Direct Oral Anticoagulants Can Minimize IV Treatment in Pediatric Patients

Pharmacokinetic differences in pediatric patients should be considered when administering direct oral anticoagulants, as should potential administration difficulties when pellets or oral solutions are not available.

With increasing recognition of pediatric venous thromboembolism (VTE), clinicians have several agents with emerging data that could help minimize intravenous treatments in children, according to a session at the Hematology/Oncology Pharmacy Association 2021 virtual conference.

Presenter Sara Timaeus, PharmD, BCOP, said pediatric VTE impacts between 1 and 5 per 100,000 children each year, with the majority caused by central venous catheters. Most cases of pediatric VTE are provoked, and despite the fact that it can occur in patients of all ages and sizes, Timaeus said there are 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 higher volume of distribution and children have higher rates 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 3 have significant barriers to use in pediatric populations. Agents with emerging 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 trials, which included children aged 0 to 17 years with acute VTE who had completed 5 to 21 days of unfractionated heparin and low molecular weight heparin and who were expected to require anticoagulation for at least 3 months. Participants received dabigatran either 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 toward increased bleeding in children receiving dabigatran, and although most cases were minor, there was 1 major bleeding event.

Based on the study findings, Timaeus said dabigatran may be an option for patients moving forward, although there are several considerations. The study used a complex dosing strategy that was never clearly defined, so questions remain about proper dosing, and there was under-representation of children younger than 2 years of age, those with central line thrombosis, and patients with cancer. Finally, because the pellets and oral suspension are not yet available, capsules may be difficult to administer to younger children.

Next, Timaeus turned to a discussion of rivaroxaban, which is a factor Xa inhibitor with adult dosing and FDA-approved indications. Phase 1 of the Einstein-Jr program evaluated single dose rivaroxaban using a dosing model that approximated adult exposure at 10 mg and 20 mg in patients between the ages of 6 months and 18 years who had completed treatment for VTE. The results showed that the model accurately predicted dosing in most patients, although patients younger than 2 years of age had lower exposure than predicted.

The phase 2 trial evaluated rivaroxaban in 3 patient groups simultaneously: those younger than 6 months of age, those between 6 months and 5 years of age, and those between the ages of 6 and 17 years. Participants received a bodyweight-adjusted 20 mg dose of rivaroxaban daily for 30 days. According to the study findings, patients weighing less than 12 kg required 3-times-per-day dosing and no major bleeding was reported.

Finally, the phase 3 program compared efficacy and safety of pediatric rivaroxaban dose regimens with standard anticoagulants in children with acute VTE. Of 335 children who received rivaroxaban, just 4 (1%) had symptomatic recurrent VTE, compared to 3% in the standard therapy arm. Similarly, 3% of children in the rivaroxaban arm experienced bleeding events, all of which were non-major, compared to 2% of children in the standard group, with 2 major and 1 non-major event.

Based on the phase 3 findings, the investigators concluded that in pediatric patients with VTE, rivaroxaban demonstrated a similar low recurrence rate without increased risk of bleeding compared to standard anticoagulation. Like dabigatran, however, rivaroxaban and the Einstein Jr program have several limitations.

Only 25% of the trial participants had catheter-related thrombosis and only 10% were between birth and 23 months of age. Furthermore, the oral solution is not yet commercially available, making administration a potential challenge.


Timaeus S. Avoiding Pokes and Prods in Kids with Clots: Use of Direct Oral Anticoagulants in Pediatric Patients. Presented at: Hematology/Oncology Pharmacy Association 2021 virtual conference; April 14, 2021. Accessed April 15, 2021.