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XARELTO® (rivaroxaban)

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XARELTO - Adverse Events in Pediatric Patients

Last Updated: 10/21/2024

SUMMARY

XARELTO is indicated for the treatment of venous thromboembolism (VTE) and the reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years after at least 5 days of initial parenteral anticoagulant treatment.¹
XARELTO is indicated for thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.¹
Male et al (2020)² reported results from the phase 3, randomized, open-label, activecontrolled EINSTEIN Junior study that evaluated the efficacy and safety of body weight-adjusted XARELTO in a 20 mg-equivalent dose compared with standard of care for the treatment of pediatric patients aged ≤17 years with acute VTE. The primary efficacy outcome was symptomatic recurrent VTE, and the primary safety outcome was the combination of overt major and clinically relevant nonmajor bleeding (CRNMB). Major or CRNMB events occurred in 10 (3%) patients in the XARELTO group and 3 (2%) patients in the comparator group. Additional adverse events (AEs) were reported.
Monagle et al (2019)³ assessed the efficacy and safety outcomes of the phase 2, multicenter, single-arm, open-label, nonrandomized EINSTEIN Junior study evaluating XARELTO treatment in pediatric patients aged ≤17 years with objectively confirmed VTE. The predefined safety outcomes were major and CRNMB. No patient had a major bleeding event, and 4 (4%) patients had a CRNMB event. AEs were reported in 61 (66%) patients. The most frequent grade ≥3 AEs were anemia (4%) and neutropenia (3%).
Kubitza et al (2018)⁴ reported results from the multicenter, open-label, nonrandomized phase 1 EINSTEIN Junior study evaluating the PK, PD, and safety of a single body weight-adjusted (10 mg- or 20 mg-equivalent) dose of XARELTO in pediatric patients aged 6 months to <18 years who had completed treatment for VTE and were at risk of recurrence. Treatment-emergent adverse events (TEAEs) were reported in 16 (27.1%) patients, of whom 4 (7%) reported TEAEs related to XARELTO. There were no major bleeding events, nonmajor clinically relevant bleeding events, or deaths.
McCrindle et al (2021)⁵ reported the efficacy and safety results for 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 enrollment. The primary efficacy outcome was incidence of any thrombotic event, and the primary safety outcome was occurrence of major bleeding events. Major bleeding event occurred in 1 patient (2%, epistaxis) in the XARELTO part B group. In the XARELTO vs aspirin part B groups, 55 (86%) vs 29 (85%) patients reported ≥1 AE, and 18 (28%) vs 8 (24%) patients reported ≥1 serious AE, respectively.
Valenti et al (2024)⁶ conducted a retrospective review to evaluate epidemiological and outcome data in a cohort of pediatric patients treated with direct oral anticoagulants (DOACs). Of the 65 patients included, 37% of patients were on apixaban, 61.5% were on XARELTO, and 1.5% were on dabigatran. Six patients had recurrent VTE (5 patients were on apixaban and 1 was on XARELTO). Out of 37 postmenarchal patients, 19% showed evidence of heavy menstrual bleeding (HMB). Of these patients, 5 were on apixaban, while 2 were on XARELTO.
Hardin et al (2021)⁷ conducted a retrospective analysis to evaluate the real-world anticoagulant use and incidence of major bleeding and VTE in pediatric patients. Overall, 778 patients were prescribed XARELTO. In the International Business Machines (IBM) MarketScan^® Commercial Claims and Encounters Database (CCAE), IBM MarketScan^® Multi-State Medicaid Database (MDCD), and Optum’s deidentified Clinformatics Data Mart DatabaseSocioEconomic Status (Optum), the unadjusted incidence rates of major bleeding and VTE were 1.2 and 18.2, 0 and 15, and 3 and 24.9 per 1000 person-years (PYs) of XARELTO exposure, respectively.
A literature search identified additional citations,⁸^-²⁰ case reports,²¹^-²⁶ and case series²⁷^-³² for your review.

