Treatment with bodyweight-adjusted rivaroxaban appears to be safe in children with acute VTE previously treated with low-molecular weight heparin, fondaparinux or a vitamin K antagonist, an Australian led study in Lancet Haematology finds.
A phase 2 program of studies evaluating the DOAC in infants through to teenagers, used bodyweight-adjusted regimens that gave a similar rivaroxaban exposure to that in young adults treated with 20 mg rivaroxaban once daily.
The study of 93 children from 54 sites worldwide used once daily, twice daily or three times daily dosing regimens of rivaroxaban.
All children over 12 years and some of the 6-11 years-olds enrolled early in the study received tablets while all other children received a paediatric suspension of rivaroxaban.
Children younger than six months were treated with rivaroxaban for seven days and older children for 30 days.
The study reported no major bleeding or recurrent VTE in any of the children.
Where repeat imaging of the index thrombosis was available at the end of the treatment period, resolution was observed in 32% of children, improvement in 57% and no change from baseline in 11%. None of the children showed a deterioration on repeat imaging.
“However, all children received standard of care anticoagulation for the index event before the start of rivaroxaban and, therefore, the observed effects on thrombotic burden cannot be fully attributed to treatment with rivaroxaban,” the study authors said.
The study found individual prothrombin time and aPTT values were within the adult reference range, and there was a linear relationship between antifactor Xa activity and plasma concentration of rivaroxaban.
In the youngest children, especially those with a body weight less than 12 kg, rivaroxaban exposure was found to be either low or sub-therapeutic.
About two-thirds of children (66%) had adverse events such as pyrexia during the study but none required discontinuation of the DOAC.
Lead author Professor Paul Monagle, from the Royal Children’s Hospital Melbourne, told the limbic the adverse events were not necessarily related to the study drug.
“I think that is just reflecting the very sick population and the kinds of patients whom we had to anticoagulate,” he said.
“It’s a big difference between anticoagulating adults, the bulk of whom are well outpatients, to anticoagulating children, the bulk of whom get their clot while they are sick inpatients.”
The study said rivaroxaban dosing in small children was revised for the phase 3 study to correct the apparent low and subtherapeutic exposure.
“Our best guess is that there is altered clearance and metabolism of the drugs, and that is why it is so important in children to do dose-finding studies and appropriate phase 2 studies throughout all the ages,” Professor Monagle said.
An accompanying Comment in Lancet Haematology, said the “landmark study has raised the bar for the generation of level 1 evidence regarding oral anticoagulants in children”.
“The main question that will need to be answered in the phase 3 trial is: will rivaroxaban be as effective as the standard of care for the treatment of acute deep vein thrombosis?”
The phase 3 study has closed and results are expected to be published shortly.
“Of course these drugs need to have approval by regulatory agencies like FDA, EMA and TGA and the expected time frame for that to happen is probably over a couple of years,” Professor Monagle said.
He noted that all of the drugs currently used to anticoagulate children were unapproved except dalteparin, which received FDA approval in May this year.
“From a clinician’s point of view we are very used to using drugs off label. It’s a question of when you believe you have sufficient data that the drug can be used safely.”