Rivaroxaban for extended anticoagulation of pediatric venous thromboembolism

Introduction

Venous thromboembolism (VTE) is a growing clinical concern among pediatric patients, due to the increasing complexity of pediatric care, notably the increasing use of central venous catheters (CVCs), increased recognition among clinicians, and improved diagnostic imaging. While treatment of VTE had traditionally relied on heparins and vitamin K antagonists, growing clinical evidence on the efficacy and safety of direct oral anticoagulants (DOACs) among adult and pediatric patients has changed the landscape of anticoagulant use (1). Recently, in light of the combined results of the EINSTEIN-JR (2) and DIVERSITY (3) clinical trials, the updated International Society of Thrombosis and Haemostasis (ISTH) and American Society of Hematology (ASH) Guidelines for VTE Treatment in Pediatric Patients have recommended the use of the DOACs rivaroxaban or dabigatran for the treatment of acute VTE (4). DOACs appear to have a slight advantage compared to standard anticoagulants, including reduced thrombus recurrence and improved thrombus resolution, while maintaining a low risk of bleeding. Moreover, DOACs convey several advantages compared to standard anticoagulants, including (I) oral administration; (II) fewer drug-drug or food-drug interactions compared to vitamin K antagonists; (III) fixed dosing without monitoring requirement; and, (IV) in the case of rivaroxaban, pediatric formulations (5,6).

Rivaroxaban is an inhibitor of activated factor X (FXa) that directly binds to free and prothrombinase-complex-bound FXa, approved for the treatment of VTE by several agencies, including the US Food & Drug Administration and European Medicines Agency (1,7,8). Immediate-release film-coated tablets or oral suspension are administered orally or via a naso-gastric or gastric tube, following at least five days of parenteral anticoagulant therapy, and should be taken with meals to optimize bioavailability. It has a short mean half-life with a rapid onset and offset of action. Dosing and frequency of administration (once, twice or thrice daily) is based on bodyweight. As it is metabolized in the liver and renally cleared, caution should be exercised in patients with renal and liver failure. Routine monitoring is usually not required, although rivaroxaban-specific, chromogenic anti-FXa assays are available in specialized laboratories for situations such as suspected overdose, impaired intestinal absorption, or adherence concerns (4).

Following a diagnosis of acute VTE, the suggested treatment duration is typically 6 weeks for a provoked VTE and between 6 and 12 months for an idiopathic VTE (4). However, treatment duration may be extended in several situations with a higher perceived risk of VTE recurrence, notably in the presence of persistent prothrombotic risk factors (long-term CVC, inherited thrombophilia, etc.) or with a history of previous VTE. There are still limited published data on the efficacy and safety of secondary anticoagulation use in children following acute VTE treatment, as well as its impact of quality of life and cost-effectiveness. Consequently, limited guidance exists regarding which patients would benefit from extended or episodic secondary anticoagulation use.

Cohort study from the EINSTEIN-Jr trial

Male et al. reported a cohort study of children with extended treatment with rivaroxaban (9), as the final part of the EINSTEIN-Jr program (2,10-12). The aims of this study were to report the efficacy and safety of extended-phase anticoagulant therapy in children and to characterise factors associated with the decision to extend anticoagulation.

Briefly, the pivotal phase 3 study showed that the use of rivaroxaban led to a similarly low risk of recurrent VTE and clinically relevant bleeding, compared to standard anticoagulants (2). This open-label, international, randomized controlled trial enrolled 491 pediatric patients aged 17 years or younger with acute VTE in 107 hospitals. Pediatric patients were randomized in a 2:1 ratio to receive (I) bodyweight-adjusted 20-mg equivalent of rivaroxaban; or (II) heparins with or without a vitamin K antagonist for up to 3 months, or up to 1 month in infants (<2 years) with CVC-related VTE (CVC-VTE). After completion of treatment, patients were eligible to continue their allocated study medication for up to nine months (2 months in infants <2 years with CVC-VTE). Decisions regarding the length of anticoagulation were at the discretion of the treating physician. Random allocation of study medication was not maintained in the extended phase of the study, as the decision to continue anticoagulation was associated with several clinical characteristics and could be influenced by the type of anticoagulant used. Therefore, this study should be considered a prospective observational cohort study.

