Appendix Table 3.

Study Design and Setting, Inclusion and Exclusion Criteria, AF and SCI Ascertainment Methods, and Other Patient Characteristics

Study, Year (Reference)	Diagnosis Method	Design (Comparison Groups)	Inclusion Criteria	Exclusion Criteria	AF Ascertainment Method	Anticoagulation	SCI Ascertainment Method
Shinkawa et al, 1995 (15)	Autopsy	Nonprospective, population-based autopsy study reporting factors related to SCI and multivariate-adjusted risk estimate for the association between AF and SCI (original cohort followed for 26 y to elucidate CVA incidence in general population)	Patients aged ≥40 y from Hisayama, Japan, were included in the original cohort. After 13 and 22 y, new patients aged >40 y were selected from Hisayama for the new study cohort. Most of the patients who died had autopsies.	Patients with stroke diagnosed before the entry examination; patients with hemorrhagic stroke as the initial stroke episode; and patients with any clinical history, symptoms, or signs of stroke	ECG	–	Photographs of the brain slices in the autopsy documents were reviewed by authors
Yamanouchi et al, 1997 (16)	Autopsy	Nonprospective study assessing prevalence of SCI in patients with NRAF using autopsy specimens	Case patients were consecutive patients with chronic NRAF and no history of anticoagulation who were aged ≥70 y and evaluated between 1986 and 1993 in the Tokyo Metropolitan Geriatric Hospital. Control patients did not have NRAF and were matched for age, sex, history of hypertension, DM, pathologically confirmed MI, and severe atherosclerosis in the cerebral arteries.	Anticoagulant therapy during the patient’s lifetime, rheumatic valvular disease, and paroxysmal AF	Chronic NRAF diagnosed by ≥2 ECGs with no SR on subsequent ECGs	No	SCIs were diagnosed by 2 neurologists and a neuropathologist using autopsy specimens, clinical records, and macroscopic brain pathology
Petersen et al, 1989 (19)	CT	Nonprospective study with calculable prevalence and risk estimate (comparing patients with AF with age- and sex-matched control patients in SR)	Patients with paroxysmal AF documented on ