Extended-phase anticoagulation for pediatric venous thromboembolism after EINSTEIN Jr

Background

Extended-phase anticoagulation, defined as anticoagulation beyond the initial 3 months of therapy, has long represented one of the most challenging decisions in pediatric venous thromboembolism (VTE). In adults, extended-phase anticoagulation has been repeatedly shown to substantially reduce recurrent VTE while also consistently increasing bleeding events. Additionally, extended phase anticoagulation with direct oral anticoagulants (DOACs) is associated with reduced recurrence rates as well as reduced bleeding events, when compared with vitamin K antagonists (1). Most recently, there is growing evidence that reduced dosing strategies for DOACs are just as effective at minimizing recurrence rates while improving bleeding rates (2). However, unlike in adults, where large trials inform prolonged and reduced-dose strategies, pediatric practice has historically relied on extrapolation, small cohorts, and expert consensus. Use of DOACs, anchored by EINSTEIN Jr, has established feasibility and short-term safety; however, optimal duration, intensity, and risk–benefit thresholds for extended therapy remain poorly defined.

The phase 3 EINSTEIN Jr trial demonstrated that rivaroxaban was non-inferior to standard anticoagulation (heparin with or without a vitamin K antagonist) for acute pediatric VTE. Over 1–3 months of treatment, recurrent VTE occurred in 1% of children receiving rivaroxaban compared with 3% in the standard-therapy group, with similarly low bleeding rates (3). These findings validated weight-adjusted rivaroxaban as an effective and safe acute option across pediatric age groups. However, the central clinical dilemma extends beyond acute management to determining when anticoagulation can safely be discontinued.

To address this gap, in 2025, Male et al. recently published a predefined extended-phase cohort within EINSTEIN Jr providing the first structured pediatric data beyond the 3-month horizon (3). The study by Male et al. is a cohort analysis of children aged 17 years or younger with acute VTE who had completed the initial anticoagulation phase of the EINSTEIN-Jr study. In the parent trial, children received 5–9 days of heparin therapy followed by randomization (2:1) to rivaroxaban or standard anticoagulation. After completing the acute treatment phase, participants were eligible for an extended anticoagulation phase.

The extension phase constituted a non-randomized cohort in which the decision to continue anticoagulation was made at the discretion of the treating physician. Children could receive extended treatment within the study for up to 9 months (or up to 2 months in children younger than 2 years with catheter-related events), administered in predefined intervals, or could discontinue the study and continue anticoagulation outside the study setting. The primary outcomes, assessed among those who continued treatment within the study, were symptomatic recurrent VTE and clinically relevant bleeding.

Within the EINSTEIN-Jr trial, 248 (51%) of 491 enrolled children were included in a predefined extended-phase cohort, a non-randomized continuation phase in which 214 patients received ongoing anticoagulation within the study protocol for up to an additional 9 months. Among these children, recurrent VTE occurred in 3 of 214 (1%), corresponding to a cumulative incidence of 3.0% (95% CI: 0.9–9.8%). Clinically relevant non-major bleeding occurred in 4 of 214 (2%), with a cumulative incidence of 3.7%. No major bleeding events or fatal VTE were reported, and outcomes were similar between rivaroxaban and standard therapy. These findings suggest that, in carefully selected higher-risk children, extending anticoagulation to approximately 12 months of total therapy is associated with low recurrence and acceptable bleeding risk. Thus, EINSTEIN Jr does not resolve duration debates but reframes them by demonstrating that extended therapy is feasible and reasonably safe in selected patients.

Confounding factors in pediatric VTE treatment

Heterogeneity remains the central clinical problem in pediatric VTE. The condition encompasses provoked events such as central venous catheter-related thrombosis, as well as unprovoked, cancer-associated, and site-specific thrombosis including cerebral sinovenous or splanchnic events. Each subtype has a distinct natural history and recurrence profile. A child with catheter-related thrombosis after line removal differs fundamentally from an adolescent with unprovoked proximal deep vein thrombosis and persistent thrombophilia (4-6). Yet randomized pediatric trials directly comparing standard and extended durations are lacking. The Kids-DOTT trial addressed 6 weeks versus 3 months in provoked VTE but did not inform management beyond 3 months (7). Consequently, decisions regarding prolonged therapy remain individualized and extrapolative.

Insights from pediatric DOAC development programs further contextualize these findings. Trials such as 2 and DIVERSITY illustrate both progress and structural limitations. A recent systematic review highlighted challenges including recruitment of very young children, adaptive dosing requirements, protocol modifications, and heterogeneity in outcome definitions (8). These factors limit statistical precision, particularly for extended-phase endpoints that rely on rare-event estimation, and this is evident within the extended cohort of EINSTEIN Jr, where wide confidence intervals underscore the uncertainty.

