ISTH 2019

Results from the EINSTEIN Junior trial, the first phase III DOAC trial completed in children with acute venous thromboembolism (VTE), were released in the late-breaker session at this year's International Society of Thrombosis and Haemostasis (ISTH) Congress.

VTE in children is rare and occurs secondary to underlying issues, such as cancer, surgery, infection and trauma. Currently, there is only one published randomised trial using anticoagulants in this setting: the REVIVE trial, which compared the efficacy and safety of low molecular weight heparin (LMWH) with heparin and coumadin.

There are currently no DOACs authorised for use in children. Children with VTE are typically treated with parenteral heparin or vitamin K antagonists (VKAs); there are no age-appropriate formulations, and adult formulations tend to be adapted for use in real-life practice, such as through pill crushing, which could affect drug stability and increase the risk for dosing errors.

"Therefore, rivaroxaban has high potential for children," explained Dr Christoph Male, Paediatric Cardiologist, Associate Professor of Paediatrics, Deputy Chair for Research, Division of Paediatric Cardiology, Medical University of Vienna, Austria, who presented the results.

Rivaroxaban can be administered via a newly developed age-appropriate suspension for younger patients, and as a tablet for older patients. "[It is] available in fixed dosage form, so you don’t need to do monitoring… which is quite problematic in children."

Trial design
EINSTEIN Junior was an open-label trial that enrolled 500 children under 18 years of age with acute VTE. They were randomised 2:1 to receive rivaroxaban or the standard of care (SOC; heparin or VKA). Dosing, as previously established in the phase I and II studies, was calculated using bodyweight-adjusted regimens that matched the exposure range of young adults treated with 20 mg rivaroxaban once daily. The main treatment period was 3 months, or 1 month in children aged <2 with catheter-related VTE.

A total of 55% of patients in the rivaroxaban arm were aged 12-18 (n=184); 20% aged 6-12 (n=67); 14% aged 2-6 (n=47); 11% aged 0-2 (n=37). The acute VTE sites for all patients were as follows: 33.0% lower extremity, 23.4% cerebral veins or sinuses, 16.0% lungs, 11.6% upper extremity, 10.4% jugular vein.

"A properly powered phase III study is not possible in such a rare disease in children… this study relies on an important principal that is used for drug development in children: extrapolation," explained Dr Male. Data obtained in adults were used to complement the paediatric data, and the trial aimed to demonstrate reasonable similarity between adults and children in terms of efficacy, safety and the clinical course of VTE. The trial used a similar design to EINSTEIN DVT/PE (n=8,182) in adults.

Endpoints and results The primary efficacy endpoint was symptomatic recurrent VTE, and the main safety outcome was a composite of major and clinically relevant non-major bleeding (CRNMB). Repeat imaging was obtained at the end of treatment, and pharmacokinetic (PK) and pharmacodynamic (PD) data were collected.

In the rivaroxaban arm, 1.2% (n=4) of patients had recurrent VTE, compared with 3.0% (n=5) in the comparator arm (hazard ratio (HR): 0.40; 95% confidence interval (CI): 0.11-1.41). "We could also see, from repeat imaging, that the number of clots that completely resolved was higher with rivaroxaban as compared to the SOC," noted Dr Male.

"With regards to bleeding, there was not a large difference," he continued. Major bleeding occurred in no patients in the rivaroxaban arm versus 1.2% (n=2) in the comparator arm, and CRNMB occurred in 3% (n=10) in the rivaroxaban arm versus 1.9% (n=3) patients in the comparator arm (HR: 1.58; 95% CI: 0.51-6.27).

In terms of PK parameters, AUC, C_max and C_trough values were within the adult reference range, regardless of formulation, age, bodyweight and therefore treatment regimens. Recurrent VTE, major bleeding, net clinical benefit and mortality was comparable between adults and in children.

Dr Male noted that rivaroxaban was at least as good as the SOC, "we could say that, in some instances, we even had an improved effect on the resolving clots," he continued, "but the way we administered rivaroxaban to these children, in an age-appropriate formulation and without the need for monitoring is definitely going to be a big advantage for the practical use."

"Given that we have now proven that this is efficacious and safe, it's very likely that, in future practice, many physicians will use this anticoagulant for the treatment of children."