Anticoagulant Treatment for Pediatric Infection-Related Cerebral Venous Thrombosis.

BACKGROUND: We aimed to describe the clinical presentation, risk of bleeding and recurrent thrombosis, and perioperative anticoagulant management of children with cerebral venous thrombosis (CVT) and an associated head or neck infection. METHODS: In this subgroup analysis of the EINSTEIN-Jr study, we included children with CVT and an associated head or neck infection who received therapeutic anticoagulants with either low-molecular-weight heparin (with or without subsequent vitamin K antagonists) or rivaroxaban for a period of 3 months. Analyses are descriptive. RESULTS: Of 74 included children, 59 (80%) had otomastoiditis, 21 (28%) a central nervous system infection, 18 (24%) sinusitis, and 9 (12%) another upper respiratory tract infection; 29 (39%) had infection of multiple regions of the head or neck. All 74 children received antibiotics and therapeutic anticoagulants; 41 (55%) underwent surgery, of whom 34 were diagnosed with CVT preoperatively. Anticoagulation was started before surgery in 12 children and interrupted 0-1 days prior to surgery. Anticoagulation was (re)started in all 34 children at a median of 1 day (interquartile range: 0-1) postoperatively, in therapeutic doses in 94%. Overall, one child (1%, 95% confidence interval: 0-7) had recurrent thrombosis, and one (1%, 95% confidence interval: 0-7) had major bleeding; neither was associated with surgery. At 3 months, no children had died, 3 (4%) had persistent focal neurologic deficits, and 2 (3%) had impaired vision. CONCLUSIONS: Children with CVT and an associated head or neck infection administered therapeutic anticoagulants generally had low risks of bleeding and thrombotic complications, including those who had surgical interventions with delay or interruption of anticoagulation.

Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Pediatric Venous Thromboembolism Treatment and Thromboprophylaxis: A Systematic Review of the Literature.

Venous thromboembolism (VTE) in children can lead to significant morbidity and mortality. Traditionally, treatment for thrombotic events in pediatric patients has been limited mainly to unfractionated heparin, low-molecular-weight heparin (LMWH), or vitamin K antagonists. Since the first non-vitamin K antagonist oral anticoagulant (NOAC) was approved for adult use, these agents have gained popularity for a variety of indications. This is largely due to their ease of administration, favorable pharmacokinetic and pharmacodynamic profile, decreased food interactions, and decreased need for therapeutic drug monitoring. Treating and preventing VTE with traditional anticoagulants in pediatric patients presents many challenges. This systematic review evaluated the current literature regarding pediatric NOAC trials. Additionally, based on an up-to-date query of clinicaltrials.gov, we detail current ongoing and as-yet unpublished clinical trials, study outcomes, and projected completion dates. Published pediatric NOAC trials have included 1,007 total children to date and have ranged from phase 1 to 4, with "indications" including both thromboembolism prophylaxis and VTE treatment. Three recent phase 3 trials, specifically involving rivaroxaban and dabigatran, have shown the agents to be at least as effective as traditional anticoagulants for acute and/or extended VTE treatment, with low frequency of recurrent thrombosis and clinically significant bleeding rates. Additionally, specially developed and tested pediatric formulations have allowed for accurate and reliable dosing, oral administration, stable pharmacokinetics and pharmacodynamics, and fewer drug or food interactions. Ongoing trials, anticipated for completion in the next few years, will reveal important information with regard to thromboembolism prophylaxis in special pediatric subpopulations and settings.

Safety and efficacy of anticoagulant therapy in pediatric catheter-related venous thrombosis (EINSTEIN-Jr CVC-VTE).

