Elsevier

The Lancet Haematology

Volume 7, Issue 1, January 2020, Pages e18-e27
The Lancet Haematology

Articles
Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial

https://doi.org/10.1016/S2352-3026(19)30219-4Get rights and content

Summary

Background

Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism.

Methods

In a multicentre, parallel-group, open-label, randomised study, children (aged 0–17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed.

Findings

From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87–95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29–35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0·40, 95% CI 0·11–1·41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0·012). Major or clinically relevant non-major bleeding in participants who received ≥1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1·58, 95% CI 0·51–6·27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths.

Interpretation

In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants.

Funding

Bayer AG and Janssen Research & Development.

Introduction

As a result of improved treatment and survival of children with life-threatening or chronic medical conditions and increased awareness among paediatricians, venous thromboembolism is being identified more often in childhood.1, 2 The incidence of venous thromboembolism in children has been estimated at 0·01–0·05 per 1000 children per year,3, 4, 5 which is 20–100 times lower than in adults.6 Children with venous thromboembolism constitute a challenge to paediatricians because, with only a single small randomised trial available,7 there is a paucity of data about the effectiveness and harms of anticoagulants in this group.8 Furthermore, the pathophysiology of thrombosis, its anatomical distribution, and pharmacological responses to anticoagulants differ between children and adults.1, 8

Research in context

Evidence before this study

Venous thromboembolism in children is predominantly seen in children with severe underlying medical or surgical problems. Guidelines for treatment of paediatric venous thromboembolism rely on low level paediatric evidence or are extrapolated from adult evidence. We searched PubMed for the period Jan 1, 1990, to Jan 1, 2019, using the terms “anticoagulants”, “heparin”, “vitamin K antagonist”, “DOAC”, “children”, “pediatric”, “treatment”, “venous thromboembolism”, and “randomised study”. The single randomised trial which we identified was done in children with venous thromboembolism almost 20 years ago and was prematurely stopped after inclusion of only 76 children owing to slow enrolment. The trial compared intravenous unfractionated heparin followed by warfarin with subcutaneous administrations of the low molecular weight heparin reviparin followed by warfarin. Recurrent thromboembolism occurred in four (10%) of 40 children and major bleeding occurred in five (13%) of 40 children treated with unfractionated heparin and warfarin, compared with two (6%) of 36 and two (6%) of 36 children treated with reviparin and warfarin. Treatment of venous thrombosis in children is further limited by the absence of paediatric anticoagulant formulations, and the need for parenteral administration and for regular laboratory monitoring.

Fixed-dose treatment with the direct oral anticoagulant rivaroxaban is efficacious and safe for treatment of venous thromboembolism in adults. In the EINSTEIN-Jr phase 1 and 2 studies, bodyweight-adjusted rivaroxaban dose regimens with tablets or a newly developed oral suspension have been established for children aged between birth and 18 years matching the exposure range of young adults treated with rivaroxaban 20 mg once daily.

Added value of this study

The EINSTEIN-Jr phase 3 study is the first completed trial of a direct oral anticoagulant in children and the largest trial of anticoagulant treatment ever done in children. The results show that treatment of children with venous thromboembolism with bodyweight-adjusted rivaroxaban tablets or suspension resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding compared with standard anticoagulants.

Implications of all the available evidence

Study outcomes and relative efficacy and safety of rivaroxaban versus standard anticoagulants in children were similar to those observed in adult studies on rivaroxaban treatment. Given this similarity of clinical course of venous thromboembolism, and relative treatment effects, the results of the EINSTEIN-Jr studies can be interpreted in the context of the body of evidence from adults, which overall provides sufficient evidence to inform practical use of rivaroxaban in children. The availability of the rivaroxaban suspension formulation will obviate the need for long-term treatment of children with parenteral anticoagulants.

Fixed-dose rivaroxaban is effective for treatment of venous thromboembolism in adults and is associated with a lower risk of major bleeding as compared with the traditional combination of heparin followed by a vitamin K antagonist.9, 10, 11 In collaboration with the European and US regulatory agencies, a strategy was developed to evaluate rivaroxaban for treatment of venous thromboembolism in children.12, 13 In the EINSTEIN-Jr phase 1 and 2 studies,14, 15, 16, 17, 18 bodyweight-adjusted rivaroxaban dose regimens were established for children aged between birth to 17 years that matched the exposure range in adults younger than 45 years treated with rivaroxaban 20 mg once-daily.19

Anticoagulants given to young children are mostly parenterally administered,8 and are limited to dosage forms designed for adults that often need pharmaceutical manipulation to achieve the required paediatric dose.7, 20 However, manipulations might affect the stability and bioavailability of these drugs, and are prone to dosing errors, thereby potentially jeopardising safety and efficacy.20 To avoid these manipulations, as well as parenteral administration of anticoagulants, a rivaroxaban oral suspension was developed, which has similar pharmacokinetic properties to the tablet formulation.17, 18 This suspension will enable precise dosing and easier administration, especially in young children.

We aimed to compare the efficacy and safety of bodyweight-adjusted paediatric rivaroxaban dose regimens with those of standard anticoagulants in children with acute venous thromboembolism who had completed at least 5 days of initial heparinisation.

Section snippets

Study design and participants

A randomised, open-label, phase 3 study was done comparing the efficacy and safety of rivaroxaban with those of standard anticoagulants for treatment of venous thromboembolism. The main study treatment period was 3 months, with the exception of children younger than 2 years who had catheter-related venous thromboembolism, for whom it was 1 month.21

Elligible children aged 0–17 years were recruited from 107 paediatric hospitals in 28 countries. The trial design has been published previously.21

Results

From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of 520 children from 107 paediatric hospitals in 28 countries (ie, Australia, Israel, Japan, and China, and countries in Europe, South America, and North America) passed the screen of eligibility criteria and were randomised (appendix pp 3–5). Nine (2%) children did not take any study medication. One child in the standard anticoagulation group was lost to follow-up. Patient characteristics are in table 1. 117 (23%) had cerebral vein or sinus

Discussion

In children of all ages with various manifestations of venous thromboembolism, treatment with bodyweight-adjusted rivaroxaban, targeting the therapeutic exposure range of young adults, resulted in a low risk of recurrent venous thromboembolism and clinically relevant bleeding, similar to standard therapy. Moreover, treatment with rivaroxaban resulted in a greater reduction of thrombus mass as compared with standard therapy at repeat imaging. Study outcome rates and relative efficacy and safety

Data sharing

A data sharing statement is provided in the appendix p 21.

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  • Cited by (0)

    *

    Dr Heubach died in March, 2017

    A list of the EINSTEIN-Jr investigators and collaborators is provided in the appendix pp 3–5

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