PRODUCT LABELING

Pediatric Use

The safety and effectiveness of XARELTO have been established in pediatric patients from birth to less than 18 years for the treatment of VTE and the reduction in risk of recurrent VTE. Use of XARELTO is supported in these age groups by evidence from adequate and wellcontrolled studies of XARELTO in adults with additional PK, safety and efficacy data from a multicenter, prospective, open-label, active-controlled randomized study in 500 pediatric patients from birth to less than 18 years of age. XARELTO was not studied and therefore dosing cannot be reliably determined or recommended in children less than 6 months who were less than 37 weeks of gestation at birth, had less than 10 days of oral feeding, or had a body weight of less than 2.6 kg.¹

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 with 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

Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents.¹

Clinical Trial Experience - Pediatric Patients

Treatment of VTE and Reduction in Risk of Recurrent VTE in Pediatric Patients

The safety assessment is based on data from the EINSTEIN Junior part 3 study in 491 patients from birth to less than 18 years of age. Patients were randomized 2:1 to receive body weight-adjusted doses of XARELTO or comparator (unfractionated heparin, low molecular weight heparin [LMWH], fondaparinux or vitamin K antagonist [VKA]).¹

Discontinuation due to bleeding events occurred in 6 (1.8%) patients in the XARELTO group and 3 (1.9%) patients in the comparator group.¹

In female patients who had experienced menarche, ages 12 to <18 years of age, menorrhagia occurred in 23 (27%) female patients in the XARELTO group and 5 (10%) female patients in the comparator group.¹ The number of patients experiencing bleeding events in the EINSTEIN Junior study has been shown in the Table: Bleeding Events in EINSTEIN Junior Study - Safety Analysis Set - Main Treatment Period.

Bleeding Events in EINSTEIN Junior Study - Safety Analysis Set - Main Treatment Period¹^,a

Parameter	XARELTO^b N=329 n (%)	Comparator Group^c N=162 n (%)
Major bleeding^d	0	2 (1.2)
Clinically relevant nonmajor bleeding^e	10 (3.0)	1 (0.6)
Trivial bleeding	113 (34.3)	44 (27.2)
Any bleeding	119 (36.2)	45 (27.8)
Abbreviations: CVC-VTE, central venous catheter-related venous thromboembolism; LMWH, low molecular weight heparin; UFH, unfractionated heparin; VKA, vitamin K antagonist.^aThese events occurred after randomization until 3 months of treatment (1 month for patients <2 years with CVCVTE). Patients may have more than 1 event.^bTreatment schedule: body weight-adjusted doses of XARELTO; randomized 2:1 (XARELTO: Comparator).^cUFH, LMWH, fondaparinux, or VKA. ^dDefined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome.^eDefined as clinically overt bleeding, which did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life.

Nonbleeding adverse reactions reported in ≥5% of XARELTO-treated patients are shown in the Table: Other Adverse Reactions Reported in XARELTO-Treated Patients by ≥5% in EINSTEIN Junior Study.

Other Adverse Reactions Reported in XARELTO-Treated Patients by ≥5% in EINSTEIN Junior Study¹^,a

Adverse Reaction	XARELTO N=329 n (%)	Comparator Group N=162 n (%)
Pain in extremity	23 (7)	7 (4.3)
Fatigue^b	23 (7)	7 (4.3)
^aAdverse reaction with Relative Risk >1.5 for XARELTO vs comparator.^bThe following terms were combined: fatigue, asthenia.

A clinically relevant adverse reaction in XARELTO-treated patients was vomiting (10.6% in the XARELTO group vs 8% in the comparator group).¹

Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease After the Fontan Procedure

The data below are based on part B of the UNIVERSE study which was designed to evaluate the safety and efficacy of XARELTO for thromboprophylaxis in 98 children with congenital heart disease (CHD) after the Fontan procedure who took at least one dose of study drug. Patients in part B were randomized 2:1 to receive either body weight-adjusted doses of XARELTO or aspirin (approximately 5 mg/kg).¹

Discontinuation due to bleeding events occurred in 1 (1.6%) patient in the XARELTO group and no patients in the aspirin group.¹

The number of patients experiencing bleeding events in the UNIVERSE study has been shown in the Table: Bleeding Events in UNIVERSE Study - Safety Analysis Set - On Treatment Plus 2 Days.¹

Bleeding Events in UNIVERSE Study - Safety Analysis Set - On Treatment Plus 2 Days¹

Parameter	XARELTO^a N=64 n (%)	Aspirin^a N=34 n (%)
Major bleeding^b	1 (1.6)	0
Epistaxis leading to transfusion	1 (1.6)	0
Clinically relevant nonmajor bleeding^c	4 (6.3)	3 (8.8)
Trivial bleeding	21 (32.8)	12 (35.3)
Any bleeding	23 (35.9)	14 (41.2)
^aTreatment schedule: body weight-adjusted doses of XARELTO or aspirin (approximately 5 mg/kg); randomized 2:1 (XARELTO:Aspirin).^bDefined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of the equivalent of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome.^cDefined as clinically overt bleeding, which did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life.