Half of the children enrolled in EINSTEIN-Jr (248/491, 51%) had their anticoagulant therapy extended, including 165/329 (50%) of children who received rivaroxaban and 83/162 (51%) of children receiving standard anticoagulants. Data are available for 214 patients (rivaroxaban: n=146; standard anticoagulants: n=68) for a median duration of anticoagulation of 93 days, as 34 individuals stopped their participation in the study. Of these, 194 were children aged ≥2 years (median age: 13 years, 47% male) whose index VTE was symptomatic in 90% of cases. Additionally, the cohort included 20 infants aged <2 years old with CVC-VTE [median age: 12 months (rivaroxaban) and 8 months (standard anticoagulants), 60% male]; 50% of index VTEs were symptomatic.

Overall, three patients out of 214 sustained a symptomatic VTE recurrence [observed incidence 1.0%, estimated 1-year cumulative incidence: 3.0%, 95% confidence interval (CI): 0.9–9.8%], all events being lower extremity deep vein thrombosis. No patient sustained a major bleeding event, while four patients had a clinically relevant non-major bleeding (CRNMB, cumulative incidence: 3.3%, 95% CI: 1.2–9.2%). Reported bleeds included epistaxis, hemorrhagic ovarian cyst, and heavy menstrual bleeding. Results were similar for children receiving extended anticoagulation with rivaroxaban or standard anticoagulants.

Presentation with a symptomatic index VTE [odds ratio (OR): 1.88, 95% CI: 1.14–3.11], unprovoked VTE or presence of a persistent prothrombotic risk factor (OR: 2.16, 95% CI: 1.46–3.19), and residual thrombosis on repeat imaging (OR: 3.79, 95% CI: 2.52–5.71) were associated with extended anticoagulation. Conversely, age, geographical location, and recurrent VTE were not associated with the clinical decision to extend anticoagulation. The authors conclude that incidences of recurrent VTE and bleeding during extended-phase anticoagulation were low, in accordance with acute-phase and adult studies.

Discussion

Findings from this study echo other available pediatric evidence. The DIVERSITY trial evaluated extended-phase anticoagulation with full-intensity dabigatran for secondary thrombosis prevention in 203 children over a median exposure of 36 weeks (range, 0–57 weeks) (13). VTE recurrence occurred in 2/203 children (1.0%), while 3/203 (1.5%) experienced major bleeding, 2/203 (1.0%) CRNMB, and 37/203 (18.2%) minor bleeding. These outcomes are similar to those reported in the extended-phase EINSTEIN-Jr study. Key differences between the trials include patient selection and study duration. The DIVERSITY extended-phase cohort enrolled children with unprovoked VTE or ongoing VTE risk factors, while EINSTEIN-Jr allowed for anticoagulation treatment prolongation at physician’s discretion and not limited to these scenarios. The extended-phase anticoagulation was longer in the DIVERSITY study (Table 1).

A subgroup of the EINSTEIN-Jr program included children with CVC-VTE aged <2 years, in whom extended anticoagulation was defined as continuation beyond one month, for a total duration of up to 3 months. The Kids-DOTT trial evaluated 6 weeks versus 3 months of anticoagulation in children with provoked VTE, using either DOACs or standard full-intensity anticoagulation (14). While the EINSTEIN-Jr extension study and Kids-DOTT differ fundamentally in their objectives and are therefore not directly comparable, there is some conceptual overlap in anticoagulant treatment for younger children. In particular, for patients <2 years of age with CVC-VTE, the extension from 1 to 3 months in EINSTEIN Jr approximates the longer 3-month treatment duration evaluated in Kids-DOTT. In the Kids-DOTT trial, recurrent VTE occurred in 4/210 (1.9%) children in the 3-month group, with major bleeding or CRNMB occurring in 5/210 (2.4%). These results provide contextual benchmarks that appear broadly consistent with the EINSTEIN-Jr cohort.