Anticoagulant treatment of pediatric central venous catheter-related venous thromboembolism (CVC-VTE) has not been specifically evaluated. In EINSTEIN-Jr, 500 children with any VTE received rivaroxaban or standard anticoagulants. A predefined analysis of the CVC-VTE cohort was performed. Children with CVC-VTE (age, birth to 17 years) were administered rivaroxaban or standard anticoagulants during the 1-month (children <2 years) or 3-month (all other children) study period. Predefined outcomes were recurrent VTE, change in thrombotic burden on repeat imaging, and bleeding. Predictors for continuation of anticoagulant therapy beyond the study period were evaluated. One hundred twenty-six children with symptomatic (n = 76, 60%) or asymptomatic (n = 50, 40%) CVC-VTE received either rivaroxaban (n = 90) or standard anticoagulants (n = 36). There was no recurrent VTE (0%; 95% confidence interval [CI], 0.0%-2.8%). Three children had the principal safety outcome: none had major bleeding and 3 children had clinically relevant nonmajor bleeding (2.4%; 95% CI, 0.7%-6.5%), all in the rivaroxaban arm. Complete or partial vein recanalization occurred in 57 (55%) and 38 (37%) of 103 evaluable children, respectively. Results were similar for symptomatic and asymptomatic CVC-VTE. Continuation of anticoagulant therapy beyond the study period occurred in 61 (48%) of children and was associated with residual VTE but only in children <2 years (odds ratio [OR], 20.9; P = .003) and continued CVC use (OR, 6.7; P = .002). Anticoagulant therapy appeared safe and efficacious and was associated with reduced clot burden in most children with symptomatic or asymptomatic CVC-VTE. Residual VTE and continued CVC use were associated with extended anticoagulation. This trial was registered at www.clinicaltrials.gov as #NCT02234843.

Rivaroxaban for treatment of pediatric venous thromboembolism. An Einstein-Jr phase 3 dose-exposure-response evaluation.

BACKGROUND: Recently, the randomized EINSTEIN-Jr study showed similar efficacy and safety for rivaroxaban and standard anticoagulation for treatment of pediatric venous thromboembolism (VTE). The rivaroxaban dosing strategy was established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling. METHODS: Rivaroxaban treatment with tablets or the newly developed granules-for-oral suspension formulation was bodyweight-adjusted and administered once-daily, twice-daily, or thrice-daily for children with bodyweights of ≥30, ≥12 to <30, and <12 kg, respectively. Previously, these regimens were confirmed for children weighing ≥20 kg but only predicted in those <20 kg. Based on sparse blood sampling, the daily area under the plasma concentration-time curve [AUC(0-24)ss ] and trough [Ctrough,ss ] and maximum [Cmax,ss ] steady-state plasma concentrations were derived using population PK modeling. Exposure-response graphs were generated to evaluate the potential relationship of individual PK parameters with recurrent VTE, repeat imaging outcomes, and bleeding or adverse events. A taste-and-texture questionnaire was collected for suspension-recipients. RESULTS: Of the 335 children (aged 0-17 years) allocated to rivaroxaban, 316 (94.3%) were evaluable for PK analyses. Rivaroxaban exposures were within the adult exposure range. No clustering was observed for any of the PK parameters with efficacy, bleeding, or adverse event outcomes. Results were similar for the tablet and suspension formulation. Acceptability and palatability of the suspension were favorable. DISCUSSION: Based on this analysis and the recently documented similar efficacy and safety of rivaroxaban compared with standard anticoagulation, we conclude that bodyweight-adjusted pediatric rivaroxaban regimens with either tablets or suspension are validated and provide for appropriate treatment of children with VTE.

Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial.

BACKGROUND: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METHODS: In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. FINDINGS: From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0·40, 95% CI 0·11-1·41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0·012). Major or clinically relevant non-major bleeding in participants who received ≥1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1·58, 95% CI 0·51-6·27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. INTERPRETATION: In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. FUNDING: Bayer AG and Janssen Research & Development.

Bodyweight-adjusted rivaroxaban for children with venous thromboembolism (EINSTEIN-Jr): results from three multicentre, single-arm, phase 2 studies.

BACKGROUND: Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents. METHODS: In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6-17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6-17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843. FINDINGS: Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2-5 years; 32 children aged 6-11 years; and 11 children aged 12-17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1·2-10·6) of these children had a clinically relevant non-major bleed (three children aged 12-17 years with menorrhagia and one child aged 6-11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0·0-3·9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (<20 kg, particularly <12 kg) showed low exposures so, for future studies, rivaroxaban dosages were revised for these weight categories, to match the target adult exposure range. 61 (66%) of 93 children had adverse events during the study. Pyrexia was the most common adverse event (ten [11%] events), and anaemia and neutropenia or febrile neutropenia were the most frequent grade 3 or worse events (four [4%] events each). No children died or were discontinued from rivaroxaban because of adverse events. INTERPRETATION: Treatment with bodyweight-adjusted rivaroxaban appears to be safe in children. The treatment regimens that we confirmed in children with bodyweights of at least 20 kg and the revised treatment regimens that we predicted in those with bodyweights less than 20 kg will be evaluated in the EINSTEIN-Jr phase 3 trial in children with acute venous thromboembolism. FUNDING: Bayer AG, Janssen Research and Development.