Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source (ESUS)

Study Overview
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Brief Summary
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This is a study in patients who recently had a brain attack (stroke) and in whom no clear cause of the stroke could be identified. These strokes are likely due to a blood clot and therefore, can be called embolic stroke of undetermined source. The abbreviation is ESUS. The study will compare 2 blood thinners. Patients will be randomly assigned to either Rivaroxaban 15 mg or Aspirin 100 mg and the study is intended to show, if patients given rivaroxaban have fewer blood clots in the brain (stroke) or in other blood vessels.

Official Title
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Multicenter, Randomized, Double-blind, Double-dummy, Active-comparator, Event-driven, Superiority Phase III Study of Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With a Recent Embolic Stroke of Undetermined Source (ESUS), Comparing Rivaroxaban 15 mg Once Daily With Aspirin 100 mg

Conditions
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Stroke

Intervention / Treatment
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* Drug: Rivaroxaban (Xarelto, BAY59-7939)
* Drug: Acetylsalicylic acid (Aspirin, BAY1019036)
* Other: Rivaroxaban-Placebo
* Other: Aspirin-Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recent ESUS (between 7 days and 6 months), defined as: Recent ischemic stroke (including transient ischemic attack with positive neuroimaging) visualized by brain imaging that is not lacunar, and Absence of cervical carotid atherosclerotic stenosis> 50% or occlusion, and No atrial fibrillation after ≥ 24-hour cardiac rhythm monitoring, and No intra-cardiac thrombus on either transesophageal or transthoracic echocardiography, and No other specific cause of stroke (for example, arteritis, dissection, migraine/vasospasm, drug abuse) Exclusion Criteria: Severely disabling stroke (modified Rankin score ≥4) Indication for chronic anticoagulation or antiplatelet therapy Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m^2

