NCT02313909: NAVIGATE ESUS

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

Terminated Phase 3 Results posted Last updated 9 January 2019

What this trial tests

Phase 3 trial testing Rivaroxaban (Xarelto, BAY59-7939) in Stroke in 7,213 participants. Terminated before completion.

Timeline

23 December 2014

Primary endpoint
15 February 2018

15 February 2018

Quick facts

Lead sponsor	Bayer
Phase	Phase 3
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	prevention
Enrollment	7,213
Start date	23 December 2014
Primary completion	15 February 2018
Estimated completion	15 February 2018
Sites	454 locations across Italy, Finland, Japan, Ireland, Poland, South Korea, Denmark, Russia

Drugs / interventions tested

• Rivaroxaban (Xarelto, BAY59-7939) — full drug profile →
• Acetylsalicylic acid (Aspirin, BAY1019036) — full drug profile →
• Rivaroxaban-Placebo — full drug profile →
• Aspirin-Placebo

Conditions studied

• Stroke — all drugs for Stroke →

Sponsor

Bayer — full company profile →

Who can join

50 and older, any sex, with Stroke. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Incidence Rate of the Composite Efficacy Outcome (Adjudicated) Primary · From randomization until the efficacy cut-off date (median 326 days)

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.

Group	Value	95% CI
Rivaroxaban 15 mg OD	5.14	4.40 – 5.97
Acetylsalicylic Acid 100 mg OD	4.78	4.07 – 5.58

Incidence Rate of a Major Bleeding Event According to the International Society on Thrombosis and Haemostasis (ISTH) Criteria (Adjudicated) Primary · From randomization until the efficacy cut-off date (median 326 days)

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 e

Group	Value	95% CI
Rivaroxaban 15 mg OD	1.82	1.39 – 2.33
Acetylsalicylic Acid 100 mg OD	0.67	0.42 – 1.00

Incidence Rate of Any of the Following: Cardiovascular Death, Recurrent Stroke, Systemic Embolism and Myocardial Infarction Secondary · From randomization until the efficacy cut-off date (median 326 days)

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 pos

Group	Value	95% CI
Rivaroxaban 15 mg OD	6.20	5.38 – 7.10
Acetylsalicylic Acid 100 mg OD	5.85	5.05 – 6.73

Incidence Rate of All-Cause Mortality Secondary · From randomization until the efficacy cut-off date (median 326 days)

All-cause mortality includes all deaths of participants due to any cause.

Group	Value	95% CI
Rivaroxaban 15 mg OD	1.88	1.45 – 2.40
Acetylsalicylic Acid 100 mg OD	1.50	1.12 – 1.97

Incidence Rate of the Following: Stroke, Ischemic Stroke, Disabling Stroke, Cardiovascular (CV) Death, Myocardial Infarction Secondary · From randomization until the efficacy cut-off date (median 326 days)

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/unk

Stroke

Group	Value	95% CI
Rivaroxaban 15 mg OD	5.11	4.37 – 5.93
Acetylsalicylic Acid 100 mg OD	4.71	4.01 – 5.51

Ischemic stroke

Group	Value	95% CI
Rivaroxaban 15 mg OD	4.71	4.01 – 5.51
Acetylsalicylic Acid 100 mg OD	4.56	3.87 – 5.34

Disabling stroke

Group	Value	95% CI
Rivaroxaban 15 mg OD	1.20	0.86 – 1.62
Acetylsalicylic Acid 100 mg OD	0.84	0.56 – 1.21

CV death(includes death due to hemorrhage)

Group	Value	95% CI
Rivaroxaban 15 mg OD	0.99	0.68 – 1.38
Acetylsalicylic Acid 100 mg OD	0.66	0.42 – 1.00

Myocardial infarction

Group	Value	95% CI
Rivaroxaban 15 mg OD	0.49	0.29 – 0.79
Acetylsalicylic Acid 100 mg OD	0.67	0.42 – 1.00

Incidence Rate of Life-Threatening Bleeding Events Secondary · From randomization until the efficacy cut-off date (median 326 days)

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 inciden

Group	Value	95% CI
Rivaroxaban 15 mg OD	1.02	0.71 – 1.42
Acetylsalicylic Acid 100 mg OD	0.43	0.24 – 0.72

Incidence Rate of Clinically Relevant Non-Major Bleeding Events Secondary · From randomization until the efficacy cut-off date (median 326 days)

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.

Group	Value	95% CI
Rivaroxaban 15 mg OD	3.52	2.91 – 4.21
Acetylsalicylic Acid 100 mg OD	2.32	1.84 – 2.90

Incidence Rate of Intracranial Hemorrhage Secondary · From randomization until the efficacy cut-off date (median 326 days)

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.