Nonbleeding adverse reactions reported in ≥5% of XARELTO-treated patients are shown in the Table: Other Adverse Reactions Reported by ≥5% of XARELTO-Treated Patients in UNIVERSE Study (Part B).

Other Adverse Reactions Reported by ≥5% of XARELTO-Treated Patients in UNIVERSE Study (Part B)¹^,a

Adverse Reaction	XARELTO N=64 n (%)	Aspirin N=34 n (%)
Cough	10 (15.6)	3 (8.8)
Vomiting	9 (14.1)	3 (8.8)
Gastroenteritis^b	8 (12.5)	1 (2.9)
Rash^b	6 (9.4)	2 (5.9)
^aAdverse reaction with Relative Risk >1.5 for XARELTO vs aspirin.^bThe following terms were combined: Gastroenteritis: gastroenteritis, gastroenteritis viral; Rash: rash, rash maculo-papular, viral rash.

Clinical Data

Treatment and Reduction in Risk of Recurrent VTE in Pediatric Patients

EINSTEIN Junior Program

Phase 3 Study

Male et al (2020)² evaluated the efficacy and safety of a bodyweight-adjusted 20 mgequivalent dose of XARELTO compared with standard of care for treatment in pediatric patients aged ≤17 years with acute VTE in the randomized, active-controlled, open-label, phase 3 EINSTEIN Junior study.

Study Design/Methods

Pediatric patients aged 0-17 years with objectively confirmed VTE who had completed at least 5 days of initial heparin therapy were eligible. Key exclusion criteria included active bleeding or high risk for bleeding, contraindicating anticoagulant therapy, a platelet count of <50 × 10⁹ cells/L, hepatic disease associated with a coagulopathy, severe renal impairment, or a life expectancy of <3 months.
Patients were randomized 2:1 to XARELTO or standard anticoagulation (heparins/VKA) for a treatment duration of 3 months (patients aged <2 years with catheter-related thrombosis had a main treatment period of 1 month).
XARELTO was administered as a body weight-adjusted 20 mg-equivalent dose once daily in patients with a body weight of ≥30 kg, twice daily in patients with a body weight of 12 to <30 kg, or thrice daily in patients with a body weight of <12 kg using either immediate release film-coated tablets (strengths of 5, 10, 15, or 20 mg) or an oral suspension (1 mg/mL).
The primary efficacy outcome was symptomatic recurrent VTE. The primary safety outcome was the composite of overt major and CRNMB.

Results

A total of 500 patients (0-23 months, n=54; 2-5 years, n=69; 6-11 years, n=101; 1217 years, n=276) were randomized (XARELTO, n=335; comparator, n=165). Nine patients did not receive any study medication.
In the XARELTO vs comparator groups, 52% vs 48% of patients were male, index VTE was caused by cerebral vein or sinus thrombosis in 22% vs 26% of patients, by catheterrelated VTE in 27% vs 22% of patients, and by noncatheter-related VTE in 51% vs 52% of patients.
Bleeding events occurring in both the XARELTO and comparator groups are presented in the Table: Bleeding Events.
The most frequent AEs occurring in both the XARELTO and comparator groups are presented in the Table: AEs During the Main Study Treatment Period.

Bleeding Events²

Event, n	XARELTO (N=329)	Comparator (N=162)
Major or clinically relevant nonmajor bleeding, n (%)	10 (3)	3 (2)
Hazard ratio (95% CI)	1.58 (0.51-6.27)
Major bleeding, n (%)	0	2 (1)
Pulmonary	0	1
Intracranial	0	1
Clinically relevant nonmajor bleeding, n (%)	10 (3)	1 (1)
Gastrointestinal	4	0
Urogenital	2	0
Skin	1	0
Nasal or mouth	3	1
Abbreviation: CI, confidence interval.

