SUMMARY

• XARELTO is indicated for thromboprophylaxis in pediatric patients aged ≥2 years with congenital heart disease (CHD) who have undergone the Fontan procedure.¹
• McCrindle et al (2021)^2,3 reported the efficacy and safety results of oral XARELTO compared with aspirin from the phase 3, randomized, multicenter, 2-part, open-label UNIVERSE study in pediatric patients aged 2 - 8 years with single-ventricle physiology who had undergone the Fontan procedure within 4 months prior to study enrollment.
  • In part A, single- and multiple-dose pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of weight-based XARELTO dosing were evaluated (n=12).
  • In part B, the safety and efficacy of weight-based XARELTO dosing (n=66) for thromboprophylaxis was evaluated compared to aspirin (n=34).
  • In both part A and B, the exposure of weight-based XARELTO dosing in children after the Fontan procedure was similar to the exposure in adults receiving a 10 mg total daily dose for thromboprophylaxis.
  • Safety outcomes:
    • One patient in the XARELTO part B group had a major bleeding event (2%; epistaxis). No major bleeding events were reported in the aspirin part B or XARELTO part A groups.
    • In the XARELTO vs aspirin part B groups, clinically relevant nonmajor bleeding occurred in 4 (6%) vs 3 (9%) patients and trivial bleeding occurred in 21 (33%) vs 12 (35%) patients.
• Duran et al (2022)⁴ conducted a single-center, case series that reported the use of XARELTO for venous thromboembolism (VTE) prophylaxis and treatment in 27 pediatric patients with CHD from May 1, 2020 to July 30, 2022.
  • One post-operative Fontan patient undergoing VTE treatment with XARELTO developed a new thrombus without resolution and experienced no bleeding events. None of the 8 post-operative Fontan patients on XARELTO prophylactically developed a new thrombus or experienced bleeding events.
• A literature search identified an additional study⁵ summarizing the PK/PD and exposure response results of XARELTO from the UNIVERSE study for your review.
• Additional citations identified during a literature search has been included in the REFERENCES section for your review.^6,7

Product Labeling

The safety and effectiveness of XARELTO have been established for use in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure. Use of XARELTO is supported in these age groups by evidence from adequate and well-controlled studies of XARELTO in adults, as well as additional data from a multicenter, prospective, open-label, active controlled study in 112 pediatric patients to evaluate the single- and multiple-dose PK properties of XARELTO and the safety and efficacy of XARELTO when used for thromboprophylaxis for 12 months in children with single ventricle physiology who had the Fontan procedure.¹

Clinical studY

UNIVERSE Study

McCrindle et al (2021)^2,3 reported the efficacy and safety results of oral XARELTO compared with aspirin from the phase 3, randomized, multicenter, 2-part, open-label UNIVERSE study in pediatric patients aged 2 - 8 years with single-ventricle physiology who had undergone the Fontan procedure within 4 months prior to study enrollment.

Study Design/Methods

• Part A was designed to characterize the single- and multiple-dose PK and PD profiles following oral administration of XARELTO, while part B evaluated the safety and efficacy of XARELTO compared to aspirin for thromboprophylaxis. Dosing interventions included:
  • XARELTO 0.1% (1 mg/mL) oral suspension twice daily by body weight in parts A and B for 12 months. See Table: XARELTO Dosing.
  • Aspirin ~5 mg/kg once daily for 12 months in part B.
• Patients were required to be clinically stable and able to tolerate oral or nasogastric feedings. An initial post-Fontan transthoracic echocardiographic screening without any evidence of thrombosis was required.
• Key exclusion criteria included thrombosis, a history of gastrointestinal disease or surgery associated with impaired absorption, active bleeding or high risk of bleeding including history of intracranial hemorrhage or contraindications to aspirin or XARELTO.
• In part A, there was a 12-day initial PK, PD, and safety assessment period, followed by a 12-month open-label treatment period, and a 30-day follow up.
• Patients in part B were randomized 2:1 on day 1 to receive XARELTO oral suspension or aspirin for 12 months.
• The primary safety outcome was major bleeding events, as defined by the International Society on Thrombosis and Haemostasis; secondary safety outcome was clinically relevant nonmajor bleeding and trivial (minimal) bleeding events.
• The primary efficacy outcome included any thrombotic event (venous or arterial) defined as the appearance of a new thrombotic burden within the cardiovascular system noted on routine surveillance or clinically indicated imaging; or the occurrence of a clinical event known to be strongly associated with thrombus, such as stroke or pulmonary embolism.
• The study was not powered to formally test for efficacy, due to the limited number of study patients and low rate of events.

Results

• A total of 112 patients were included (12 in the XARELTO part A group, 66 in the XARELTO part B group, and 34 in the aspirin part B group).
• In the XARELTO part A group, the mean age at screening was 2.5 (±0.7) years, 58% patients were male, mean weight was 13.8 (±2.4) kg, mean duration between the Fontan procedure and first study drug dose was 12 (±17) days.
• In the XARELTO vs aspirin part B groups, the mean age at screening was 4.1 (±1.7) years vs 4.2 (±1.8) years, 55% vs 68% patients were male, mean weight was 15.8 (±3.7) kg vs 15.7 (±3.1) kg, mean duration between the Fontan procedure and first study drug dose was 45 (±41) days vs 37 (±35) days.
• In both part A and B, the exposure of XARELTO in children after the Fontan procedure was similar to the exposure in adults receiving a 10 mg total daily dose for thromboprophylaxis.
• One patient in the XARELTO part B group had a major bleeding event (2%; epistaxis). The epistaxis was in a noncritical site and was considered a major bleeding event because the patient required a blood transfusion. Bleeding events are presented in Table: Summary of Bleeding Events.
• Thrombotic events in part B (efficacy) occurred in 1 (2%) patient in the XARELTO group (pulmonary embolism) and 3 (9%) patients in the aspirin group (2 patients with venous thrombosis and 1 patient with ischemic stroke). One patient (8%) in the XARELTO part A group had a venous thrombotic event. The study was not powered to evaluate efficacy.
• In the XARELTO vs aspirin part B groups, 86% (n=55) vs 85% (n=29) of patients reported ≥1 adverse event, and 28% (n=18) vs 24% (n=8) of patients reported ≥1 serious adverse event, respectively.
  • The rates of adverse events and serious adverse events were generally balanced between both treatment groups, except for pleural effusions (19% in the XARELTO group vs 6% in the aspirin group), which were considered not related to the study drug by the investigators.
  • Infections (63% in the XARELTO group vs 65% in the aspirin group) were the most common adverse event reported in both treatment groups.

CASE Series

Duran et al (2022)⁴ conducted a single-center, case series that reported the use of XARELTO for VTE prophylaxis and treatment in 27 pediatric patients with CHD from May 1, 2020 to July 30, 2022.

• Patient outcomes assessed were the development of symptomatic recurrent VTE, development of VTE while on prophylactic treatment, resolution of existing thrombi, and major or clinically relevant non-major bleeding episodes.
• Of the 27 patients started on XARELTO, 12 (44%) were started for VTE treatment and 15 (56%) were started for prophylaxis. 
  • There were 10 (37%) post-operative Fontan patients.
• The median age for XARELTO initiation was 42 months (IQR 11-56 months) and there were 9 (33%) female patients.

One post-operative Fontan patient undergoing VTE treatment with XARELTO developed a new thrombus without resolution and experienced no bleeding events. None of the 8 post-operative Fontan patients on XARELTO prophylactically developed a new thrombus or experienced bleeding events.

Literature search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 25 September 2024