Group	Value	95% CI
Rivaroxaban 15 mg OD	0.70	0.45 – 1.04
Acetylsalicylic Acid 100 mg OD	0.35	0.18 – 0.61

Adverse events — posted to ClinicalTrials.gov

Time frame: From start of study drug administration until 2 days after the last dose of study drug, an average of 279 days. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Rivaroxaban 15 mg OD

Serious: 466/3562 (13%)

Deaths: 73/3562

Acetylsalicylic Acid 100 mg OD

Serious: 434/3559 (12%)

Deaths: 58/3559

Serious adverse events (485 terms)

Reaction	System	Rivaroxaban 15 mg OD	Acetylsalicylic Acid 100 m…
Atrial fibrillation	Cardiac disorders	—	—
Pneumonia	Infections and infestations	—	—
Osteoarthritis	Musculoskeletal and connective tissue disorders	—	—
Syncope	Nervous system disorders	—	—
Seizure	Nervous system disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Cataract	Eye disorders	—	—
Prostate cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Epilepsy	Nervous system disorders	—	—
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	—	—
Inguinal hernia	Gastrointestinal disorders	—	—
Cholelithiasis	Hepatobiliary disorders	—	—
Gastroenteritis	Infections and infestations	—	—
Urinary tract infection	Infections and infestations	—	—
Femoral neck fracture	Injury, poisoning and procedural complications	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Hypertension	Vascular disorders	—	—
Atrial flutter	Cardiac disorders	—	—
Femur fracture	Injury, poisoning and procedural complications	—	—
Hip fracture	Injury, poisoning and procedural complications	—	—
Lung neoplasm malignant	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Partial seizures	Nervous system disorders	—	—
Peripheral arterial occlusive disease	Vascular disorders	—	—
Iron deficiency anaemia	Blood and lymphatic system disorders	—	—

Other adverse events (284 terms — click to expand)

Reaction	System	Rivaroxaban 15 mg OD	Acetylsalicylic Acid 100 m…
Atrial fibrillation	Cardiac disorders	—	—
Hypertension	Vascular disorders	—	—
Medication error	Injury, poisoning and procedural complications	—	—
Headache	Nervous system disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—
Dizziness	Nervous system disorders	—	—
Incorrect dose administered	Injury, poisoning and procedural complications	—	—
Nausea	Gastrointestinal disorders	—	—
Treatment noncompliance	Social circumstances	—	—
Vertigo	Ear and labyrinth disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Chest pain	General disorders	—	—
Urinary tract infection	Infections and infestations	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Rash	Skin and subcutaneous tissue disorders	—	—
Palpitations	Cardiac disorders	—	—
Dyspepsia	Gastrointestinal disorders	—	—
Fatigue	General disorders	—	—
Hypersensitivity	Immune system disorders	—	—
Gastroenteritis	Infections and infestations	—	—
Limb injury	Injury, poisoning and procedural complications	—	—
Medication monitoring error	Injury, poisoning and procedural complications	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—
Hypoaesthesia	Nervous system disorders	—	—
Syncope	Nervous system disorders	—	—
Depression	Psychiatric disorders	—	—
Renal failure	Renal and urinary disorders	—	—
Drug eruption	Skin and subcutaneous tissue disorders	—	—
Urticaria	Skin and subcutaneous tissue disorders	—	—
Peripheral arterial occlusive disease	Vascular disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Antiphospholipid syndrome	Blood and lymphatic system disorders	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—
Atrial flutter	Cardiac disorders	—	—
Myocardial ischaemia	Cardiac disorders	—	—
Vertigo positional	Ear and labyrinth disorders	—	—

Most-reported serious reactions: Atrial fibrillation, Pneumonia, Osteoarthritis, Syncope, Seizure, Anaemia, Cataract, Prostate cancer.

Data from ClinicalTrials.gov NCT02313909 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source.
   Hart RG, Sharma M, Mundl H, Kasner SE, et al · · 2018 · cited 665× · PMID 29766772 · DOI 10.1056/nejmoa1802686
2. Cardioembolic Stroke.
   Kamel H, Healey JS. · · 2017 · cited 300× · PMID 28154101 · DOI 10.1161/circresaha.116.308407
3. Systemic inflammation after stroke: implications for post-stroke comorbidities.
   Simats A, Liesz A. · · 2022 · cited 179× · PMID 35971650 · DOI 10.15252/emmm.202216269
4. Device Closure of Patent Foramen Ovale After Stroke: Pooled Analysis of Completed Randomized Trials.
   Kent DM, Dahabreh IJ, Ruthazer R, Furlan AJ, et al · · 2016 · cited 148× · PMID 26916479 · DOI 10.1016/j.jacc.2015.12.023
5. Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies.
   Wilson D, Ambler G, Lee KJ, Lim JS, et al · · 2019 · cited 134× · PMID 31130428 · DOI 10.1016/s1474-4422(19)30197-8
6. The value of transesophageal echocardiography for embolic strokes of undetermined source.
   Katsanos AH, Bhole R, Frogoudaki A, Giannopoulos S, et al · · 2016 · cited 78× · PMID 27488602 · DOI 10.1212/wnl.0000000000003063
7. Aortic Arch Atherosclerosis in Patients With Embolic Stroke of Undetermined Source: An Exploratory Analysis of the NAVIGATE ESUS Trial.
   Ntaios G, Pearce LA, Meseguer E, Endres M, et al · · 2019 · cited 67× · PMID 31526123 · DOI 10.1161/strokeaha.119.025813
8. Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: Design of the NAVIGATE ESUS randomized trial.
   Hart RG, Sharma M, Mundl H, Shoamanesh A, et al · · 2016 · cited 65× · PMID 31008276 · DOI 10.1177/2396987316663049