric Haematology, Emma Children's Hospital, University Medical Centres, Location Academic Medical Centre, Amsterdam, Netherlands. 26. Department of Paediatric Haematology and Stem Cell Transplantation, Central Hospital of Southern Pest, National Institute of Haematology and Infectious Diseases, Budapest, Hungary. 27. Nemours Children's Specialty Care, Jacksonville, FL, USA. 28. Department of Paediatrics, University of Alberta, Edmonton, AB, Canada. 29. Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, USA. 30. Bayer, Whippany, NJ, USA. 31. Department of Medicine, McMaster University, Hamilton, ON, Canada. 32. Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre, Maastricht, Netherlands. 33. Department of Clinical Haematology, Royal Children's Hospital, Haematology Research Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, VIC, Australia.
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) tobodyweight-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.
RCT Entities:
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.
Authors: Philip Connor; Mayte Sánchez van Kammen; Anthonie W A Lensing; Elizabeth Chalmers; Krisztián Kállay; Kerry Hege; Paolo Simioni; Tina Biss; Fanny Bajolle; Damien Bonnet; Sebastian Grunt; Riten Kumar; Olga Lvova; Rukhmi Bhat; An Van Damme; Joseph Palumbo; Amparo Santamaria; Paola Saracco; Jeanette Payne; Susan Baird; Kamar Godder; Veerle Labarque; Christoph Male; Ida Martinelli; Michelle Morales Soto; Jayashree Motwani; Sanjay Shah; Helene L Hooimeijer; Martin H Prins; Dagmar Kubitza; William T Smith; Scott D Berkowitz; Akos F Pap; Madhurima Majumder; Paul Monagle; Jonathan M Coutinho Journal: Blood Adv Date: 2020-12-22
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