Subscribe to RSS
DOI: 10.1055/s-0043-1778106
Venous Thromboembolism in Children: The Rivaroxaban Experience
Abstract
The incidence of venous thromboembolism (VTE) in the pediatric population has increased more than 10-fold in the last 20 years, as a consequence of the advancement of resuscitation and surgical techniques and the global increase in life expectancy of children suffering from chronic pathologies. Monitoring anticoagulant therapy to achieve outcomes within the target range in childhood VTE, parenteral administration of medications, and frequent blood tests in children are often cumbersome. Availability of safe and effective oral agents with pediatric data to support use would be of clear benefit. A physiologically based pharmacokinetic model was developed to estimate the appropriate dosing schedule for rivaroxaban in children. This incorporated growth/maturation and variability in anthropometrics (e.g., body height, weight, and body mass index), anatomy (e.g., organ weight), physiology (e.g., blood flow rates), metabolism and excretion. Rivaroxaban use in pediatric population underwent a complete investigational program, consisting mainly of one phase I pharmacokinetics/pharmacodynamics trial, three phase II trials, one phase III trial. The phase III trial enrolled 500 patients from birth to <18 years and documented the efficacy and safety of rivaroxaban regimens at dose equivalent to the adult 20 mg dose for the prevention of fatal or symptomatic nonfatal recurrent VTE and major bleeding versus heparin or vitamin K antagonists. Results were similar to those in rivaroxaban studies in adults. The efficacy and safety of rivaroxaban in children reported in the EINSTEIN JUNIOR trial provide further support to previous trials in adults (EINSTEIN Program), which demonstrate a favorable profile for the use of rivaroxaban for the management of VTE in challenging patient populations. Other clinical evidence contributing to the use of rivaroxaban among different risk groups in pediatric VTE population confirms the consistency with principal trial. Our review aims to describe the rationale for using rivaroxaban oral suspension in clinical practice and to summarize its multiple indications in each vascular bed (e.g., cerebral venous thrombosis, symptomatic or asymptomatic central venous catheter-associated thrombosis), etiology, and patients setting.
Publication History
Article published online:
05 January 2024
© 2024. Thieme. All rights reserved.
Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA
-
References
- 1 van Ommen CH, Heijboer H, Büller HR, Hirasing RA, Heijmans HS, Peters M. Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands. J Pediatr 2001; 139 (05) 676-681
- 2 Stein PD, Kayali F, Olson RE. Incidence of venous thromboembolism in infants and children: data from the National Hospital Discharge Survey. J Pediatr 2004; 145 (04) 563-565
- 3 Raskob GE, Angchaisuksiri P, Blanco AN. et al; ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to global disease burden. Arterioscler Thromb Vasc Biol 2014; 34 (11) 2363-2371
- 4 Sandoval JA, Sheehan MP, Stonerock CE, Shafique S, Rescorla FJ, Dalsing MC. Incidence, risk factors, and treatment patterns for deep venous thrombosis in hospitalized children: an increasing population at risk. J Vasc Surg 2008; 47 (04) 837-843
- 5 Raffini L, Huang YS, Witmer C, Feudtner C. Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007. Pediatrics 2009; 124 (04) 1001-1008
- 6 Tuckuviene R, Christensen AL, Helgestad J, Johnsen SP, Kristensen SR. Pediatric venous and arterial noncerebral thromboembolism in Denmark: a nationwide population-based study. J Pediatr 2011; 159 (04) 663-669
- 7 Macartney CA, Chan AK. Thrombosis in children. Semin Thromb Hemost 2011; 37 (07) 763-771