AEs During the Main Study Treatment Period²^,a

Event, n (%)	XARELTO (N=329)			Comparator (N=162)
Event, n (%)	Grade 1-2	Grade 3	Grade 4	Grade 1-2	Grade 3	Grade 4
Any event	231 (70)	39 (12)	4 (1)	100 (62)	23 (14)	1 (1)
Blood and lymphatic system disorders	29 (9)	8 (2)	1 (<1)	12 (7)	4 (2)	0
Bone marrow failure	2 (<1)	0	1 (<1)	0	0	0
Febrile neutropenia	3 (1)	7 (2)	0	0	1 (1)	0
Thrombocytopenia	10 (3)	4 (1)	0	2 (1)	0	0
Cardiac disorders	8 (2)	1 (<1)	1 (<1)	4 (2)	2 (1)	0
Low cardiac output syndrome	0	0	1 (<1)	0	0	0
Pericardial hemorrhage	0	0	1 (<1)	0	0	0
Eye disorders	18 (5)	0	0	7 (4)	0	0
Gastrointestinal disorders	101 (31)	9 (3)	0	44 (27)	1 (1)	0
Abdominal pain	17 (5)	2 (1)	0	8 (5)	1 (1)	0
Constipation	10 (3)	0	0	12 (7)	0	0
Diarrhea	22 (7)	2 (1)	0	9 (6)	0	0
Nausea	21 (6)	0	0	7 (4)	0	0
Vomiting	31 (9)	4 (1)	0	13 (8)	0	0
General disorders and administration site conditions	74 (22)	7 (2)	0	51 (31)	1 (1)	0
Fatigue	18 (5)	2 (1)	0	6 (4)	0	0
Pyrexia	35 (11)	0	0	13 (8)	0	0
Infections and infestations	110 (33)	5 (2)	1 (<1)	44 (27)	5 (3)	0
Nasopharyngitis	25 (8)	0	0	8 (5)	0	0
Sepsis	0	0	1 (<1)	0	0	0
Injury, poisoning, and procedural complications	74 (22)	4 (1)	0	27 (17)	3 (2)	1 (1)
Contusion	14 (4)	0	0	10 (6)	0	0
Subdural hemorrhage	0	0	0	0	0	1 (1)
Investigations	27 (8)	9 (3)	1 (<1)	17 (10)	5 (3)	0
Alanine aminotransferase increased	4 (1)	3 (1)	0	4 (2)	3 (2)	0
Hepatic enzyme increased	2 (1)	1 (<1)	1 (<1)	0	0	0
Platelet count decreased	6 (2)	3 (1)	0	2 (1)	0	0
Metabolism and nutrition disorders	26 (8)	1 (<1)	0	7 (4)	0	0
Musculoskeletal and connective tissue disorders	52 (16)	4 (1)	0	19 (12)	0	0
Pain in extremity	22 (7)	2 (1)	0	8 (5)	0	0
Neoplasms benign, malignant, and unspecified (including cysts and polyps)	1 (<1)	0	0	1 (1)	2 (1)	0
Nervous system disorders	78 (24)	5 (2)	0	34 (21)	4 (2)	0
Headache	56 (17)	1 (<1)	0	22 (14)	2 (1)	0
Reproductive system and breast disorders	27 (8)	2 (1)	0	13 (8)	0	0
Menorrhagia	23 (7)	0	0	5 (3)	0	0
Respiratory, thoracic, and mediastinal disorders	78 (24)	2 (1)	1 (<1)	33 (20)	1 (1)	0
Cough	16 (5)	0	0	10 (6)	0	0
Epistaxis	38 (12)	0	0	18 (11)	0	0
Respiratory failure	0	0	1 (<1)	0	0	0
Skin and subcutaneous tissue disorders	61 (19)	0	0	25 (15)	1 (1)	0
Abbreviations: AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities.^aEvents are described as defined by MedDRA. Data shown for all randomized patients who received at least 1 dose of treatment. All grade ≥4 events are shown, but grade 3 events are shown only if they occurred in at least 3 (1%) children in the XARELTO group and at least 2 (1%) children in the comparator group. Grade ≤2 events are only shown if there were grade 3 or worse events. Grade ≤2 events were also to be shown if they had occurred in at least 5% of children. A single grade 5 event occurred (myxofibrosarcoma in the XARELTO group) that was not treatment related.

Phase 2 Study

Monagle et al (2019)³ reported the efficacy and safety results from the EINSTEIN Junior program phase 2 program, which consisted of three multicenter, single-arm, open-label, nonrandomized studies that evaluated age and body weight-adjusted XARELTO dosage regimens in pediatric patients aged ≤17 years.

Study Design/Methods

Pediatric patients with objectively confirmed VTE treated with LMWH, fondaparinux, and/or VKA for at least 2 months (≥6 weeks in the case of catheter-related thrombosis) were eligible. Key exclusion criteria included active bleeding or high risk of bleeding contraindicating anticoagulant therapy and estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m².
XARELTO was dosed according to an age and body weight-adjusted dosing schedule to achieve a similar exposure as observed in adults treated with XARELTO 20 mg once daily for VTE. Patients received XARELTO for a total of 30 days (7 days for those younger than 6 months).
Predefined efficacy endpoints were symptomatic recurrent VTE, asymptomatic deterioration on repeat imaging, and PK and PD findings at the end of the study treatment period. The predefined safety outcomes were major and CRNMB.

Results

A total of 93 pediatric patients (<6 months, n=10; 6 months to 1 year, n=15; 25 years, n=25; 6-11 years, n=32; and 12-17 years, n=11) were enrolled.
No patient had a major bleeding event, and 4 (4%) patients had a CRNMB event (3 with menorrhagia and 1 with gingival bleeding in the 617year age group).
AEs were reported in 61 (66%) patients. The most frequent grade 3 or worse AEs were anemia (4%) and neutropenia (3%). No patient discontinued XARELTO due to AEs. AEs are summarized in the Table: Adverse Events.

Adverse Events³^,a

Event, n (%)	Grade 1-2	Grade 3	Grade 4
Any event	48 (52)	11 (12)	2 (2)
Acute lymphocytic leukemia, recurrent	0	1 (1)	0
Alanine aminotransferase (increased)	0	2 (2)	0
Anemia	0	4 (4)	0
Asthma	0	1 (1)	0
Atrial thrombosis^b	0	1 (1)	0
Bronchomalacia	0	1 (1)	0
Cardiac arrest	0	0	1 (1)
Febrile neutropenia	1 (1)	0	1 (1)
Gingival bleeding	0	1 (1)	0
Influenza B virus (positive test)	0	1 (1)	0
Neutropenia	2 (2)	3 (3)	0
Platelet count (decreased)	0	1 (1)	0
Post-thrombotic syndrome	0	1 (1)	0
Pyrexia	9 (10)	1 (1)	0
Thrombocytopenia	0	1 (1)	0
Tracheomalacia	0	1 (1)	0
Abbreviations: MedDRA, Medical Dictionary for Regulatory Activities.^aEvents are described as defined by MedDRA. Data shown for all patients who received at least 1 dose of treatment (N=93). All grade ≥3 events are shown, but grade ≤2 events are only shown if there were grade ≥3 events. Grade ≤2 events were also to be shown if they had occurred in at least 10% of children. No grade 5 event occurred.^bAtrial thrombosis was discovered at the end of study treatment but was also retrospectively confirmed at baseline.

Phase 1 Study

Kubitza et al (2018)⁴ reported results from the multicenter, open-label, nonrandomized phase 1 EINSTEIN Junior study evaluating the PK, PD, and safety of a single dose of body weight-adjusted XARELTO in pediatric patients aged 6 months to <18 years.

Study Design/Methods

Pediatric patients who had completed standard-of-care anticoagulant treatment for acute VTE and were at risk of recurrence were eligible. Key exclusion criteria included any condition requiring ongoing anticoagulation, known bleeding disorder, or clinically relevant bleeding event during previous VTE treatment.
Patients were stratified into 4 age groups (0.5-2 years, 2-6 years, 6-12 years, and 1218 years) and received a single body weight-adjusted XARELTO dose equivalent to adult doses of 10 mg or 20 mg, either as a tablet or oral suspension, depending on age.

Results

A total of 59 patients (0.5-2 years, n=10; 2-6 years, n=16; 6-12 years, n=24; 1218 years, n=9) were enrolled and received XARELTO.
There were no major bleeding events, nonmajor clinically relevant bleeding events, or deaths.
TEAEs were reported in 16 (27.1%) patients and were mostly mild (16.9%) or moderate (8.5%). No TEAEs or serious AEs were caused by procedures required in the protocol.
- One 17-year-old boy with several prothrombotic risk factors had pelvic venous thrombosis 7 days after administration of XARELTO.
TEAEs considered to be related to XARELTO were reported in 4 (7%) patients and included abdominal discomfort (mild intensity, no treatment required), dyspepsia (mild intensity, no treatment required), allergic dermatitis (moderate intensity, remedial therapy given), and urticaria (mild intensity, remedial therapy given). All these TEAEs resolved.

