Rivaroxaban for Children Aged Over 2 Years With Giant Coronary Artery Aneurysms After Kawasaki Disease

It is a binary variable. This composite outcome indicates whether any of the following events occurred within 3 months after treatment initiation: (a) newly developed coronary artery thrombosis; (b) major bleeding event; (c) clinically relevant non-major bleeding event; or (d) major adverse cardiovascular event (defined as unstable angina, acute myocardial infarction, hospitalization for heart failure, unplanned coronary revascularization, stroke, or cardiovascular death).

It is binary data. Every echocardiography conducted during study period will be assessed by masked sonographer. The masked sonographers will assess whether new thrombosis occurs in coronary arteries, and recorded the number of involved coronary arteries.

It is time to event data. Every echocardiography conducted during study period will be assessed by masked sonographer. The masked sonographers will assess whether new thrombosis occurs in coronary arteries, and recorded the time to first new thrombosis in coronary arteries.

It is a binary variable. Major bleeding is defined as 1.Fatal bleeding; 2.Clinically overt bleeding associated with a decrease in Hgb of ≥20 g/L (2 g/dL) in a 24-h period; 3.Critical site bleeding, such as retroperitoneal, pulmonary, pericardial, intracranial, or otherwise involves the central nervous system; 4.Bleeding that requires an intervention via an invasive procedure; 5.Overt bleeding for which a reversal agent is administered.

Clinically relevant non-major bleeding event is defined as 1.Bleeding that results in a medical or procedural intervention not meeting major bleeding criteria, including a medication change (reducing, holding, or changing anticoagulation or addition of new medication) ; 2.Bleeding that results in hospitalization or increased level of care; 3.Overt bleeding for which a blood product is administered, and does not meet the criteria for major bleeding

It is a binary variable. Major bleeding is defined as 1.Fatal bleeding; 2.Clinically overt bleeding associated with a decrease in Hgb of ≥20 g/L (2 g/dL) in a 24-h period; 3.Critical site bleeding, such as retroperitoneal, pulmonary, pericardial, intracranial, or otherwise involves the central nervous system; 4.Bleeding that requires an intervention via an invasive procedure; 5.Overt bleeding for which a reversal agent is administered.

It is a binary variable. Clinically relevant non-major bleeding event is defined as 1.Bleeding that results in a medical or procedural intervention not meeting major bleeding criteria, including a medication change (reducing, holding, or changing anticoagulation or addition of new medication) ; 2.Bleeding that results in hospitalization or increased level of care; 3.Overt bleeding for which a blood product is administered, and does not meet the criteria for major bleeding

It is a binary variable. PIBNI is defined as bleeding for which medical attention is sought (phone call, telehealth, clinic, or emergency department visit) but does not result in hospitalization, increased level of inpatient care, or an intervention by the medical team

It is a binary variable. Minor bleeding is defined as any overt or macroscopic evidence of bleeding that does not ful ll the above criteria for either fi major bleeding, clinically relevant, non-major bleeding, or patient important bleeding without intervention

It is binary variable. Major adverse cardiovascular event (MACE) includes unstable angina, acute myocardial infarction, stroke, hospitalization for heart failure, unplanned revascularization, cardiovascular death. If any of the MACEs occur during the study period, it will be recorded as 1; otherwise, it will be recorded as 0. The definition of each MACE refers to the following guidelines and consensus: 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials, 2019 European society of Cardiology (ESC) guidelines for the diagnosis and management of chronic coronary syndromes, Fourth universal definition of myocardial infarction, and 2023 ESC Guidelines for the management of acute coronary syndromes.

It is time to event data. Major adverse cardiovascular event (MACE) includes unstable angina, acute myocardial infarction, stroke, hospitalization for heart failure, unplanned revascularization, cardiovascular death. If any of the MACEs occur during the study period, the time to MACE will be recorded.

It is a text variable. If any adverse events( including durg allergy, severe infection, hepatic dysfunction, renal dysfunction, hypertension, fatigue, abdominal pain or others) occur will be reported to the data and safety monitoring board. The detail of adverse event will be recorded, including classification of adverse event, time of occurrence, symptoms, treatment, resolution time, and outcome.

For experimental group, plasma concentration of rivaroxaban concentration will be measured by high performance liquid chromatography tandem mass spectrometer. Based on the principle of sparse sampling, predefined timepoints for measurement include: 1. Day 1, 20 minutes -1 h after the first dose; 2. Day 1, 7±1 h after the first dose; 3. After at least three continuous doses (≥ Day 4): before the scheduled dose at that day, which is defined as the trough concentration; 4. After at least three continuous doses (≥ Day 4): 3±1 h the scheduled dose at that day, which is defined as the peak concentration. 5. Peak concentrations during scheduled follow-up: 45±10 days, and 90±10 days; 6. Trough concentrations during scheduled follow-up: 45±10 days, and 90±10 days;

For experimental group, anti-factor Xa activity will be measured by rivaroxaban calibrated chromogenic anti-factor Xa assay. Based on the principle of sparse sampling, predefined timepoints for measurement include: 1. Peak concentrations in scheduled follow-up (45±10 days, and 90±10 days): 3±1 h the scheduled dose at that day; 2. Trough concentrations in scheduled follow-up (45±10 days, and 90±10 days): before the scheduled dose at that day

It is a binary variable. During study period, researchers will assess and recommend to discontinue anticoagulant if coronary artery lesions regress, which will be confirmed by echocardiography, coronary artery computerized tomography angiography, or coronary artery angiography.

This is a repeated measurement. On day 0, an initial echocardiography will be performed by masked sonographer to assess coronary artery lesions. The maximum internal diameter of coronary artery lesion will be measured and recorded. With data of height, bodyweight and internal diameter, Z-score will be calculated (Journal of the American Society of Echocardiography, 2011, 24(1)). If multiple coronary artery aneurysms exists, internal diameter and Z-score will be measured, calculated and recorded separately. Repeated echocardiographies will be conducted at each scheduled visit (45±10 days、90±10 days).

Total healthcare resource utilization cost directly related to anticoagulation monitoring. This includes:

• Laboratory test costs (e.g., INR testing cost in the control group, calculated as the number of INR tests multiplied by the unit cost per test; anti-Xa activity testing cost in the intervention group, calculated as the number of anti-Xa tests multiplied by the unit cost per test);
• Medical service costs (e.g., additional outpatient or emergency visits, medication adjustments, follow-up visits, consultations, and telephone follow-ups due to abnormal INR values).

For experimental group, the rest blood sample from rivaroxaban plasma concentration measurement will be collected for genetic polymorphisms examination. Genes related to rivaroxaban metabolism and transport will be examined, including CYP3A4, ABCB1, ABCG2, and et.cl CYP3A4: Cytochrome P450 Family 3 Subfamily A Member 4, ABCB1: ATP Binding Cassette Subfamily B Member 1; ABCG2: ATP Binding Cassette Subfamily G Member 2