Extrapolation from adult studies

Adult extended-phase trials offer conceptual guidance but cannot be directly extrapolated to children. The adult EINSTEIN CHOICE trial demonstrated that reduced-dose rivaroxaban preserved efficacy while lowering bleeding compared with full-dose therapy or aspirin (9). Broader adult data indicate that extended DOAC therapy substantially reduces recurrence, though bleeding risk accumulates over time (2,10,11). Reduced-dose strategies appear to balance recurrence and bleeding risk more favorably during extended treatment. These patterns support consideration of pediatric step-down dosing after 3–6 months in selected high-risk children rather than reflexive indefinite full-dose therapy. Nevertheless, developmental hemostasis, growth, evolving risk factors, and the prospect of prolonged bleeding exposure complicate indefinite anticoagulation in children.

Limitations

Importantly, selection of patients for extended therapy was not arbitrary. Children selected for prolonged treatment more commonly had symptomatic index VTE, unprovoked events or persistent provoking factors, and residual thrombosis on imaging. This approach aligns with the 2018 and updated 2024 guidance from the American Society of Hematology, which favor longer treatment in higher-risk children while acknowledging the very low certainty of evidence beyond 3–6 months (12,13). However, it nevertheless creates significant selection bias within this study. This bias is compounded by the fact that those patients not selected for extended anticoagulation were not followed for recurrence or persistence of thrombosis. While the data presented from this study strongly suggest both safety and efficacy for extended phase anticoagulation, the lack of comparison to patients discontinuing therapy prevents definitive conclusions.

The EINSTEIN Jr trial focuses on treatment with rivaroxaban as opposed to multiple DOACs. Overall, meta-analyses generally agree that the efficacy of DOACs is relatively similar and generalizable when compared to warfarin; however, this is clearly untrue for their safety profiles. Rivaroxaban often has increased bleeding when compared to other DOACs in common prothrombotic conditions such as atrial fibrillation and malignancy (14,15). On the other hand, apixaban has been shown to have the lowest bleeding rates while maintaining similar stroke/VTE prevention versus other DOACs. Therefore, the results from EINSTEIN Jr, which show an acceptable bleeding risk, should not be automatically applied to the use of other DOACs in the pediatric population.

Additionally, the use of DOACs in antiphospholipid syndrome (APS) remains controversial. There were only 10 cases of APS in the EINSTEIN Jr phase 3 trial and it is unclear if any of these cases were included in the extended phase trial. While the estimated incidence of pediatric APS is less than 1/100,000 children per year, the association of DOACs with recurrent thrombosis in APS makes this an important consideration. Evidence and guidance for children with APS are also largely extrapolated from adult data, supplemented by pediatric-specific consensus such as the 2017 SHARE recommendations and recent pediatric series. Both the SHARE recommendations and pediatric cohort data support long-term anticoagulation in the setting of APS with persistent antibodies (16,17). In cases of arterial thrombosis or recurrent thrombotic events, adult guidelines recommend warfarin therapy with either standard-intensity (INR 2–3) or higher-intensity targets (INR 3–4), sometimes combined with low-dose aspirin; this approach is commonly applied in older adolescents with arterial APS or recurrent VTE (18-20).

However, guidance from the International Society on Thrombosis and Haemostasis advises against DOAC use in triple-positive or arterial APS, recommending very cautious or exceptional use otherwise (21,22). Pediatric data are sparse and raise additional concerns; in one pediatric APS series, DOACs were used in older adolescents and recurrent thrombosis occurred in two of four patients, in the context of non-adherence, highlighting both safety concerns and the potential vulnerability conferred by short drug half-lives (16). Given the significance of both extended anticoagulation in APS, and the current evidence against the use of DOACs, EINSTEIN Jr would benefit from a discussion of these patients within its cohort, specifically whether they were selected for extended anticoagulation and which anticoagulant regimen they received.

Conclusions

Updated 2024 guidance from the American Society of Hematology and the International Society on Thrombosis and Haemostasis emphasizes that rivaroxaban and dabigatran are acceptable first-line agents for many pediatric VTEs, primarily in the acute phase, but that evidence supporting indefinite or very prolonged therapy remains insufficient.

The EINSTEIN Jr study demonstrates that extended-phase anticoagulation in selected children is associated with low recurrence and acceptable non-major bleeding using rivaroxaban or standard agents. Current practice and 2024 guideline recommendations remain substantially extrapolated from adult data, with extended therapy generally reserved for unprovoked events, persistent risk factors, residual thrombosis, or recurrence. Priority research areas include studying site-specific VTE, developing risk-stratified approaches, evaluating reduced-dose DOAC regimens for long-term secondary prevention, evaluating DOAC safety in pediatric APS, and conducting comparative trials of 6–12 months versus indefinite therapy in high-risk children. Until such evidence emerges, extended anticoagulation in pediatric VTE should remain individualized, balancing recurrence prevention against cumulative bleeding risk.

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-2026-0193/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-2026-0193/coif). J.T. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Octapharma for advisory board meeting, and from Evaheart for member of DSMB; and support for attending the advisory board meeting from Octapharma. 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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