Thromboprophylaxis in Pediatric Patients who have Undergone the Fontan Procedure

UNIVERSE Study

McCrindle et al (2021)⁵^,³³ reported safety and efficacy results of XARELTO 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 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 with aspirin for thromboprophylaxis. Dosing interventions included the following:
- XARELTO 0.1% (1 mg/mL) oral suspension twice daily by body weight (equivalent to 10 mg once daily dose in adults) in parts A and B for 12 months.
- Aspirin ~5 mg/kg once daily for 12 months in part B.
Patients in part B were randomized 2:1 on day 1 to receive XARELTO oral suspension or aspirin for 12 months.
Patients were required to be clinically stable and 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 clinically relevant impaired absorption, active bleeding or high risk of bleeding including history of intracranial hemorrhage or contraindications to aspirin or XARELTO.
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 primary safety outcome was major bleeding events, as defined by the International Society on Thrombosis and Haemostasis. The secondary safety outcome was CRNMB and trivial (minimal) bleeding 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, mean age at screening was 2.5 (±0.7) years, 58% were male, mean weight was 13.8 (±2.4) kg, and mean duration between the Fontan procedure and the first study drug dose was 12 (±17) days. In the XARELTO vs aspirin
part B groups, mean age at screening was 4.1 (±1.7) vs 4.2 (±1.8) years, 55% vs 68% were male, mean weight was 15.8 (±3.7) vs 15.7 (±3.1) kg, and mean duration between the Fontan procedure and the first study drug dose was 45 (±41) vs 37 (±35) days.
One or more on-treatment bleeding events were reported in 4 (33%) patients in the XARELTO part A, 23 (36%) patients in the XARELTO part B, and 14 (41%) patients in the aspirin part B groups. 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 the Table: Summary of Bleeding Events.
In the XARELTO part A group, 11 (92%) patients reported ≥1 AE and 6 (50%) patients reported ≥1 serious AE. In the XARELTO vs aspirin part B groups, 55 (86%) vs 29 (85%) of patients reported ≥1 AE, and 18 (28%) vs 8 (24%) patients reported ≥1 serious AE, respectively. AEs have been summarized in the Table: Summary of AEs.

Summary of Bleeding Events⁵^,a

Event, n (%)	XARELTO		Aspirin
Event, n (%)	Part A (N=12)	Part B (N=64)	Part B (N=34)
Patients with ≥1 on-treatment bleeding event	4 (33)	23 (36)	14 (41)
Major bleeding	0	1 (2)	0
Clinically relevant nonmajor bleeding	1 (8)	4 (6)	3 (9)
Gastrointestinal	0	2 (3)	1 (3)
Lower gastrointestinal	0	2 (3)	1 (3)
Gingival	0	1 (2)	0
Hematoma	0	0	1(3)
Skin	1 (8)	1 (2)	1(3)
Subconjunctival	0	0	1 (3)
Trivial bleeding	3 (25)	21 (33)	12 (35)
Epistaxis	0	7 (11)	3 (9)
Gastrointestinal	0	1 (2)	1(3)
Lower gastrointestinal	0	0	1 (3)
Upper gastrointestinal	0	1 (2)	1(3)
Gingival	1 (8)	3 (5)	1 (3)
Hematoma	2 (17)	7 (11)	2 (6)
Skin	0	14 (22)	8 (24)
Vascular access site	0	2 (3)	0
^aPercentages are based on the number of patients, not the number of events. A patient may appear in different sites/categories. Safety analysis included all patients in part A who received at least 1 dose of study drug and all patients in part B who were randomized and received at least 1 dose of study drug. The primary safety outcome was major bleeding that met the International Society on Thrombosis and Haemostasis definition: overt bleeding and: (1) associated with a decrease in hemoglobin of ≥2 g/dL; (2) leading to a transfusion of the equivalent of ≥2 units of packed red blood cells or whole blood in adults; (3) occurring in a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal; or (4) contributing to death.

