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Paediatric patients with VTE – disease burden – risk factors
Learn about the challenges of treating children with VTE
Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is primarily regarded as a disease that affects adults.1 Although the incidence in adults is approximately 100 times higher than in children1-3, it has been increasingly recognized that paediatric VTE is also associated with substantial morbidity and mortality.4,5 While the overall incidence of paediatric VTE is estimated to be 0.07–0.14 per 10,000 children,2,3 the incidence of VTE in hospitalized children is around 100–1000 times higher, occurring in ≥58 cases per 10,000 hospital admissions (Figure 1).6,7 Thus, the children most commonly affected are those who are already hospitalized with other conditions, such as malignancy or heart disease,5,8,9 highlighting that this is a particularly vulnerable group of patients.
Figure 1: Annual incidence of VTE in hospitalized children6
In contrast to VTE in adults, paediatric VTE is rarely idiopathic.5 More than 90% of paediatric VTE events are related to underlying medical or surgical factors,2,3 and are considered provoked.5 The presence of central venous catheters is the most common risk factor, contributing to >90% of all neonatal VTE and >50% of all cases of VTE in other age groups.2,3,9 In addition to central venous catheters, trauma, cancer and infections have also been reported as major risk factors for VTE in children (Table 1).8,9
Table 1: Risk factors for paediatric VTE8
The majority of paediatric VTE events are reported during early infancy, followed by another peak during adolescence.5 In the past two decades, the incidence of paediatric VTE has increased due to medical advances and improved clinical outcomes in illnesses that previously caused mortality.4 One of the main reasons for this increase is the frequent use of central venous catheters in the treatment of neonates.4
Thus, the increasing incidence of paediatric VTE, associated with increased mortality and morbidity, especially in hospitalized children, highlights the need for effective prevention and treatment strategies in this group of patients. However, current treatment guidelines are based on very little evidence.10
So far, there is only one anticoagulant, dalteparin, that was FDA-approved for the reduction of VTE recurrence in paediatric patients aged one month and older in May 2019.11 Current treatment guidelines are largely based on evidence obtained from adult studies, smaller dose-finding and observational studies in children, and expert opinion.12 Management of paediatric VTE usually includes unfractionated heparin, low molecular weight heparin and oral vitamin K antagonists (VKAs).13 The standard practice in paediatric VTE is to monitor anticoagulant therapy within target therapeutic ranges, extrapolated from studies in adults.14
However, VKAs and heparins have been associated with various disadvantages in children, including challenges with intravenous or subcutaneous injections, and frequent blood sampling for laboratory monitoring.12,15 In addition, major differences between adults and children in the epidemiology and pathophysiology of VTE, the physiology of the haemostatic system and the impact of this on the pharmacology of antithrombotic agents highlight the need for specific evidence-based guidelines for the prevention and treatment of VTE in children.7
The lack of evidence-based treatment guidelines in paediatric VTE is due to limited data obtained from clinical trials of anticoagulants in children with VTE. Planning and conducting clinical trials in this particular patient population is challenging because of the low incidence of paediatric VTE and the correspondingly low recruitment rate.7,12 In addition, the different underlying conditions in paediatric VTE may complicate studies due to significant variations in bleeding risk factors, vascular access and concurrent medication.7 Study variables such as diagnostic modalities and treatment outcomes are also affected by the heterogenous nature of VTE in children. Paediatric VTE includes a wide range of events in different age groups, with different underlying pathophysiology, natural history and complications. Another challenge is the developing physiology of haemostasis in children. Developmental, age-related changes of the haemostatic system affect the pharmacology of anticoagulant agents, thus impacting on dosing, monitoring and adverse event rates.
Only a limited number of randomized clinical trials (RCTs) have been conducted in children, none of which have substantially increased the level of evidence for guidelines.7 There are no completed RCTs that enrolled >200 children, three RCTs closed early due to slow recruitment, and one was not powered for efficacy (Table 2).
Table 2: Failed/uncompleted randomized trials of anticoagulation in children with VTE7
Thus, it is important to consider the above-mentioned unique aspects of paediatric patients with VTE when designing and conducting clinical studies to provide evidence-based treatment guidelines for this specific patient population.
Although VTE is increasingly recognized in paediatric practice, management of VTE in children is mainly based on extrapolation from studies in adults. The differences in VTE between paediatric and adult patients, including differences in epidemiology, pathophysiology and the haemostatic system, highlight the need for specific evidence-based guidelines for the prevention and treatment of VTE in children. Therefore, it is essential to improve the design and conduct of clinical studies that address the pharmacokinetics/ pharmacodynamics, efficacy and safety of antithrombotic treatments, in this particularly vulnerable group of patients.
Paediatric VTE has been associated with a number of adverse clinical outcomes, including mortality, recurrent thrombosis and post-thrombotic syndrome.16 In a Canadian registry, mortality directly attributable to VTE occurred in 2.2% of children with VTE (Figure 2).16 All of the children who died as result of thrombosis had central-venous-catheter-associated VTE. Recurrent thrombosis and post-thrombotic syndrome were reported in 8.1% and 12.4% of patients, respectively.
Figure 2: VTE-related morbidity and mortality in 405 children with VTE16
Current standard of care in the management of VTE in children has been associated with several disadvantages (Figure 3).