The ENNOBLE-ATE trial was a phase 3, prospective, randomized, open-label study in patients under 18 years of age with cardiac disease (15). Children were initially randomized 2:1 to age- and weight-based oral edoxaban or standard anticoagulation for a 3-month main study period. Both groups were then eligible to continue in an open-label edoxaban extension arm for up to 1 year. Edoxaban was administered at full-intensity doses, despite being used for primary prophylaxis. Among 144 children receiving extended edoxaban therapy, 1 major bleed or CRNMB occurred (0.7%), similar to the EINSTEIN-Jr extended phase bleeding outcomes. In the ENNOBLE-ATE population, the thrombotic events were arterial (2 strokes and 2 coronary artery thromboses/myocardial infarctions) rather than venous, which limits direct comparisons with venous thromboprophylaxis studies regarding thrombosis-related outcomes.

The UNIVERSE trial also evaluated rivaroxaban in pediatric populations, but in a fundamentally different clinical context. This randomized, open-label study compared prophylactic-dose rivaroxaban with aspirin for thromboprophylaxis in children aged 2–8 years following the Fontan procedure for single ventricle physiology (16). In UNIVERSE, safety outcomes showed 1/64 (1.5%) children in the rivaroxaban arm experienced major bleeding, 4/64 (6.3%) had CRNMB, and 1/64 (1.5%) had a thrombotic event. The UNIVERSE and EINSTEIN Jr extension trials differ in several key aspects, including indication (primary thromboprophylaxis post-Fontan versus secondary prevention after VTE), anticoagulant intensity (prophylactic versus treatment dose), and patient population (congenital heart disease versus general pediatric VTE). When comparing safety outcomes, it is important to consider the higher-risk population of children with recent cardiac surgery enrolled in the UNIVERSE trial.

Similarly, the SAXOPHONE trial was a randomized, open-label, phase 2 study comparing therapeutic-intensity apixaban versus standard of care (vitamin K antagonists or low-molecular-weight heparin) for primary thromboprophylaxis in children with congenital or acquired heart disease (17). In SAXOPHONE, major bleeding and CRNMB each occurred in 1/126 (0.8%) patients in the apixaban arm, and there were no thrombotic events. These outcomes are comparable to those of the EINSTEIN Jr extended phase trial. The SAXOPHONE trial also assessed quality of life metrics, recognizing that ease of administration and reduced monitoring requirements are important considerations for pediatric anticoagulation.

Despite substantial differences in study design and populations, these trials collectively contribute valuable evidence supporting the safety and efficacy of DOACs for extended thromboprophylaxis in pediatric patients. Table 1 summarizes the patients’ baseline characteristics and outcomes among the various pediatric trials.

The efficacy and safety profile of extended rivaroxaban therapy in pediatric patients appears similar to that observed in adults, with low rates of recurrent VTE and bleeding that mirror those reported in landmark adult trials such as EINSTEIN-Extension (18). In EINSTEIN-Extension, a total of 602 adults who had completed 6 to 12 months of anticoagulation were randomized to continue full-intensity rivaroxaban for an additional 6 to 12 months, while 595 adults were assigned to placebo. Recurrent VTE occurred in 8/602 (1%) patients, major bleeding in 4/602 (0.7%) and CRNMB in 32/602 (7.7%). Compared with placebo, the number needed to treat to prevent one recurrent VTE was 15, while the number needed to harm (major bleeding) was 147. The clinical characteristics associated with extended anticoagulation were similar between adult and pediatric populations, namely, primarily unprovoked VTE and the presence of persistent risk factors. The pediatric extended-phase recurrent VTE rate of 1% is comparable to adult extended anticoagulation outcomes, and the absence of major bleeding in extended EINSTEIN-Jr compares favorably to the low 0.7% rate in the adult EINSTEIN-Extension study. Both studies provide evidence that extended rivaroxaban therapy maintains its efficacy without a substantial increase in bleeding risk relative to the acute treatment phase.

Strengths and limitations

The extended phase EINSTEIN Jr trial has notable strengths. It provides valuable real-world data on pediatric VTE, an area with limited evidence. The study enrolled a diverse population across 107 hospitals in 28 countries, enhancing generalizability. The inclusion of children who received extended anticoagulation outside the study framework allowed for insight into factors associated with treatment decisions in clinical practice.