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rivaroxaban<br>Rivaroxaban 15 mg orally once daily | Drug: Rivaroxaban (Xarelto, BAY59-7939)<br>* 15 mg, once daily, orally, tablet<br>Other: Rivaroxaban-Placebo<br>* Matching placebo, once daily, orally, tablet<br>|
| Active Comparator: Aspirin<br>Aspirin 100 mg orally once daily | Drug: Acetylsalicylic acid (Aspirin, BAY1019036)<br>* 100 mg, once daily, orally, tablet<br>Other: Aspirin-Placebo<br>* Matching placebo, once daily, orally, tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Rate of the Composite Efficacy Outcome (Adjudicated) | Components of composite efficacy outcome (adjudicated) includes stroke (ischemic, hemorrhagic, and undefined stroke, TIA with positive neuroimaging) and systemic embolism. Incidence rate estimated as number of participants with incident events divided by cumulative at-risk time, where participant is no longer at risk once an incident event occurred. | From randomization until the efficacy cut-off date (median 326 days) | 
| Incidence Rate of a Major Bleeding Event According to the International Society on Thrombosis and Haemostasis (ISTH) Criteria (Adjudicated) | Major bleeding event (as per ISTH), defined as bleeding event that met at least one of following: fatal bleeding; symptomatic bleeding in a critical area or organ (intraarticular, intramuscular with compartment syndrome, intraocular, intraspinal, pericardial, or retroperitoneal); symptomatic intracranial haemorrhage; clinically overt bleeding associated with a recent decrease in the hemoglobin level of greater than or equal to (>=) 2 grams per decilitre (g/dL) (20 grams per liter [g/L]; 1.24 millimoles per liter [mmol/L]) compared to the most recent hemoglobin value available before the event; clinically overt bleeding leading to transfusion of 2 or more units of packed red blood cells or whole blood. The results were based on classification of events that have been positively adjudicated as major bleeding events. Incidence rate estimated as number of subjects with incident events divided by cumulative at-risk time, where subject is no longer at risk once an incident event occurred. | From randomization until the efficacy cut-off date (median 326 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Rate of Any of the Following: Cardiovascular Death, Recurrent Stroke, Systemic Embolism and Myocardial Infarction | Incidence rate estimated as number of participants with incident events divided by cumulative at-risk time, where participant is no longer at risk once an incident event occurred. Cardiovascular death includes death due to hemorrhage and death with undetermined/unknown cause. Systemic embolism is defined as abrupt vascular insufficiency associated with clinical or radiological evidence of arterial occlusion in the absence of other likely mechanisms. The diagnosis of myocardial infarction requires the combination of: 1)evidence of myocardial necrosis (either changes in cardiac biomarkers or post-mortem pathological findings); and 2)supporting information derived from the clinical presentation, electrocardiographic changes, or the results of myocardial or coronary artery imaging. | From randomization until the efficacy cut-off date (median 326 days) | 
| Incidence Rate of All-Cause Mortality | All-cause mortality includes all deaths of participants due to any cause. | From randomization until the efficacy cut-off date (median 326 days) | 
| Incidence Rate of the Following: Stroke, Ischemic Stroke, Disabling Stroke, Cardiovascular (CV) Death, Myocardial Infarction | Disabling stroke is defined as stroke with modified Rankin score (mRS) greater than or equal to (>=) 4 as assessed by investigator. mRS spans 0-6, running from perfect health to death. A score of 0-3 indicates functional status ranging from no symptoms to moderate disability (defined in the mRS as requiring some help, but able to walk without assistance); mRS 4-6 indicates functional status ranging from moderately severe disability (unable to walk or to attend to own bodily needs without assistance)through to death. CV death includes death due to hemorrhage and death with undetermined/unknown cause. Diagnosis of myocardial infarction requires combination of: 1) evidence of myocardial necrosis either changes in cardiac biomarkers or post-mortem pathological findings); 2) supporting information derived from clinical presentation, electrocardiographic changes, or results of myocardial or coronary artery imaging. | From randomization until the efficacy cut-off date (median 326 days) | 
| Incidence Rate of Life-Threatening Bleeding Events | Life-threatening bleeding was defined as a subset of major bleeding that met at least one of the following criteria: 1) fatal bleeding; 2) symptomatic intracranial haemorrhage; 3) reduction in hemoglobin of at least 5 g/dl (50 g/l; 3.10 mmol/L); 4) transfusion of at least 4 units of packed red cells or whole blood; 5) associated with hypotension requiring the use of intravenous inotropic agents; 6) necessitated surgical intervention. Incidence rate estimated as number of participants with incident events divided by cumulative at-risk time, where participant is no longer at risk once an incident event occurred. | From randomization until the efficacy cut-off date (median 326 days) | 
| Incidence Rate of Clinically Relevant Non-Major Bleeding Events | Non-major clinically relevant bleeding was defined as non-major overt bleeding but required medical attention (example: hospitalization, medical treatment for bleeding), and/or was associated with the study drug interruption of more than 14 days. The results were based on the outcome events at or after randomization until the efficacy cut-off date. Incidence rate estimated as number of participants with incident events divided by cumulative at-risk time, where participant is no longer at risk once an incident event occurred. | From randomization until the efficacy cut-off date (median 326 days) | 
| Incidence Rate of Intracranial Hemorrhage | Intracranial hemorrhage included all bleeding events that occurred in intracerebral, sub arachnoidal as well as subdural or epidural sites. The below table displays results for all randomized participants and the outcomes at or after randomization until the efficacy cut-off date. Incidence rate estimated as number of participants with incident events divided by cumulative at-risk time, where participant is no longer at risk once an incident event occurred. | From randomization until the efficacy cut-off date (median 326 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rivaroxaban, Xarelto, Aspirin, Acetylsalicylic acid (ASA), Oral Anticoagulant, Blood Thinner, Stroke, Ischemic Stroke, Cryptogenic Stroke, Embolic stroke of undetermined source, ESUS, Transient Ischemic Attack, Thromboembolism, Cerebrovascular Disease