Introduction
Venous thromboembolism (VTE) is a rare condition in pediatric patients that is being increasingly diagnosed, usually as a secondary complication in hospitalized children [1-3]. Among pediatric patients, especially those with comorbidities (e.g., cancer), the most common triggered thrombosis is central venous line (CVL)-associated VTE.
Whereas among adults, direct oral anticoagulants (DOACs) have become the preferred treatment of VTE, anticoagulant therapy in children is challenging, due to the evolving maturation of a child’s hemostatic system with age, which affects not only the risk of recurrent VTE but also the pharmacokinetics and responses to anticoagulant and antiplatelet therapies.
Standard of care (SOC) treatment may involve either subcutaneous injections (this is an issue with pediatric patients, once parenteral unfractionated heparin and low-molecular-weight heparin [LMWH] or fundaparinux are applied) or oral vitamin K antagonists, which require frequent International Normalized Ratio (INR) monitoring [4].
Risk factors for recurrent VTE, failure to monitor VTE adequately and limited vascular access may contribute to treatment complexity. Furthermore, the duration of anticoagulant therapy may vary, depending on the triggering factor, thrombus resolution and comorbidities or presence of severe genetic thrombophilic risk factors [5].
Currently, most pediatric treatment guidelines rely upon extrapolation from adult care and experts’ opinion. Thus, as randomized controlled trials (RCTs) dealing with anticoagulant therapy in children are scarce, there is an unmet need to properly evaluate the use of DOACs in pediatric patients with VTE.
The EINSTEIN-Jr program
The EINSTEIN-Jr program, which evaluated the safety and efficacy of body weight-adjusted pediatric rivaroxaban regimens for the treatment of VTE in children, as well as pharmacokinetic parameters, recently published their RCT results [6-8]. These EINSTEIN-Jr RCTs evaluated 500 pediatric patients of all ages, with acute VTE, of whom 335 were allocated to rivaroxaban.
The body weight-adjusted pediatric rivaroxaban-dosing regimens successfully targeted the adult rivaroxaban exposure range without requiring laboratory monitoring. Treatment resulted in a similarly low risk of recurrent VTE and clinically relevant bleeding, compared with SOC therapy. No major bleeding events were observed in the 335 children who received rivaroxaban.
The authors concluded that the absolute incidences of study outcomes and relative treatment effects observed with rivaroxaban were similar to those in the large rivaroxaban VTE studies in adults. Interestingly, the majority of rivaroxaban pediatric patients (126 children) presented with CVL-related thrombosis. Anticoagulant therapy appeared safe and efficacious in all children and was associated with reduced clot burden in most children with symptomatic or asymptomatic CVL-VTE [8].
The newly published manuscript
In their newly published manuscript “Dabigatran etexilate for the treatment of acute venous thromboembolism in children: results of an open-label, phase 2b/3, randomised, non-inferiority clinical trial,” Halton et al. reviewed the safety and efficacy of dabigatran treatment in children treated within the DIVERSITY study [9].
A total of 328 children were enrolled and 267 were randomized. Among randomized children, 177 pediatric VTE patients received dabigatran compared with 90 children receiving SOC therapy. The authors reported similar composite endpoints of both patient groups. An age-adjusted and weight-adjusted dabigatran-dosing algorithm was appropriate in children aged birth to less than 18 years with VTE.
Dabigatran was non-inferior to SOC in terms of efficacy, with similar pharmacokinetic–pharmacodynamic relationships as those seen in adults. One on-treatment death occurred in the SOC group (retroperitoneal bleeding, not considered treatment related by the study investigators) [9]. This RCT clearly adds an important perspective upon the current gaps of knowledge in this field. Notably, while 70% of rivaroxaban pediatric patients presented with CVL-related thrombosis, the percentage of patients treated due to CVL thrombosis was surprisingly low (20–30%) among patients within the DIVERSITY study, and thus this RCT may be somewhat less representative of unselected pediatric VTE populations.
Interestingly, Halton et al. chose to focus upon the study’s composite outcomes rather than upon predefined outcomes of VTE RCTs (these usually include: recurrent VTE, change in thrombotic burden as demonstrated by n repeat imaging studies and bleeding complications). The rate of major bleeds, as specified in the study’s supplementary material, was similar between patients receiving dabigatran or SOC, yet it was higher than expected among pediatric patients and yielded one case of fatality.
Notably, the occurrence of gastrointestinal bleeds (9/176 patients in the dabigatran group versus none in the SOC) certainly warrants further attention and future caution should be applied while prescribing DOAC therapy to children. Another pediatric DOAC study addressing edoxaban therapy for pediatric VTE is still ongoing [10].
In summary
In summary, recent multicenter RCTs provide important data regarding the potential use of DOACs in pediatric VTE. Dabigatran, as well as rivaroxaban, currently represent attractive therapeutic options; nevertheless, caution is advised, especially when treating children with increased bleeding risk. Further dedicated multicenter international RCTs are required for the establishment and validation of specific pediatric VTE anticoagulant treatment guidelines.
References
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- van Ommen CH, Heijboer H, Büller HR, Hirasing RA, Heijmans HS, Peters Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands. J Pediatr. 2001;139(5):676-681.
- 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. 2009;124(4):1001–1008
- Monagle P, Newall F. Management of thrombosis in children and neonates: practical use of anticoagulants in children. Hematology Am Soc Hematol Educ Program. 2018;2018(1):399-404.
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- Young G, Lensing AWA, Monagle P, et al. Rivaroxaban for treatment of pediatric venous thromboembolism. An Einstein-Jr phase 3 dose-exposure-response evaluation. J Thromb Haemost. 2020;18(7):1672-1685.
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- 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.
- Halton J, Brandão LR, Luciani M, et al. Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial. Lancet Haematol. 2021;8(1):e22-e33.
- Van Ommen Ch, Albisetti M, Chan AK, et al. The Edoxaban Hokusai VTE PEDIATRICS Study: An open-label, multicenter, randomized study of edoxaban for pediatric venous thromboembolic disease. Res Pract Thromb Haemost. 2020;4(5):886-892.