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• W3197923118 abstract "Options for the prevention and treatment of venous thromboembolism (VTE) in childhood have largely been limited to oral vitamin K antagonists (VKA), injectable low-molecular-weight heparins (LMWH) or unfractionated heparin (UFH). The direct oral anticoagulants (DOACs), which are now extensively used in adult practice, have the advantage of an oral agent that does not require monitoring. This is attractive in children, particularly younger children, in whom daily subcutaneous injections of LMWH or poor stability of anticoagulant control with a VKA can be problematic. The use of DOACs in individuals <18 years of age has previously been limited by a lack of clinical trial data on efficacy and safety in this age group. Paediatric development programmes have followed the successful DOAC studies in adult populations and include paediatric studies of the direct thrombin inhibitor dabigatran and the factor Xa antagonists rivaroxaban, apixaban and edoxaban. Studies of single-dose or short-duration DOAC therapy were initially used to establish pharmacokinetic and pharmacodynamic characteristics in children and adolescents.1-5 These studies confirmed that administration of a bodyweight-adjusted dose in all age groups resulted in DOAC concentrations that were comparable to those of a therapeutic dose in adults. In addition, there were no significant safety or tolerability concerns in these early studies. The EINSTEIN Junior Phase 3 study (EINSTEIN-Jr) randomised 500 children aged <18 years in a 2:1 ratio of rivaroxaban:standard anticoagulant (heparin or VKA) to receive a bodyweight-adjusted dose of oral rivaroxaban, providing equivalent exposure to an adult dose of 20 mg daily, for treatment of venous thrombosis.6 Children received a minimum of five days parenteral anticoagulation prior to commencing rivaroxaban. Rivaroxaban, as film-coated tablets or granules for suspension, was administered 1–3 times daily depending on body weight.6 Duration of therapeutic anticoagulation was a minimum of three months, reduced to one month for line-associated thrombosis in children <2 years of age. This non-inferiority study showed a low rate of VTE recurrence with rivaroxaban (1%) and standard anticoagulants (3%). Complete thrombus resolution occurred in a greater proportion of children treated with rivaroxaban over standard anticoagulants (38% vs 26%, respectively, P = 0·012) without an increase in major or clinically relevant non-major bleeding (3% vs 2%). A subgroup analysis of children with cerebral venous thrombosis (CVT, n = 114) who were randomised in EINSTEIN-Jr and evaluated after an initial three months of treatment, reported complete recanalisation of the cerebral venous sinuses in a greater proportion of children who received rivaroxaban compared to standard anticoagulants (25% vs 15%, P = 0·012) with no VTE recurrence in the rivaroxaban arm and equivalent safety characteristics to standard anticoagulants.7 The study included only nine term neonates and infants, four of whom were randomised to receive rivaroxaban. Children who were anticoagulated for symptomatic or asymptomatic central venous catheter (CVC)-related VTE in EINSTEIN-Jr (n = 126) received rivaroxaban or standard anticoagulants for one month (<2-year-old children) or three months (all other children) and were reported in a further subgroup analysis.8 There was no recurrent VTE, none had a major bleeding event and complete/partial vein recanalisation occurred in 92%. Continuation beyond the initial one or three months, due to residual thrombosis and/or ongoing CVC requirement, was indicated in 48% including 61% of those <2 years. There was no comparison of outcomes between those treated with rivaroxaban or standard anticoagulants due to low numbers. The DIVERSITY Phase 2b/3 study randomised 267 children aged <18 years of age in a 2:1 ratio of dabigatran:standard anticoagulant (heparin, VKA or fondaparinux) to receive age- and bodyweight-adjusted doses of oral dabigatran for treatment of venous thrombosis.9 Children received a minimum of five days parenteral anticoagulation prior to commencing dabigatran. Dabigatran tablets, pellets or oral suspension were administered twice daily to provide exposure similar to adult populations treated therapeutically with dabigatran.10 Participants received therapeutic anticoagulation for a minimum of three months. Dabigatran dose adjustment was permitted once to achieve trough dabigatran levels of 50–250 ng/ml, required in 62/117 (35%) patients assigned to dabigatran with 56 requiring an increase in dose. Dabigatran was non-inferior to standard anticoagulants in terms of a composite efficacy end-point of the proportion of children with complete thrombus resolution (46% of those treated with dabigatran vs 42% standard of care), freedom from recurrent VTE (96% vs 92%) and freedom from VTE-related death (100% vs 99%). Major bleeding occurred at a frequency of 2% in both groups. Adverse events related to the gastrointestinal tract were reported more often in the group treated with dabigatran but there was no gastrointestinal bleeding. The impact of dose adjustment was minimal and trough dabigatran concentrations were similar to those seen in adults: the authors concluded that dabigatran concentrations did not need to be monitored or doses adjusted in children in routine clinical practice.9 In a single-arm, open-label trial anticoagulation with dabigatran was continued as secondary prophylaxis in children (n = 203) who had been treated with either dabigatran or standard anticoagulants for three months and who had a risk of recurrent VTE. Dabigatran was given for up to 12 months, less if the risk factor(s) for VTE resolved. Rates of recurrence (1%), major bleeding events (1·5%) and post-thrombotic syndrome (1·2% in those with extremity or central-line thrombosis) were acceptable.11 Phase 3 studies of the factor Xa antagonists apixaban and edoxaban for the prevention and treatment of childhood VTE are ongoing (NCT02464969; NCT0236965312; NCT0298147213; NCT0279847114; NCT03395639). Paediatric formulations were available during clinical trials of the DOACs, usually in the form of powder or granules for suspension. Commercially available tablets or capsules can be used in larger children in order to deliver a weight-based dose. However, the administration of bodyweight-adjusted doses of a DOAC to smaller children, including those who are unable to swallow tablets, will be reliant on the availability of a suitable liquid oral preparation. Monitoring of LMWH and VKA therapy in children, in addition to the training of parents/carers in the administration of subcutaneous injections and point-of-care monitoring of VKAs, provides opportunities to develop the relationship between the parent/carer and the prescribing team. The introduction of DOACs into paediatric practice is likely to reduce the number of contacts with the prescriber but there will remain a need to provide counselling, education and advice, along with a point of contact. The young person and/or their parent or carer should be counselled about the risk of bleeding during anticoagulation with a DOAC and informed about the lack of data on the dosing, efficacy and safety of reversal agents in the paediatric population. Post-authorisation studies of DOAC use in children and real-life data will be valuable, particularly for very young children and those with specific indications or characteristics who were either under-represented or excluded from participation in clinical trials. While the advice and information in this guidance is believed to be true and accurate at the time of going to press, neither the authors, the BSH nor the publishers accept any legal responsibility for the content of this guidance." @default.
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• W3197923118 date "2021-08-30" @default.
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• W3197923118 title "Addendum to British Society for Haematology guideline on the investigation, management and prevention of venous thrombosis in children (<i>Br. J. Haematol</i>. 2011; 154: 196–207)" @default.
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• W3197923118 doi "https://doi.org/10.1111/bjh.17794" @default.
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