A new randomized trial lays the groundwork for the direct oral anticoagulant rivaroxaban (Xarelto; Janssen/Bayer) as a potential treatment option for children with venous thromboembolism (VTE).
Its findings point to a low recurrence risk and thrombotic burden on treatment with weight-adjusted rivaroxaban compared with standard anticoagulant therapy in patients 18 or younger with VTE, without promoting more bleeding,
"EINSTEIN-Jr is the largest pediatric study ever conducted for the treatment of VTE and shows that the efficacy and safety profile of rivaroxaban in a pediatric population with VTE is comparable to what has been observed in previous studies of adults with VTE," lead investigator Christoph Male, MD, Medical University of Vienna, Austria, told Medscape Medical News.
Although it wasn't the primary endpoint, the composite rate of recurrent VTE or major bleeding was reduced by a significant 70% in the rivaroxaban group compared with the standard anticoagulation group.
Male had presented the results of the phase 3 study July 8 at the International Society on Thrombosis and Haemostasis (ISTH) 2019 Congress in Melbourne, Australia.
Whereas VTE more commonly occurs in adults, it affects approximately 58 per 10,000 hospitalized children in the United States, according to background information from Janssen. There are limited treatment options for these young patients, and no direct oral anticoagulant is currently approved for use in this setting.
Current treatment is mainly based on observational data in this group and extrapolation of data obtained in adults, Male noted in his presentation. That's even though the pathophysiology and anatomic distribution of VTE, along with anticoagulant responses, can differ between children and adults.
"The EINSTEIN-Jr study with rivaroxaban represents a significant advance for pediatric VTE treatment," Male said.
The study is "firmly based and well-conducted," Richard C. Becker, MD, from the University of Cincinnati College of Medicine in Ohio, told Medscape Medical News.
"EINSTEIN-Jr is the first clinical trial comparing rivaroxaban and an active comparator in children with VTE," observed Becker, who was not involved in the study.
"The trial followed phase 1 and phase 2 studies designed to determine the pharmacokinetics of weight-adjusted rivaroxaban employing three dosing and formulation strategies. The findings establish a solid foundation for an expanded armamentarium for treatment."
The study enrolled 500 children aged up to 18 years with confirmed acute VTE treated with heparins or fondaparinux for the first few days. From day 6 to 9, they were randomly assigned in a 2:1 ratio to receive weight-adjusted rivaroxaban (at a 20 mg equivalent dose) or standard of care (heparin/vitamin K antagonist) for 3 months, with the option to continue treatment in 3-month increments up to a total of 12 months.
In addition to a tablet form of rivaroxaban, an oral suspension formulation of the drug has been developed, with similar pharmacokinetic properties as the tablet formulation, which enabled precise dosing and easier administration, especially in young children, Male reported.
Table. Rivaroxaban Dosage Regimens for Children by Body Weight in EINSTEIN-Jr
| Body weight (kg) |
Rivaroxaban Dosage Regimen (mg) |
Total Daily Dosage (mg) |
| 2.6 to <3 |
0.8 TID |
2.4 |
| 3 to <4 |
0.9 TID |
2.7 |
| 4 to <5 |
1.4 TID |
4.2 |
| 5 to <7 |
1.6 TID |
4.8 |
| 7 to <8 |
1.8 TID |
5.4 |
| 8 to <9 |
2.4 TID |
7.2 |
| 9 to <10 |
2.8 TID |
8.4 |
| 10 to <12 |
3.0 TID |
9.0 |
| 12 to <30 |
5.0 BID |
10.0 |
| 30 to <50 |
15.0 OD |
15.0 |
| >50 |
20.0 OD |
20.0 |
The main efficacy outcome of the study was symptomatic recurrent VTE, which occurred in 1.2% of rivaroxaban patients and 3% of the standard anticoagulation group, for a hazard ratio (HR) of 0.40 (95% confidence interval [CI], 0.11 - 1.41). There were no fatal VTE events in either treatment group.
Major or clinically relevant nonmajor bleeding occurred in 3% of the rivaroxaban group and 1.9% of the standard anticoagulation group, a nonsignificant difference (HR 1.58; 95% CI, 0.51 - 6.27). There were no major bleeding events in the rivaroxaban group and two in the standard anticoagulant group, Male reported.
Net clinical benefit, defined as a composite of recurrent VTE or major bleeding, occurred in 1.2% of the rivaroxaban patients and 4.2% of the standard anticoagulation group, for an HR of 0.30 (95% CI, 0.08 - 0.93).
Imaging tests showed that normalization of clot burden occurred in 38.5% of the rivaroxaban group and 26.1% of the standard anticoagulation group (odds ratio 1.71; 95% CI, 1.12 - 2.59).
"As the largest randomized trial to date in children with venous thrombosis, EINSTEIN-Jr is a welcome addition to our knowledge for treating venous thrombosis in the pediatric population," Mary Cushman, MD, who directs the thrombosis and hemostasis program at University of Vermont Medical Center, Burlington, told Medscape Medical News.
"While we await the final published report of this trial, the findings presented at the ISTH congress are very helpful."
Cushman, unaffiliated with the trial, noted that the proposed pediatric dosing algorithm achieved expected on-therapy drug levels, and that the clinical efficacy was similar to use of heparins or vitamin-K antagonists.
"For adult hematologists who often treat teens with VTE, for the large number of 12 to 18 year olds in this trial (92 on comparator and 184 on rivaroxaban), the clinical outcomes of recurrent thrombosis and bleeding with rivaroxaban were similar to the comparator, which is very reassuring," she said.
“For pediatric hematologists treating these and even younger patients across the pediatric spectrum, the findings also provide reassurance, since 151 participants treated with rivaroxaban and 73 treated with comparator were younger than age 12."
Cushman said the main weakness of the trial was that it was open-label, albeit by necessity, and only 54 patients aged 2 or younger were included.
"While this is a great advance to knowledge, clinicians treating patients in this age group might be reluctant to adopt rivaroxaban use until more data is available (or at least until the final results of this trial are published in full form)," she said.
EINSTEIN-Jr was funded by Bayer AG and Janssen Research. Male disclosed that he sits on steering and/or advisory boards for Bayer, Bristol-Myers Squibb, and Pfizer. Cushman and Becker have disclosed no relevant financial relationships.
International Society on Thrombosis and Haemostasis (ISTH) 2019 Congress: Abstract LB 01.5. Presented July 8, 2019.
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Cite this: EINSTEIN-Jr: Rivaroxaban Safe, Effective in Kids With Venous Thromboembolism - Medscape - Jul 19, 2019.
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