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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: 2020

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

Journal: The Lancet Haematology

Citation: Lancet Haematol. 2020 Jan;7(1):e18-e27

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 (0–17y) 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 complete clot resolution on repeat imaging (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
        Symptomatic recurrent VTE: 1% (4/335) rivaroxaban vs 3% (5/165) standard (HR 0.40; 95% CI 0.11–1.41).
No major bleeding in rivaroxaban arm (0/329) vs 2/162 (1%) in comparator (1 pulmonary, 1 intracranial). CRNM bleeding 10/329 (3%) vs 1/162 (<1%); composite HR 1.58 (0.51–6.27).
Significantly greater complete clot resolution on repeat imaging: 38% (128/335) vs 26% (43/165); OR 1.70 (95% CI 1.11–2.58); P=0.012.
Net clinical benefit (recurrent VTE + major bleed): 1% (4/335) vs 4% (7/165); 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) developed for children <6y, eliminating need for parenteral anticoagulation and routine laboratory monitoring.
Bodyweight-adjusted dosing targeting adult 20 mg once-daily exposure: once/twice/thrice daily depending on weight (≥30 kg once, 12–<30 kg twice, <12 kg thrice).
97% first-episode VTE; 51% non-catheter-related, 27% catheter-related, 22% cerebral vein/sinus thrombosis (rivaroxaban arm).
Not formally powered for non-inferiority (upper 95% CI of 1.41 lies within pre-specified adult margins of 1.75/1.50).
Bayer and Janssen funded. Supported 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 central outcome adjudication

Enrollment Period: Nov 14, 2014 – Sept 28, 2018

Follow-up Duration: 3 months (1 month in children <2y with catheter-related VTE); median 91 days (IQR 87–95) for 3-month arm and 31 days (IQR 29–35) for 1-month arm

Centers: 107

Countries: Australia, Israel, Japan, China, Countries in Europe, South America, and North America (28 countries total)

Sample Size: 500

Analysis: Efficacy: intention-to-treat (all randomised); safety: modified ITT (≥1 dose). Cox proportional hazards stratified by index event; van Elteren test for ordered categorical imaging outcomes

Inclusion Criteria

Age 0–17 years with objectively documented acute VTE (DVT, PE, cerebral vein/sinus thrombosis, or other)
Completed at least 5 days of initial parenteral heparinisation (UFH, LMWH, or fondaparinux)
Children <0.5 years required gestational age ≥37 weeks at birth, birthweight >2600 g, and oral feeding for at least 10 days

Exclusion Criteria

Active bleeding or high bleeding risk contraindicating anticoagulant therapy
Platelet count <50 × 10⁹/L
Hepatic disease associated with coagulopathy; ALT >5× ULN or elevated bilirubin
Severe renal impairment: eGFR <30 mL/min/1.73 m² (or, for age <1 year, creatinine >97.5th percentile for age)
Concomitant use of strong CYP3A4 and/or P-gp inhibitors
Concomitant use of strong CYP3A4 inducers
Sustained uncontrolled hypertension (>95th percentile for age)
Pregnancy, breastfeeding, or inadequate contraception in females of childbearing potential
Life expectancy <3 months
Contraindication to anticoagulation

Baseline Characteristics

Characteristic	Comorbidities	Qualifying Event

Arms

Field	Rivaroxaban	Control
Intervention	Bodyweight-adjusted oral rivaroxaban (immediate-release tablets or 1 mg/mL oral suspension) targeting adult 20 mg once-daily equivalent exposure; once-daily ≥30 kg, twice-daily 12–<30 kg, thrice-daily <12 kg	Heparin (UFH, LMWH, or fondaparinux) continued or switched to vitamin K antagonist at treating physician's discretion, at therapeutic doses per international guidelines
Duration	3 months (or 1 month for children <2y with catheter-related thrombosis)	3 months (or 1 month for children <2y with catheter-related thrombosis)

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Symptomatic recurrent VTE (centrally adjudicated)	Primary	5/165 (3%)	4/335 (1%)	0.4	NS
Complete resolution of index thrombosis on repeat imaging	Secondary	43/165 (26%)	128/335 (38%)	OR 1.70 (95% CI 1.11–2.58)	0.012
Composite: symptomatic recurrent VTE or deterioration on repeat imaging	Secondary	6/165 (4%)	5/335 (1%)	HR 0.41 (95% CI 0.12–1.36)
Net clinical benefit (composite recurrent VTE or major bleeding)	Secondary	7/165 (4%)	4/335 (1%)	HR 0.30 (95% CI 0.08–0.93)
Major Bleeding	Adverse	2/162 (1%) [1 pulmonary, 1 intracranial]	0/329 (0%)
Clinically relevant non-major bleeding	Adverse	1/162 (<1%)	10/329 (3%)
Major or clinically relevant non-major bleeding (composite)	Adverse	3/162 (2%)	10/329 (3%)	HR 1.58 (95% CI 0.51–6.27)

Subgroup Analysis

Treatment effect consistent across age groups (0–23 months, 2–5y, 6–11y, 12–17y), VTE type (cerebral vein/sinus vs catheter-related vs non-catheter-related), and geographic regions

Criticisms

Open-label design could introduce bias despite blinded central adjudication
Relatively short treatment/follow-up duration (median ~3 months)
Low event rates limited statistical power for rare outcomes
Not formally powered for non-inferiority — interpretation relies partly on extrapolation from adult data

Funding

Bayer AG and Janssen Research & Development

Based on: EINSTEIN Jr (The Lancet Haematology, 2020)

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

Citation: Lancet Haematol. 2020 Jan;7(1):e18-e27

Content summarized and formatted by NeuroTrials.ai.

EINSTEIN Jr

(2020)

Objective

Rivaroxaban versus standard anticoagulation in children with acute venous thromboembolism.

Study Summary

• Rivaroxaban showed similar efficacy to standard anticoagulants in children with VTE and was associated with a comparable safety profile, with greater complete clot resolution on repeat imaging.

Intervention

Bodyweight-adjusted rivaroxaban (targeting adult 20 mg once-daily exposure) given once, twice, or thrice daily by body weight as tablets or 1 mg/mL oral suspension vs. standard anticoagulation (initial UFH/LMWH/fondaparinux continued as heparin alone or switched to a vitamin K antagonist) for 3 months (or 1 month in children <2y with catheter-related VTE).

Inclusion Criteria

Children aged 0–17 years with objectively confirmed acute VTE (DVT, PE, cerebral vein/sinus thrombosis, or other) who had completed at least 5 days of initial parenteral heparinisation. Excluded active bleeding or high bleeding risk, platelet count <50×10⁹/L, hepatic disease with coagulopathy, severe renal impairment (eGFR <30 mL/min/1.73 m² or age <1y creatinine >97.5th percentile), ALT >5× ULN or elevated bilirubin, concomitant strong CYP3A4/P-gp inhibitors or strong CYP3A4 inducers, sustained uncontrolled hypertension (>95th percentile for age), pregnancy/breastfeeding/inadequate contraception, or life expectancy <3 months.

Study Design

Arms: Rivaroxaban vs. Standard Anticoagulation

Patients per Arm: Rivaroxaban: 335, Standard Therapy: 165

Outcome

• Symptomatic recurrent VTE: 1% (4/335, rivaroxaban) vs. 3% (5/165, standard), HR 0.40 (95% CI 0.11–1.41).• Major bleeding: 0/329 (0%) vs. 2/162 (1%).• Clinically relevant non-major bleeding: 10/329 (3%) vs. 1/162 (<1%).• Major or CRNM bleeding (composite): 10/329 (3%) vs. 3/162 (2%), HR 1.58 (95% CI 0.51–6.27).• Complete resolution of index thrombosis on repeat imaging: 128/335 (38%) vs. 43/165 (26%), OR 1.70 (95% CI 1.11–2.58; p=0.012).• Net clinical benefit (recurrent VTE or major bleeding): 4/335 (1%) vs. 7/165 (4%), HR 0.30 (95% CI 0.08–0.93).

Bottom Line

Major Points

Symptomatic recurrent VTE: 1% (4/335) rivaroxaban vs 3% (5/165) standard (HR 0.40; 95% CI 0.11–1.41).
No major bleeding in rivaroxaban arm (0/329) vs 2/162 (1%) in comparator (1 pulmonary, 1 intracranial). CRNM bleeding 10/329 (3%) vs 1/162 (<1%); composite HR 1.58 (0.51–6.27).
Significantly greater complete clot resolution on repeat imaging: 38% (128/335) vs 26% (43/165); OR 1.70 (95% CI 1.11–2.58); P=0.012.
Net clinical benefit (recurrent VTE + major bleed): 1% (4/335) vs 4% (7/165); 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) developed for children <6y, eliminating need for parenteral anticoagulation and routine laboratory monitoring.
Bodyweight-adjusted dosing targeting adult 20 mg once-daily exposure: once/twice/thrice daily depending on weight (≥30 kg once, 12–<30 kg twice, <12 kg thrice).
97% first-episode VTE; 51% non-catheter-related, 27% catheter-related, 22% cerebral vein/sinus thrombosis (rivaroxaban arm).
Not formally powered for non-inferiority (upper 95% CI of 1.41 lies within pre-specified adult margins of 1.75/1.50).
Bayer and Janssen funded. Supported regulatory approval of rivaroxaban for pediatric VTE.

Study Design

Study Type: Randomized, open-label, multicenter, active-controlled, phase 3 trial
Randomization: Yes
Blinding: Open-label with blinded central outcome adjudication
Sample Size: 500
Follow-up: 3 months (1 month in children <2y with catheter-related VTE); median 91 days (IQR 87–95) for 3-month arm and 31 days (IQR 29–35) for 1-month arm
Centers: 107
Countries: Australia, Israel, Japan, China, Countries in Europe, South America, and North America (28 countries total)

Primary Outcome

Definition: Symptomatic recurrent VTE (centrally adjudicated)

Control	Intervention	HR/OR	P-value
5/165 (3%)	4/335 (1%)	0.4 (0.11–1.41)	NS

Limitations & Criticisms

Open-label design could introduce bias despite blinded central adjudication
Relatively short treatment/follow-up duration (median ~3 months)
Low event rates limited statistical power for rare outcomes
Not formally powered for non-inferiority — interpretation relies partly on extrapolation from adult data

Citation

Lancet Haematol. 2020 Jan;7(1):e18-e27

View Original Publication →

EINSTEIN Jr

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

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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