There are also some limitations. The study employed a non-randomized cohort design, limiting causal inference about the benefits of extended versus no extended anticoagulation. The decision to extend treatment was left to physician’s discretion, likely favoring patients with different perceived bleeding and thrombotic risks, introducing potential selection bias. In addition, prior anticoagulant exposure may have influenced treatment continuation, introducing further treatment selection bias. Additionally, while enrolling 214 children in an extended anticoagulation trial is a notable achievement, the low event rates preclude definitive conclusions about comparative efficacy and safety between rivaroxaban and standard anticoagulants during extended treatment. For example, the wide confidence interval around the 3.0% VTE recurrence estimate (95% CI: 0.9–9.8%) underscores its imprecision and warrants cautious interpretation.

Unmet research needs

While the unprecedented emergence of data on pediatric thrombosis in recent years is exciting, several questions remain unanswered. First, for adult patients, low-intensity dosing regimens were shown to be non-inferior to full-intensity regimens in patients requiring secondary VTE prevention with several anticoagulants such as rivaroxaban and apixaban (19-21). Pediatric prophylactic regimens for several DOACs are available and have been tested in children requiring primary VTE prevention, notably for congenital heart disease or acute lymphoblastic leukemia (16,17,22). Lower doses of anticoagulants may have the potential to reduce the rate of major bleeding and CRNMB, which are associated with increased complications, decreased quality of life, and increased healthcare use. Future research should therefore explore whether low-intensity dosing regimens of rivaroxaban are similarly efficacious and safe for pediatric patients requiring extended secondary anticoagulation.

Moreover, in this trial, the following factors were associated with extended anticoagulation: symptomatic VTE, unprovoked VTE or persistent prothrombotic risk factors, and residual thrombosis on repeat imaging. While these results reflect acceptance of available guidelines, in the case of unprovoked VTE or persistent prothrombotic risk factors, it also highlights a high-priority area for research. It remains unknown whether children with residual thrombus but no other risk factors benefit from prolonged anticoagulation, and there is ongoing uncertainty about which prothrombotic risk factors justify extended therapy, as evidenced by variability in clinical practice (23). Currently, no formal clinical decision-making frameworks exist to guide which children should receive extended anticoagulation, making identification of high-risk subgroups, such as those with residual thrombus, inherited thrombophilia, cancer-associated thrombosis, or chronic inflammatory conditions, among others, a high-priority unmet research need. Future studies are urgently needed to develop evidence-based, personalized strategies for secondary anticoagulation (24), and to compare the efficacy, safety, and patient-centered outcomes of different anticoagulant regimens.

Conclusions

The EINSTEIN-Jr phase 3 prospective observational cohort study evaluating extended-phase anticoagulant therapy provides new evidence to guide long-term management of pediatric VTE. In children requiring anticoagulation beyond the initial treatment period, the study found that extended therapy with rivaroxaban was associated with low rates of recurrent thrombosis and a favorable safety profile. These findings are consistent with the findings of the acute-phase treatment of the EINSTEIN-Jr program and extend its applicability to longer-term therapy.

From a clinical practice standpoint, these results support the use of rivaroxaban as a practical alternative to prolonged parenteral anticoagulation or vitamin K antagonists in pediatric patients requiring extended therapy. The availability of an oral anticoagulant, including in pediatric formulations, its predictable pharmacokinetics, and the absence of routine laboratory monitoring address longstanding challenges associated with long-term pediatric anticoagulation. For patients and families, this may translate into reduced treatment burden and enhanced quality of life. For the health care system, this may reduce monitoring requirements, clinic visits, and injection-related education, thereby decreasing care burden and associated costs.

While important knowledge gaps remain, this study supports the use of rivaroxaban for children requiring extended anticoagulation. By providing robust pediatric data, it makes a meaningful contribution to the evolving landscape of VTE management and is likely to inform clinical decision-making.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Pediatrics. The article has undergone external peer review.

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0130/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0130/coif). M.C.P was supported by the Fonds de recherche du Québec en Santé award. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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