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Treatment of Venous Thromboembolism in Children
This section looks at the epidemiology and treatment of VTE in paediatric patients
In this section:
Epidemiology
VTE, including DVT and PE, is primarily regarded as an adult disease;1 however, VTE can also affect children.2 Although the overall incidence of VTE in children is low (estimated to be 0.07–0.14 per 10,000 children),3,4 it is around 100–1000 times higher in hospitalized children (occurring in up to 58 cases per 10,000 hospital admissions),5,6 making it a leading cause of hospital-acquired morbidity in this vulnerable patient population.7 The majority of venous thromboembolic events in paediatric patients are reported during infancy and during adolescence.8
Risk factors for VTE in paediatric patients
More than 90% of venous thromboembolic events in paediatric patients are provoked by underlying medical or surgical factors.3,9,10 This is in contrast to adult patients, in whom up to half of venous thromboembolic events are idiopathic.9 Multiple risk factors have been associated with VTE in paediatric patients,8 and children typically have more than one risk factor at the time of their thrombotic event.7 The single most important risk factor is the presence of a central venous catheter, which doubles the risk of VTE and contributes to >90% of all cases of neonatal VTE and >50% of all cases of VTE in other age groups.9,10
Sites of VTE in paediatric patients
In adults, the primary sites for VTE are the lower limbs (i.e. DVT) and pulmonary arteries (i.e. PE).11 In contrast, in children, VTE location is more variable; other common locations for VTE in paediatric patients (besides the lower limbs and pulmonary arteries) include:3,10,12-14
- The cerebral veins and sinuses (cerebral sinovenous thrombosis)
- The upper extremities (typically associated with central venous catheter use)
- The renal veins (the most common spontaneous VTE in neonates)
Location of venous thrombi in children (aged ≥29 days to 18 years) enrolled in the Italian Registry of Thrombosis in Children12
Adverse clinical outcomes in children with VTE
VTE has been associated with a number of adverse clinical outcomes, including mortality and recurrent thrombosis. In a Canadian registry, mortality directly attributable to VTE and recurrent thrombosis occurred in 2.2% and 8.1% of children with VTE, respectively.15 Other chronic complications are influenced by VTE location, and include post-thrombotic syndrome (following DVT), chronic renal insufficiency (following renal vein thrombosis) and neurological deficits (following cerebral sinovenous thrombosis).9,14
Clinical evidence for the treatment of VTE in paediatric patients
Because it is more challenging to conduct clinical trials in children and paediatric VTE is a rare and heterogeneous disease, there was, until recently, a relatively paucity of data from randomized clinical trials evaluating the use of anticoagulants in children.2,10,16
Heparins and VKAs for the treatment of VTE in paediatric patients
The current standard of care in the management of VTE in paediatric patients usually includes UFH, LMWH and oral VKAs.2,5,17 Real-world data indicate that most children with VTE are treated with LMWH.12,13 Recommendations for dosing and therapeutic range for both heparins and VKAs are derived from adult studies, as well as smaller dose-finding and observational studies in children.2,18 Only two randomized controlled trials assessing heparins/VKAs for the treatment of VTE in children have attempted to enrol >200 children10 – the first, REVIVE, was terminated early due to recruitment problems, and the second, Kids-DOTT, has been running since 2007 and is not estimated to complete until 2022.19-21 (In the setting of prevention of VTE in paediatric patients with LMWH, the recently completed THROMBOTECT trial, supporting the use of enoxaparin for thromboprophylaxis in children with acute lymphoblastic leukaemia during induction therapy, successfully enrolled 949 children whereas the PROTEKT trial closed early after recruitment of 186 of 600 children.10,22,23