- 8 Setty BA, O'Brien SH, Kerlin BA. Pediatric venous thromboembolism in the United States: a tertiary care complication of chronic diseases. Pediatr Blood Cancer 2012; 59 (02) 258-264
- 9 Heit JA. Epidemiology of venous thromboembolism. Nat Rev Cardiol 2015; 12 (08) 464-474
- 10 Chan AKC, Monagle P. Updates in thrombosis in pediatrics: where are we after 20 years?. Hematology (Am Soc Hematol Educ Program) 2012; 2012: 439-443
- 11 Chan A, Lensing AWA, Kubitza D. et al. Clinical presentation and therapeutic management of venous thrombosis in young children: a retrospective analysis. Thromb J 2018; 16: 29
- 12 Baglin T, Luddington R, Brown K, Baglin C. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003; 362 (9383) 523-526
- 13 Ageno W, Samperiz A, Caballero R. et al; RIETE investigators. Duration of anticoagulation after venous thromboembolism in real world clinical practice. Thromb Res 2015; 135 (04) 666-672
- 14 Monagle P, Chan AK, Goldenberg NA. et al. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141: e737S-e801S
- 15 Attard C, Monagle P, Kubitza D, Ignjatovic V. The in vitro anticoagulant effect of rivaroxaban in children. Thromb Res 2012; 130 (05) 804-807
- 16 Attard C, Monagle P, Kubitza D, Ignjatovic V. The in-vitro anticoagulant effect of rivaroxaban in neonates. Blood Coagul Fibrinolysis 2014; 25 (03) 237-240
- 17 Willmann S, Thelen K, Kubitza D. et al. Pharmacokinetics of rivaroxaban in children using physiologically based and population pharmacokinetic modelling: an EINSTEIN-Jr phase I study. Thromb J 2018; 16: 32
- 18 Willmann S, Becker C, Burghaus R. et al. Development of a paediatric population-based model of the pharmacokinetics of rivaroxaban. Clin Pharmacokinet 2014; 53 (01) 89-102
- 19 Kubitza D, Willmann S, Becka M. et al. Exploratory evaluation of pharmacodynamics, pharmacokinetics and safety of rivaroxaban in children and adolescents: an EINSTEIN-Jr phase I study. Thromb J 2018; 16: 31
- 20 Monagle P, Lensing AWA, Thelen K. et al; 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; 6 (10) e500-e509
- 21 Male C, Lensing AWA, Palumbo JS. et al; 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; 7 (01) e18-e27
- 22 Prins MH, Lensing AW, Bauersachs R. et al; EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013; 11 (01) 21
- 23 Bauersachs RM, Lensing AWA, Prins MH. et al. Rivaroxaban versus enoxaparin/vitamin K antagonist therapy in patients with venous thromboembolism and renal impairment. Thromb J 2014; 12: 25-32
- 24 Prins MH, Lensing AWA, Brighton TA. et al. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials. Lancet Haematol 2014; 1 (01) e37-e46
- 25 Young AM, Marshall A, Thirlwall J. et al. Comparison of an oral Factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol 2018; 36 (20) 2017-2023
- 26 Palumbo JS, Lensing AWA, Brandão LR. et al. Anticoagulation in pediatric cancer-associated venous thromboembolism: a subgroup analysis of EINSTEIN-Jr. Blood Adv 2022; 6 (22) 5821-5828
- 27 Hassan E, Motwani J. Real world experience of efficacy and safety of rivaroxaban in paediatric venous thromboembolism. Thromb Res 2023; 221: 92-96
- 28 Marten S, Tittl L, Naue C, Beyer-Westendorf J. Treatment of VTE with rivaroxaban in adolescents – preliminary findings from the prospective Dresden NOAC Registry (NCT01588119). Hamostaseologie 2019; 39 (Suppl_1): S1-S92
- 29 Marcotte P, Tole S, Bouhelier E. et al. Rivaroxaban in children with nephrotic syndrome. Pediatr Hematol Oncol 2023; 40: 688-695
- 30 Connor P, Sánchez van Kammen M, Lensing AWA. et al. Safety and efficacy of rivaroxaban in pediatric cerebral venous thrombosis (EINSTEIN-Jr CVT). Blood Adv 2020; 4 (24) 6250-6258
- 31 Thom K, Lensing AWA, Nurmeev I. et al. Safety and efficacy of anticoagulant therapy in pediatric catheter-related venous thrombosis (EINSTEIN-Jr CVC-VTE). Blood Adv 2020; 4 (19) 4632-4639