Apixaban for the treatment of venous thromboembolic events in paediatric patients: an open-label, multicentre, randomised, controlled descriptive trial.

BACKGROUND: Contemporary data show an increasing incidence of venous thromboembolism in children, yet there are few evidence-based treatment guidelines on direct oral anticoagulant use for venous thromboembolism in this population. We aimed to investigate the safety and efficacy of apixaban in paediatric patients with venous thromboembolism. METHODS: This prospective, open-label, multicentre, randomised, controlled descriptive study was conducted in 120 sites in 14 countries and included a 12-week main treatment phase followed by an optional 6-12-week extension in the apixaban treatment group for patients who required additional anticoagulation for their index event, were adherent to apixaban administration, and had completed all study visits and activities. Patients were eligible if they were younger than 18 years with an index venous thromboembolism event confirmed by the investigator via imaging and were currently tolerating enteric medications. Exclusion criteria included more than 14 days of standard-of-care anticoagulant treatment before random assignment, active bleeding or a high risk of bleeding, and baseline abnormal liver function or inadequate kidney function. Patients were randomly assigned 2:1 to oral apixaban or standard-of-care (unfractionated heparin, low-molecular-weight heparin, or vitamin K antagonists) per local practice via a central randomisation and drug assignment system (stratified by age). The study used a fixed-dose-by-bodyweight-tier oral apixaban regimen (with nasogastric or gastric feeding, if required). Neonates initiated 0·1 mg oral apixaban twice daily for days 1-7, with the dose remaining at 0·1 mg twice daily thereafter unless otherwise indicated by the results of pharmacokinetics analysis on day 1. For children aged 28 days or older, doses ranged from 0·6 mg twice daily for the first 7 days and 0·3 mg thereafter (4 kg to <5 kg tier) and 10 mg twice daily for the first 7 days and 5 mg twice daily thereafter (highest weight tier, ≥35 kg). The primary efficacy endpoint was a composite of incidence of recurrent venous thromboembolism and venous thromboembolism-related mortality during the main phase (analysed in all randomly assigned patients). The primary safety endpoint was a composite of major bleeding and clinically relevant non-major bleeding during the main phase (analysed in all randomly assigned and treated patients). Efficacy and safety endpoints were adjudicated by an independent committee whose members were masked to treatment assignment. Adverse events were monitored using a combination of solicited and unsolicited event collection. The study is registered with ClinicalTrials.gov (NCT02464969) and is complete. FINDINGS: Between Nov 22, 2015, and April 30, 2024, 229 patients were randomly assigned: 155 to apixaban and 74 to standard of care. Median age was 14·2 years (IQR 6·1-16·5), with 137 (60%) patients age 12 years to younger than 18 years, 44 (19%) age 2 years to younger than 12 years, 32 (14%) age 28 days to younger than 2 years, and 16 (7%) age 27 days or younger. 128 (56%) patients were female, 101 (44%) were male, and 175 (76%) were White. Median treatment duration during the main phase was 83 days (IQR 78-90) in the apixaban group and 83 days (77-86) in the standard-of-care group. The primary efficacy endpoint occurred in four (2·6% [95% CI 0·8-6·7]) of 155 patients assigned to apixaban and two (2·7% [0·2-9·9]) of 74 assigned to standard of care; all events were recurrent venous thromboembolism. The primary safety endpoint occurred in two (1·3% [0·1-5·0]) of 152 apixaban-treated patients and one (1·4% [0·0-8·1]) of 73 standard-of-care-treated patients; all events were clinically relevant non-major bleeding, with no major bleeding events. Rates of any-grade adverse events were numerically similar in the apixaban (131 [86%] of 152 patients) and standard-of-care (61 [84%] of 73]) groups. The most common events were headache (25 [16%] in the apixaban group vs 11 [15%] in the standard-of-care group), epistaxis (24 [16%] vs 14 [19%]), and vomiting (20 [13%] vs four [5%]). There were three treatment-related serious adverse events with apixaban (two [1%] participants with haematochezia and one [1%] with cerebral venous sinus thrombosis) and none with standard of care. There were no treatment-related deaths during the study. INTERPRETATION: In this descriptive study, the safety and efficacy profile of a fixed-dose-by-bodyweight-tier apixaban regimen was similar to that of standard of care for the treatment of venous thromboembolism and prevention of venous thromboembolism recurrence in children younger than 18 years, providing a potential additional treatment option in this patient population. FUNDING: Pfizer and Bristol Myers Squibb.

Duke Scholars

Author Jennifer Ann Rothman Pediatrics, Hematology-Oncology