Atrial Fibrillation in Cryptogenic Stroke and TIA (NOR-FIB)

The Nordic Atrial Fibrillation and Stroke Study

Background:

Different studies with real-life data and randomized controlled trials have shown a detection rate of paroxysmal atrial fibrillation (AF) of 10-20% in patients with cryptogenic stroke using insertable continuous cardiac monitoring for 6 months. More studies are needed, however, to identify factors which can be used to select the patients where the possibility of detecting AF with prolonged rhythm monitoring is highest, to evaluate the best duration of rhythm monitoring, to determine the optimal definition of short-term AF that warrants intervention and to evaluate whether intervention results in improved clinical outcomes.

Methods: The NOR-FIB study is a multi-centre prospective observational trial, designed to evaluate detection of AF in cryptogenic stroke and transient ischemic attack (TIA). Patients admitted with cryptogenic stroke or TIA in stroke units in the Nordic countries, aged 18-80 years are included and have the Reveal LINQ® Insertable cardiac monitor system implanted for 12 months for the purpose of AF detection. Biomarkers that may identify patients, who could derive the most clinical benefit from the detection of AF by prolonged monitoring, are being studied.

Conclusion: This NOR-FIB study will increase our knowledge regarding the occurrence of AF in patients with cryptogenic stroke and TIA that potentially can improve secondary prevention. The study will provide information on biomarkers that may be used to select cryptogenic TIA and stroke patients for long-term monitoring as well as information on the significance of short-term AF and optimal duration of cardiac rhythm monitoring.

Study Overview

• Status: Completed
• Conditions: Ischemic Stroke; Atrial Fibrillation; TIA
• Intervention / Treatment: Device: Medtronic Reveal LINQ

• Study Type: Observational
• Enrollment (Actual): 259

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway, 0424
    • Oslo University Hospital
  • Grålum
    • Sarpsborg, Grålum, Norway, 1714
      • Østfold Hospital Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients admitted to stroke units with cryptogenic ischemic stroke or TIA

Description

Inclusion Criteria:

1. Cryptogenic ischemic stroke patients or symptomatic TIA < 21 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. Before inclusion to the study, the following tests are required as standard tests to establish the diagnosis of cryptogenic stroke or TIA:

   1. Brain MRI or CT†
   2. 12-lead ECG for AF detection
   3. 24-h ECG monitoring for AF detection and premature atrial complex analysis (e.g. Holter)
   4. TEE (transesophageal echocardiography) highly recommended or TTE (transthoracic echocardiography)
   5. Colour Duplex ultrasound examination of the pre-cerebral arteries
   6. CTA or MRA of head and neck to rule out other causes of stroke pathologies
3. Age 18 to 80 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 TIA events.

Exclusion Criteria:

1. Known etiology of TIA or stroke.
2. TIA without documented cerebral ischemia on Diffusion Weighed 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 anticoagulation
9. Permanent indication for OAC treatment at enrollment.
10. Permanent contra-indication for OAC.
11. Life expectancy less than 1 year.
12. Pregnancy
13. An indication for an Implantable Pulse Generator (IPG), Implantable Cardioverter-Defibrillator (ICD), Cardiac Resynchronization Therapy (CRT) or an implantable hemodynamic monitoring system.
14. Patient otherwise not eligible for the study or adherent for follow-up (e.g. non-resident) or has concurrent disease which may affect clinical outcome (e.g. multiple sclerosis, cancer).

