Phase 2 Studies Find Rivaroxaban Safe for Pediatric VTE

By Anne Harding

August 23, 2019

NEW YORK (Reuters Health) - Body weight-adjusted rivaroxaban is safe for treating children with venous thromboembolism (VTE), according to the results of three new phase 2 studies.

Current treatment for VTE in children typically involves injections of anticoagulant medication and frequent blood sampling for monitoring, Dr. Anthonie W. A. Lensing of Bayer AG in Wuppertal, Germany, one of the study's authors, told Reuters Health by phone.

"A lot of tears, a lot of fears, and no evidence base," he said, referring to this practice.

In adults, the direct oral anticoagulant (DOAC) rivaroxaban, developed by Bayer, is as effective as older anticoagulant therapies, carries a lower bleeding risk and does not require regular blood tests for monitoring.

Dr. Lensing and his colleagues worked with the U.S. Food and Drug Administration and the European Medicines Agency to develop a pediatric clinical trial program to evaluate rivaroxaban as part of the U.S. Pediatric Equity Act, which allows a patent extension on drugs if manufacturers evaluate their safety and efficacy in children.

The phase 2 trials, all single-arm, evaluated body weight-adjusted rivaroxaban doses in three age groups: younger than six months; six months to five years; and 6-17 years. The 93 study participants had confirmed VTE and were in their final phase of anticoagulant treatment.

Children younger than six months received rivaroxaban treatment for seven days, and older children were treated for 30 days.

None of the children developed recurrent VTE, and no major bleeding events occurred, the researchers report in The Lancet Haematology, online August 13.

Taking one tablet daily resulted in exposure similar to the adult reference range in children who weighed at least 30 kilograms, while children weighing at least 20 kg but less than 30 kg required twice-daily dosing.

Children weighing less than 20 kg, and especially less than 12 kg, had low exposures, so the authors revised dosages for this weight category, and recommend thrice-daily dosing for patients weighing less than 12 kg. They also developed a suspension form of the drug for use in younger children.

Phase 3 of the EINSTEIN-Jr trial is now complete, with "highly successful" results, and will be published in the next few months in The Lancet Haematology, Dr. Lensing said.

The new findings suggest that rivaroxaban is "safe and effective" in children and requires further evaluation in this group, Dr. Anjali A. Sharathkumar of Carver School of Medicine at the University of Iowa in Iowa City told Reuters Health by email.

In a comment accompanying the study, Dr. Sharathkumar noted that the increased dosing frequency for younger children could be burdensome for families, leading to worse adherence, and that dosing for children heavier than 50 kg must be clarified in future studies.

"This landmark study has raised the bar for generation of level 1 evidence regarding oral anticoagulants in children," she adds. "Clearly, this phase 2 study has enabled the successful launch of the follow-up phase 3 study, which will have a substantial effect on the clinical management of children with venous thromboembolism."

Bayer AG and Janssen Research and Development funded the study.


Lancet Haematol 2019.