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  • NOR-FIB The Nordic Atrial Fibrillation and Stroke Study

    NOR-FIB protocol V 1.2. REK 2013/2371 1

    The Nordic Atrial Fibrillation and Stroke Study (NOR-FIB)

    Atrial Fibrillation in Cryptogenic Stroke and TIA

    STUDY PROTOCOL by

    Anne Hege Aamodt, MD, PhD, FESO2David Russell MD, PhD, FESO, FRCP, Prof1,2

    Dan Atar, MD PhD, FESC, Prof1,3 1Institute of Clinical Medicine, University of Oslo

    2Department of Neurology, Oslo University Hospital3Department of Cardiology, Oslo University Hospital

    ClinicalTrials.gov Identifier: NCT02937077 REK 2013/2371

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    PROTOCOL SYNOPSIS Sponsor: Oslo University Hospital Protocol number: REK2013/2371

    ClinicalTrials.gov Identifier: NCT02937077 Title: The Nordic Atrial Fibrillation and Stroke Study (NOR-FIB Study) Study design: International multi-center prospective observational study of the occurrence of AF in cryptogenic stroke / TIA patients with ICMs for 12 months. Objective: To assess the incidence of atrial fibrillation detection using ICM (Reveal LINQ) in patients with cryptogenic stroke or TIA. To identify biomarkers that can be used as predictors of incident atrial fibrillation. Number of subjects: 500 Number of centers: Up to 25 Duration of study participation: Enrollment: approximately 18 months Follow-up period: 12 months 20 days Total study duration: 30 months Primary endpoint: AF detection rate within 12 months Secondary endpoints:

    1. AF detection rate within 6 months2. Levels of NT-proBNP and BNP3. Levels of Troponin-T and Troponin-I4. Levels of cardiovascular biomarkers5. CHA2DS2-VASc score prior to stroke or TIA6. Incidence of recurrent stroke or TIA within 12 months.7. Use and type of oral anticoagulation - percentage of patients who are using OAC

    drugs at the 12-month follow-up visit.8. Use of antiarrhythmic drugs - percentage of patients who are using antiarrhythmic

    drugs at the 12-month follow-up visit.9. Health Outcome as Evaluated by an EQ-5D Questionnaire - EQ-5D quality of life

    score, which is a continuous measure of quality of life.

    Inclusion criteria: 1. Cryptogenic ischemic stroke or TIA patients 10 days from symptom start.2. A stroke/TIA is considered to be cryptogenic if no cause can be determined despite an

    extensive workup according to the standard protocol of the participating center. Beforeinclusion to the study, the following tests are required to establish the diagnosis ofcryptogenic stroke or TIA:

    a. Brain MRI or CT.b. 12-lead ECG for AF detection.c. 24-h ECG monitoring for AF detection and premature atrial complex analysis

    (e.g. Holter or telemetry).d. TTE (transthoracic echocardiography)e. TEE (transesophageal echocardiography) in patients aged 65 yearsf. Colour Duplex ultrasound examination of the pre-cerebral arteries.g. CTA or MRA of head and neck to rule out other causes of stroke.h. Screening for thrombophilia < 50 years of age.

    3. Age > 18 years at onset of TIA/stroke.4. A participation consent form signed by the patient or a legally authorized representative.TIA cases with acute non-lacunar infarct on Diffusion Weighted Imaging are included as

  • NOR-FIB The Nordic Atrial Fibrillation and Stroke Study

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    TIA events.

    Exclusion criteria: 1. Known etiology of TIA or stroke.2. TIA without documented cerebral ischemia on Diffusion Weighted Imaging.3. Untreated hyperthyroidism.4. Myocardial infarction less than 1 month prior to the stroke or TIA.5. Coronary bypass grafting less than 1 month prior to the stroke or TIA.6. Valvular heart disease requiring immediate surgical intervention.7. History of atrial fibrillation or atrial flutter.8. Patent Foramen Ovale (PFO) or PFO where there is or was an indication to start oral

    anticoagulation9. Permanent indication for OAC treatment at enrollment.10. Permanent contra-indication for OAC.11. Life expectancy less than 1 year.12. Pregnancy now or < 3 months.13. An indication for an Implantable Pulse Generator (IPG), Implantable Cardioverter-

    Defibrillator (ICD), Cardiac Resynchronization Therapy (CRT) or an implantablehemodynamic monitoring system.