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Atrial fibrillation detection rate	within 6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
AF detection rate	within 12 months
Levels of miRNAs related to atrial fibrillation	12 months
Levels of NT-proBNP	baseline and 12 months
Levels of Troponin-T	baseline and 12 months
Levels of inflammation biomarkers	baseline and 12 months
Prestroke/pre-TIA CHA2DS2-VASc score	baseline
Incidence of recurrent stroke or TIA - percentage of stroke/TIA within 12 9. Incidence of recurrent stroke or TIA - percentage of stroke/TIA	12 months
Use of oral anticoagulation - percentage of patients who are using OAC drugs	12 months
Use of antiarrhythmic drugs - percentage of patients who are using antiarrhythmic drugs	12 month
Health Outcome as Evaluated by an EQ-5D Questionnaire - EQ-5D quality of life score	12 months

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Collaborators: Vestre Viken Hospital Trust; Ullevaal University Hospital; Rigshospitalet, Denmark; University Hospital of North Norway; Diakonhjemmet Hospital; Bispebjerg Hospital; Ostfold Hospital Trust; Helse Stavanger HF; Haukeland University Hospital; Sykehuset Innlandet HF; The Hospital of Vestfold; Herlev Hospital; Sykehuset Telemark; Nordlandssykehuset HF; Molde Hospital; Skane University Hospital; Drammen sykehus
• Investigators: Study Chair: Dan Atar, MD, PhD, Oslo University Hospital

Publications and helpful links

General Publications

• Li L, Yiin GS, Geraghty OC, Schulz UG, Kuker W, Mehta Z, Rothwell PM; Oxford Vascular Study. Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study. Lancet Neurol. 2015 Sep;14(9):903-913. doi: 10.1016/S1474-4422(15)00132-5. Epub 2015 Jul 27.
• Tomson TT, Passman R. The Reveal LINQ insertable cardiac monitor. Expert Rev Med Devices. 2015 Jan;12(1):7-18. doi: 10.1586/17434440.2014.953059. Epub 2014 Aug 26.
• Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA, Morillo CA, Rymer MM, Thijs V, Rogers T, Beckers F, Lindborg K, Brachmann J; CRYSTAL AF Investigators. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014 Jun 26;370(26):2478-86. doi: 10.1056/NEJMoa1313600.
• Ziegler PD, Rogers JD, Ferreira SW, Nichols AJ, Sarkar S, Koehler JL, Warman EN, Richards M. Real-World Experience with Insertable Cardiac Monitors to Find Atrial Fibrillation in Cryptogenic Stroke. Cerebrovasc Dis. 2015;40(3-4):175-81. doi: 10.1159/000439063. Epub 2015 Aug 28.
• Christensen LM, Krieger DW, Hojberg S, Pedersen OD, Karlsen FM, Jacobsen MD, Worck R, Nielsen H, Aegidius K, Jeppesen LL, Rosenbaum S, Marstrand J, Christensen H. Paroxysmal atrial fibrillation occurs often in cryptogenic ischaemic stroke. Final results from the SURPRISE study. Eur J Neurol. 2014 Jun;21(6):884-9. doi: 10.1111/ene.12400. Epub 2014 Mar 15.
• Wu N, Chen X, Cai T, Wu L, Xiang Y, Zhang M, Li Y, Song Z, Zhong L. Association of inflammatory and hemostatic markers with stroke and thromboembolic events in atrial fibrillation: a systematic review and meta-analysis. Can J Cardiol. 2015 Mar;31(3):278-86. doi: 10.1016/j.cjca.2014.12.002. Epub 2014 Dec 9.
• Howlett PJ, Hatch FS, Alexeenko V, Jabr RI, Leatham EW, Fry CH. Diagnosing Paroxysmal Atrial Fibrillation: Are Biomarkers the Solution to This Elusive Arrhythmia? Biomed Res Int. 2015;2015:910267. doi: 10.1155/2015/910267. Epub 2015 Jul 1.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 1, 2016
• Primary Completion (ACTUAL): October 1, 2021
• Study Completion (ACTUAL): October 1, 2021

Study Registration Dates

• First Submitted: March 4, 2016
• First Submitted That Met QC Criteria: October 15, 2016
• First Posted (ESTIMATE): October 18, 2016

Study Record Updates

• Last Update Posted (ACTUAL): January 25, 2022
• Last Update Submitted That Met QC Criteria: January 9, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: etiology
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arrhythmias, Cardiac; Stroke; Ischemic Stroke; Atrial Fibrillation
• Other Study ID Numbers: 2013/2371

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Plan to share IPD