With the increasing recognition of pediatric venous thromboembolism (VTE), clinicians have several resources with new data that can help minimize intravenous treatment in children, according to a session at the Hematology / Oncology Pharmacy Association Virtual Conference 2021.
Presenter Sara Timaeus, PharmD, BCOP, said pediatric VTE affects between 1 and 5 per 100,000 children each year, with the majority caused by central venous catheters. Most cases of VTE in children are provoked, and despite the fact that it can occur in patients of all ages and sizes, Timaeus said there is a lack of high-quality clinical data.
With all direct oral anticoagulants, Timeaus said there are several important pharmacokinetic considerations for pediatric patients. Infants have a much greater volume of distribution and children have a higher rate of drug elimination, with lower rates of drug-protein binding.
Current guidelines recommend the use of unfractionated heparin, low molecular weight heparin, and warfarin, although Timaeus said all three have significant barriers to use in pediatric populations. Agents with new data include dabigatran, rivaroxaban, apixaban and edoxaban, although Timaeus focused her presentation on the first 2.
The efficacy and safety of dabigatran was investigated in the DIVERSITY phase 2b and 3 studies, which included children 0 to 17 years of age with acute VTE who had undergone 5 to 21 days of unfractionated heparin and low molecular weight heparin and were expected to require anticoagulation. for at least 3 months. Participants received dabigatran in capsules, pellets, or as an oral solution, although Timaeus noted that the pellets and oral solution are not yet commercially available.
Of the 177 participants who received dabigatran, 46% met the composite endpoint compared to 42% in the standard therapy group. Timaeus noted that there was a trend towards more bleeding in children receiving dabigatran, and although most cases were mild, there was 1 major bleeding.
Based on the study results, Timaeus said that dabigatran may be an option for patients who are progressing, although there are several considerations. The study used a complex dosing strategy that was never clearly defined, so questions remain about the correct dosing, and there was an underrepresentation of children less than 2 years of age, those with central-line thrombosis and patients with cancer. Finally, because the granules and oral suspension are not yet available, capsules may be difficult to administer to younger children.
Next, Timaeus turned to a discussion of rivaroxaban, an adult-dose factor Xa inhibitor and FDA-approved indications. Phase 1 of the Einstein-Jr program evaluated a single dose of rivaroxaban using a dosing model that approximated adult exposure at 10 mg and 20 mg in patients aged 6 months to 18 years who had completed treatment for VTE. The results showed that the model accurately predicted dosing in most patients, although patients less than 2 years of age had lower than predicted exposure.
The phase 2 study evaluated rivaroxaban in 3 patient groups simultaneously: patients less than 6 months, patients between 6 months and 5 years, and patients between 6 and 17 years. Participants received a body weight adjusted dose of 20 mg rivaroxaban daily for 30 days. According to the study findings, patients weighing less than 12 kg required three times daily dosing and no major bleeding was reported.
Finally, the Phase 3 program compared the efficacy and safety of pediatric dose regimens for rivaroxaban with standard anticoagulants in children with acute VTE. Of the 335 children who received rivaroxaban, only 4 (1%) had symptomatic recurrent VTE, compared to 3% in the standard therapy arm. Similarly, 3% of the children in the rivaroxaban arm experienced bleeding, all of which were non-serious, compared to 2% of the children in the standard group, with 2 serious and 1 non-serious event.
Based on the phase 3 findings, the researchers concluded that in pediatric patients with VTE, rivaroxaban showed a similarly low recurrence rate with no increased risk of bleeding compared to standard anticoagulation. However, like dabigatran, rivaroxaban and the Einstein Jr program have several limitations.
Only 25% of the subjects had catheter-related thrombosis and only 10% were between birth and 23 months of age. In addition, the drink is not yet commercially available, making administration a potential challenge.
Timaeus S. Prevention of Pokes and Prods in Children with Blood Clots: Use of Direct Oral Anticoagulants in Pediatric Patients. Presented at: Hematology / Oncology Pharmacy Association 2021 Virtual Conference; April 14, 2021. Access until April 15, 2021.