    14. Patients otherwise not available for follow-up (e.g. non-resident) or patients withconcurrent disease which may affect clinical outcome (e.g. multiple sclerosis, cancer)

    Schedule of assessments Assessment Methods Screening Inclusion 180 days

    follow-up Telephone

    365 days follow-up

    Range 0 0 20 days 20 days NIHSS X X ECG X X X Pre-stroke modified Rankin Scale X

    Cerebral MR/CT X Colour Duplex of the precerebral arteries X

    24 h Holter X Echocardiography TTE/TEE X Blood labs X X Modified Rankin Scale (mRS) X X Pre-stroke mRS X Pre-stroke Barthel Index X Barthel Index X EuroQol 5D-5L X X Concomitant Medication X X X X Recurrent stroke/TIA X X X Major cardiovascular events X X X Adverse Events X X X X

  • NOR-FIB The Nordic Atrial Fibrillation and Stroke Study

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    Table of contents

    1. BACKGROUND AND STATUS OF KNOWLEDGE. 5 1.1. Impact on patient care and stroke management 6

    2. HYPOTHESIS AND AIMS 6

    3. FEASIBILITY. 63.1. Study design, methods and analyses.. 6 3.2. Roles, organization and cooperation . 10 3.3. Plan for milestones, dissemination and publishing 12 3.4. Implementation plan.. 12 3.5. Funding.. 12

    4. USER INTERACTION.. 12

    5. ETHICAL PERSPECTIVES. 12

    6. REFERENCES 13

    7. APPENDIX 1 INFORMATION AND CONSENT FORM...... 15

    8. APPENDIX 2 SOP BLOOD SAMPLES 19

    9. APPENDIX 3 ECHOCARDIOGRAPHY SOP. 20

    APPENDIX 4 REVEAL LINQ AND CARELINK.. 21 4 REVEAL LINQ AND CARELINK.. 21 10.

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    1. Background and status of knowledge

    Stroke is one of the leading causes of death and disability worldwide resulting in high health-related and economic consequences.1 2 1/4 of strokes are recurrent strokes. Up to 40% of the ischemic strokes and TIAs remain without a definitive etiology despite a modern extensive diagnostic work-up.3, 4, 5 6These are defined as cryptogenic strokes. The risk of stroke recurrence in these patients is considerable and it is therefore very important to determine their etiology so that secondary prevention may be optimal.5 7

    Atrial fibrillation (AF) is the most common cardiac arrhythmia in the population, affecting 1-2% of the general population.8 No consensus has been reached about how atrial fibrillation should be investigated in patients with stroke and TIA, and its prevalence after a cryptogenic stroke remains uncertain.9 AF may be responsible for up to 1 of 3 cryptogenic strokes.10, 11 Paroxysmal AF is more common than permanent AF in acute stroke and TIA patients12, but carries the same stroke risk as permanent AF.13 However, the recognition of paroxysmal AF is often missed as most paroxysmal AF patients are asymptomatic and ECG examinations are often carried out intermittently.

    Advanced diagnostic techniques, including long-term rhythm monitoring to detect paroxysmal AF may be useful in reducing the proportion of patients diagnosed with cryptogenic strokes.7, 9 The yield has varied greatly in different studies depending on the interval of monitoring from stroke/TIA onset, duration of monitoring, as well as the choice of monitoring device.9

    Continuous ECG recordings can be performed using insertable cardiac monitor (ICM) implantable electronic devices or by external devices. One previous study with Reveal XT showed that the number of ICMs required to detect a first episode of AF was 14 for 6 months of monitoring, 10 for 12 months, and 4 for 36 months.14 However, there were long time intervals from the onset of stroke or TIA to randomization. The likelihood of revealing paroxysmal AF is increased when continuous cardiac monitoring is started early after the onset of symptoms.15 Recently, another ICM, Reveal LINQ has been developed which weighs less and is considerably less invasive than any previous loop recorder. It requires a short insertion procedure time and clinical resources.16, 17

    Cardiovascular biomarkers can be used to predict the probable cause of cryptogenic stroke.18 19 NT-proBNP, a peptide cleaved from pro-BNP to release brain natriuretic peptide, has been shown to be increased in paroxysmal AF patients20, 21 as well as cryptogenic stroke patients with confirmed paroxysmal AF.22 Similarly troponins, another established cardiac biomarkers, are increased in cryptogenic stroke patients with new onset AF.23 Numerous other cardiovascular biomarkers have been studied in relation to thrombus formation and ischemic events in AF.24, 25 26, 27 28 So far the results has been conflicting and further studies are required to address the clinical implications of cardiovascular biomarkers in the prediction of AF-related thromboembolism.

    More studies are needed to establish the benefits of AF detection with newer monitoring devices and to identify factors which may help to select patients where prolonged rhythm monitoring would be most successful. New studies are also needed to assess the optimal duration of rhythm monitoring, the best definition of short-term AF where active treatment is required and to evaluate whether intervention results in improved secondary prevention.

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    1.1. Impact on patient care and stroke management This study will increase knowledge regarding cryptogenic stroke and TIA and hopefully improve