Rivaroxaban Seems Safe, Effective for Pediatric Acute VTE

By Marilynn Larkin

November 14, 2019

NEW YORK (Reuters Health) - In children with acute venous thromboembolism (VTE), treatment with the direct oral anticoagulant rivaroxaban results in a similarly low recurrence risk and a lower thrombotic burden as parenteral anticoagulants, without increasing bleeding, researchers say.

"As for many pediatric diseases, currently available medications for thrombosis have never been systematically studied and licensed for children," Dr. Christopher Male of the University of Vienna told Reuters Health by email. "Current standard anticoagulants have a number of disadvantages, such as parenteral administration and need for frequent monitoring."

"The pivotal study had two key results," he said. "One, outcome frequencies such as recurrent thrombosis and bleeding, as well as relative treatment effects (rivaroxaban versus standard anticoagulants), were quite similar between adults and children, demonstrating that...the large body of data from adults can be used to inform the still-limited pediatric evidence."

Secondly, he noted, "rivaroxaban in weight-adjusted fixed-dose regimens was shown to be at least as effective and safe in children as standard anticoagulants."

That said, he added, weight-relative doses and dosing frequency were different for younger children and infants, "showing that dosing cannot be simply down-scaled from adults but needs to be systematically studied and clinically validated."

The open-label, randomized study involved 500 children up to age 17 with acute VTE in 107 pediatric hospitals in 28 countries. Participants who had started on heparin were assigned (2:1) to body weight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist).

Randomization was stratified by age and VTE site. The 37 children under age two with catheter-related VTE were treated for one month; the other 463 participants were treated for three months.

As reported online in The Lancet Haematology, after a median follow-up of 31 days in the children treated for one month, and 91 days in the children treated for three months, symptomatic recurrent VTE occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio, 0·40).

Repeat imaging showed rivaroxaban improved the thrombotic burden compared with standard anticoagulants. Major or clinically relevant non-major bleeding occurred in 10 (3%) of 329 children receiving at least one dose of rivaroxaban (all non-major) and in three (2%) of 162 children receiving standard anticoagulants (two major and one non-major; HR 1.58).

As Dr. Male noted, absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation were similar to those in studies in adults. No treatment-related deaths occurred.

Study coauthor Dr. Paul Monagle of the University of Melbourne, commented in a separate email, "Clinicians need to pay careful attention to the eligibility and exclusion criteria for the study and not extrapolate use of rivaroxaban beyond those criteria. Rivaroxaban will not be suitable for every child with a thrombosis, but certainly creates a more palatable option for many children."

"We desperately need long-term cohort/registry data now about real-world use of rivaroxaban," he added. "Randomized controlled trials are not designed to detect low frequency or long-term off-target effects, and yet it is critical that we know if such problems exist. We need to develop appropriate reversal strategies."

"FDA/EMA licensing will take another couple of years, and prior to that the availability of oral suspension may be limited so in the meantime use may be restricted to older children who can be given adult preparations," he concluded.

Dr. Sarah O'Brien of Nationwide Children's Hospital in Columbus, Ohio, author of a related editorial, called the findings "exciting."

"I encourage providers to closely examine the characteristics of the study population in this phase 3 trial and compare them to the patients they tend to treat," she told Reuters Health by email. "For example, many of our thrombosis patients are hospitalized neonates. Yet, neonates were under-represented in this study, and had to be full-term and receiving oral or tube feeding for at least 10 days in order to meet the eligibility criteria."

"On the opposite end of the spectrum, obese adolescents, another high-risk population, were also under-represented," she said.

"Our community must also consider how the widespread introduction of DOACs will affect our day-to-day anticoagulation practices," she noted. "It will be key for pediatric anticoagulation programs to determine what the pre-determined touchpoints will be for our patients who do not require laboratory monitoring. For example, programs may want to institute a weekly phone call in between discharge from the hospital and the first clinic appointment in order to check on dosing, adherence, and bleeding symptoms."

The study was funded by Bayer AG and Janssen Research and Development. Dr. Male and numerous coauthors received funds from the company.

SOURCE: http://bit.ly/2q9k7D3 and http://bit.ly/2Qh2yM6

Lancet Haematol 2019.