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EINSTEIN Jr

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

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Year of Publication: 2019

Authors: Christoph Male, Anthonie Lensing, Joseph Palumbo, ..., Marcela Torres

Journal: The Lancet Haematology

Citation: Lancet Haematol. 2019 Jan;6(1):e89–e98

Link: https://www.thelancet.com/journals/lanha...0219-4/fulltext

Clinical Question

Is rivaroxaban as effective and safe as standard anticoagulants for the treatment of acute venous thromboembolism (VTE) in children?

Bottom Line

In 500 children (0-17yr) with acute VTE, bodyweight-adjusted rivaroxaban resulted in similar recurrent VTE (1% vs 3%; HR 0.40; 0.11-1.41) vs standard anticoagulation, with no increase in major bleeding (0% vs 1%). Rivaroxaban produced significantly greater clot resolution (complete 38% vs 26%; OR 1.70; P=0.012). First completed phase 3 DOAC trial in children. Oral suspension developed for young children.

        Major Points
        Recurrent VTE: 1% (4/335) rivaroxaban vs 3% (5/165) standard (HR 0.40; 0.11-1.41).
No major bleeding in rivaroxaban arm (0%) vs 2 in comparator (1%). CRNM bleeding 3% vs 1%.
Significantly greater clot resolution: complete 38% vs 26% (OR 1.70; 95% CI 1.11-2.58; P=0.012).
Net clinical benefit (recurrent VTE + major bleed): 1% vs 4% (HR 0.30; 0.08-0.93).
First completed phase 3 DOAC trial in children — largest pediatric anticoagulation trial (500 children, 107 hospitals, 28 countries).
Novel oral suspension (1 mg/mL) for children <6yr eliminates parenteral anticoagulation/lab monitoring.
Bodyweight-adjusted dosing targeting adult 20mg-equivalent exposure: once/twice/thrice daily based on weight.
97% first-episode VTE; 51% non-catheter-related, 27% catheter-related, 22% cerebral vein/sinus thrombosis.
Not formally powered for non-inferiority (upper CI 1.41 exceeds standard margins).
Bayer/Janssen funded. Led to regulatory approval of rivaroxaban for pediatric VTE.

      

Design

Study Type: Randomized, open-label, multicenter, active-controlled, phase 3 trial

Randomization: 1

Blinding: Open-label with blinded outcome adjudication

Enrollment Period: July 2014 – Feb 2018

Follow-up Duration: 3 months (6 months in children <2y with catheter-related VTE)

Centers: 107

Countries: Europe, North America, South America, Asia

Sample Size: 335

Analysis: Intention-to-treat and per-protocol analysis; time-to-event using Cox regression

Inclusion Criteria

Age 0–17 years with documented acute VTE (DVT, PE, or cerebral sinus thrombosis)
Stable after initial parenteral anticoagulation (5–9 days)
Weight-adjusted rivaroxaban dosing feasible

Exclusion Criteria

Active bleeding or bleeding risk
Platelet count <50 x 10⁹/L
Severe renal or hepatic impairment
Known contraindication to anticoagulation
Planned thrombolysis or surgery
Participation in other trials

Arms

Field	Rivaroxaban	Control
Intervention	Oral rivaroxaban (tablets or suspension), dosed by body weight to match adult exposure	Unfractionated heparin, LMWH, or fondaparinux followed by VKAs (e.g., warfarin)
Duration	3 months (or 6 months for children <2y with catheter-related thrombosis)	3 or 6 months

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Symptomatic recurrent VTE	Primary	3/121 (2.5%)	4/335 (1.2%)	0.33	NS
Change in thrombotic burden (imaging)	Secondary	80%	81%		NS
Major Bleeding	Adverse		1/335 (0.3%) vs 1/121 (0.8%)
Clinically relevant non-major bleeding	Adverse		9 (2.7%) vs 2 (1.7%)
Any bleeding	Adverse		72/335 (21%) vs 21/121 (17%)

Subgroup Analysis

Treatment effect consistent across age groups (0–2y, 2–12y, 12–17y), VTE type, and regions [oai_citation:1‡EINSTEIN Jr.pdf](file-service://file-9bRknGZZ88FShsh5xVQ8x9)

Criticisms

Open-label design could introduce bias despite blinded adjudication
Relatively short treatment/follow-up duration
Event rates were low, limiting statistical power for rare outcomes
No power to assess superiority

Funding

Bayer and Janssen

Based on: EINSTEIN Jr (The Lancet Haematology, 2019)