VKAs and heparins have been associated with various disadvantages in children, including challenges with subcutaneous injections, and frequent blood sampling for laboratory monitoring.2,24
NOACs for the treatment of VTE in paediatric patients
NOACs have the potential to overcome some of the limitations of the current standard of care (LMWH/VKAs) for treatment of VTE in paediatric patients.24 All of the NOACs currently approved for the treatment and secondary prevention of recurrent VTE in adults have recently completed (rivaroxaban and dabigatran) or ongoing clinical development programmes (apixaban and edoxaban) assessing their use for the treatment of VTE in paediatric patients.25-35
Rivaroxaban for the treatment of VTE in paediatric patients
The EINSTEIN JUNIOR clinical development programme consisted of a phase I study, three phase II studies and onephase III study, enrolling over 650 children across the 5 studies.25,26,28 Together, the phase I and II studies established bodyweight-adjusted rivaroxaban regimens (including an oral suspension) for use in children, matching the rivaroxaban 20 mg once daily dose used in adults.26 The EINSTEIN JUNIOR phase III study recruited 500 children, aged 0–18 years, with acute VTE treated with heparins or fondaparinux, and randomized them (2:1) to receive bodyweight-adjusted rivaroxaban or standard anticoagulation (heparins or fondaparinux alone, or overlapping with and followed by a VKA).25,36
The results of EINSTEIN JUNIOR phase III study were consistent with those from the EINSTEIN programme in adult patients – rivaroxaban-treated children experienced low rates of recurrent VTE without increased risk of bleeding compared with standard anticoagulants. Repeat imaging showed a significantly reduced thrombotic burden with rivaroxaban.36
Recurrent VTE, clinically relevant bleeding and major bleeding in children treated with rivaroxaban or standard anticoagulation in the EINSTEIN JUNIOR phase III study36
Dabigatran for the treatment of VTE in paediatric patients
The efficacy and safety of dabigatran for the treatment of VTE in children is being investigated in a clinical development programme that includes five studies, including two ongoing phase III studies.30-33 The completed phase II studies, which included 35 patients treated with dabigatran, demonstrated that dabigatran was well tolerated, and the pharmacokinetic/pharmacodynamic relationship in paediatric patients was similar to that seen in adults.30,31,33 Of the ongoing phase III studies, one is comparing dabigatran to standard of care in ~220 children with acute VTE (DIVERSITY study) and the other is a single-arm study assessing the safety of dabigatran for secondary VTE prevention in ~200 children with VTE and persistent VTE risk factors.32,33,37,38 Interim results from both studies suggest that dabigatran is safe and effective for the treatment and secondary prevention of VTE in children.37,38
Guideline recommendations for the treatment of VTE in paediatric patients
Guideline recommendations for the treatment of VTE in paediatric patients have been largely based on weak evidence (obtained from adult studies, smaller dose-finding and observational studies in children) and expert opinion.2,5,39 Guidelines on the treatment of VTE in paediatric patients include:
- The 2012 American College of Chest Physicians (ACCP) guidelines: contains separate guidance on the treatment of VTE in neonates (birth–28 days) and children (28 days–18 years)2
- The 2018 American Society of Hematology (ASH) guidelines: recommendations are broadly aligned with those for children in the 2012 ACCP guidelines (no distinction is made between neonates and children)5
Both sets of guidelines suggest either LMWH or VKAs for the treatment of VTE in paediatric patients. Because the use of VKAs is especially challenging in neonates, the ACCP guidelines suggest to use LMWH or UFH followed by LMWH in neonates.2,5, At the time these guidelines were written, the phase III trials of NOACs for the treatment of VTE in paediatric patients were not completed; consequently, NOACs were not considered as a treatment option in children with VTE.