Summary of AEs⁵^,a

Events, n (%)	XARELTO		Aspirin
Events, n (%)	Part A (N=12)	Part B (N=64)	Part B (N=34)
Participants with ≥1 AE	11 (92)	55 (86)	29 (85)
Infections	8 (67)	40 (63)	22 (65)
Respiratory, thoracic, and mediastinal disorders	5 (42)	29 (45)	9 (26)
Pleural effusion	3 (25)	12 (19)	2 (6)
Gastrointestinal disorders	6 (50)	19 (30)	9 (26)
Injury, poisoning, and procedural complications	4 (33)	18 (28)	10 (29)
Skin and subcutaneous tissue disorders	3 (25)	19 (30)	9 (26)
General disorders and administration site conditions	1 (8)	17 (27)	8 (24)
Vascular disorders	2 (17)	3 (5)	1 (3)
Participants with ≥1 serious AE	6 (50)	18 (28)	8 (24)
Infections	3 (25)	5 (8)	4 (12)
Respiratory, thoracic, and mediastinal disorders	2 (17)	9 (14)	3 (9)
Pleural effusion	2 (17)	9 (14)	2 (6)
Abbreviations: AE, adverse event.^aAll AEs were treatment-emergent (defined as an AE or serious AE that occurs after the first dose and up to 2 days after the last dose of study drug). Participants are counted only once for any given event, regardless of the number of times they experienced the event.

Retrospective Studies

Valenti et al (2024)⁶ conducted a retrospective review to evaluate epidemiological and outcome data in a cohort of pediatric patients treated with DOACs.

Study Design/Methods

Patients were identified from a single pediatric center from January 1, 2013, to December 31, 2022.
The primary outcome was the occurrence of bleeding (defined according to the International Society of Thrombosis and Haemostasis criteria) and recurrence outcomes.

Results

Overall, 64 patients were identified to be on therapeutic doses of DOACs for their VTE treatment, whereas 1 patient was on a prophylactic dose. Of the 65 patients, 40% were male. Age ranged from 4 to 22 years (mean age: 16.3 years); 94% of the patients were >12 years old.

Overall, 61.5% of patients were on XARELTO, 37% were on apixaban and 1.5% were on dabigatran; treatment duration ranged from 6 weeks to a median duration of 6 months.
By the end of the initial treatment phase, 57% of patients had complete and 20% had partial thrombus resolution, 18.5% had no change in thrombus size on follow-up imaging, and 3% patients were lost to follow up.
Six patients had recurrent VTE; 5 patients were on apixaban and 1 was on XARELTO.
Bleeding events were reported in 11 of 65 patients. Out of these events, 1 was a major bleeding event. CRNMB was seen in 6 patients.
Out of 37 postmenarchal patients, 7 showed evidence of HMB. Of these patients, 5 were on apixaban, while 2 were on XARELTO.

Hardin et al (2021)⁷ conducted a retrospective analysis to evaluate the real-world anticoagulant use and incidence of major bleeding and VTE in pediatric patients.

Study Design/Methods

Pediatric patients aged <18 years were identified from 3 large US health claims databases (CCAE, MDCD, and Optum) from January 1, 2010, to December 31, 2019.
Key outcome measures included major bleeding and VTE events.

Results

Overall, 778 patients were prescribed XARELTO across the 3 databases. Use of XARELTO categorized as per age group and sex across the 3 databases is presented in the Table: Use of XARELTO According to Age Group, Sex, and Database.

Use of XARELTO According to Age Group, Sex, and Database⁷

Drug Exposure	CCAE Population n (%)	MDCD Population n (%)	Optum Population n (%)
XARELTO	401 (100.0)	217 (100.0)	160 (100.0)
Age group (years)
1 to <2	-	1 (0.5)	-
2 to <7	1 (0.2)	6 (2.8)	-
7 to <12	8 (2.0)	7 (3.2)	3(1.9)
12 to <18	392 (97.8)	203 (93.5)	157 (98.1)
Male	184 (45.9)	126 (58.1)	77 (48.1)
Female	217 (54.1)	91 (41.9)	83 (51.9)
Abbreviations: CCAE, International Business Machines (IBM) MarketScan^® Commercial Claims and Encounters Database; MDCD, IBM MarketScan^® Multi-State Medicaid Database; Optum, Optum’s deidentified Clinformatics Data Mart Database-Socio-Economic Status.

In CCAE, MDCD, and Optum, the unadjusted incidence rates of major bleeding and VTE were 1.2 and 18.2, 0 and 15, and 3 and 24.9 per 1000 PYs of XARELTO exposure, respectively.

Literature search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 04 October 2024.

References

Show

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