2012 ACCP guideline recommendations for the treatment of VTE in neonates (birth–28 days)2
2012 ACCP guideline recommendations for the treatment of VTE in children (28 days–18 years)2
References
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- Monagle P, Chan AKC, 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. Return to content
- Andrew M, David M, Adams M et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood 1994;83:1251–1257. Return to content
- van Ommen CH, Heijboer H, Büller HR et al. Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands. J Pediatr 2001;139:676–681. Return to content
- Monagle P, Cuello CA, Augustine C et al. American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism. Blood Advances 2018;2:3292–3316. Return to content
- 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;124:1001–1008. Return to content
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- Ageno W, Haas S, Weitz JI et al. Characteristics and management of patients with venous thromboembolism: The GARFIELD-VTE registry. Thromb Haemost 2019;119:319–327. Return to content
- Giordano P, Grassi M, Saracco P et al. Paediatric venous thromboembolism: a report from the Italian Registry of Thrombosis in Children (RITI). Blood Transfus 2018;16:363–370. Return to content
- 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. Return to content
- Chan AK, Deveber G, Monagle P et al. Venous thrombosis in children. J Thromb Haemost 2003;1:1443–1455. Return to content
- Monagle P, Adams M, Mahoney M et al. Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry. Pediatr Res 2000;47:763–766. Return to content
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- Massicotte P, Julian JA, Gent M et al. An open-label randomized controlled trial of low molecular weight heparin compared to heparin and coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial. Thromb Res 2003;109:85–92. Return to content
- Goldenberg NA, Abshire T, Blatchford PJ et al. Multicenter randomized controlled trial on duration of therapy for thrombosis in children and young adults (the Kids-DOTT trial): pilot/feasibility phase findings. J Thromb Haemost 2015;13:1597–1605. Return to content
- Johns Hopkins All Children's Hospital, National Heart L, and Blood Institute (NHLBI), . Evaluation of the duration of therapy for thrombosis in children (Kids-DOTT). 2019. Available at: https://clinicaltrials.gov/ct2/show/NCT00687882 [accessed 26 September 2019]. Return to content
- Greiner J, Schrappe M, Claviez A et al. THROMBOTECT - a randomized study comparing low molecular weight heparin, antithrombin and unfractionated heparin for thromboprophylaxis during induction therapy of acute lymphoblastic leukemia in children and adolescents. Haematologica 2019;104:756–765. Return to content
- Massicotte P, Julian JA, Gent M et al. An open-label randomized controlled trial of low molecular weight heparin for the prevention of central venous line-related thrombotic complications in children: the PROTEKT trial. Thromb Res 2003;109:101–108. Return to content
- Male C, Thom K, O'Brien SH. Direct oral anticoagulants: What will be their role in children? Thromb Res 2019;173:178–185. Return to content
- Lensing AWA, Male C, Young G et al. Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study. Thromb J 2018;16:34. Return to content
- Monagle P, Lensing AWA, Thelen K et al. Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies. Lancet Haematol 2019: doi:10.1016/s2352-3026(19)30161-9. Return to content
- 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. Return to content
- 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. Return to content
- Pfizer, Bristol-Myers Squibb. Apixaban for the acute treatment of venous thromboembolism in children. 2019. Available at: https://clinicaltrials.gov/ct2/show/NCT02464969 [accessed 12 August 2019]. Pfizer, Bristol-Myers Squibb. Apixaban for the acute treatment of venous thromboembolism in children. 2019. Available at: https://clinicaltrials.gov/ct2/show/NCT02464969 [accessed 12 August 2019]. Return to content
- Halton JML, Albisetti M, Biss B et al. Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics, safety, and tolerability. J Thromb Haemost 2017;15:2147–2157. Return to content
- Halton JML, Picard AC, Harper R et al. Pharmacokinetics, pharmacodynamics, safety and tolerability of dabigatran etexilate oral liquid formulation in infants with venous thromboembolism. Thromb Haemost 2017;117:2168–2175. Return to content
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- Luciani M, Albisetti M, Biss B et al. Phase 3, single-arm, multicenter study of dabigatran etexilate for secondary prevention of venous thromboembolism in children: Rationale and design. Res Pract Thromb Haemost 2018;2:580–590. Return to content
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- Brandão L, Albisetti M, Halton J et al. Safety of dabigatran etexilate for secondary prevention of venous thromboembolism in paediatric patient. Res Pract Thromb Haemost 2019;3:138–139. Return to content
- Albisetti M, Brandão L, Bomgaars L et al. Efficacy and safety of dabigatran etexilate for treatment of venous thromboemboism in paediatric patients - Results of the DIVERSITY trial. Res Pract Thromb Haemost 2019;3:139–140. Return to content
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Updated date 10/10/2022
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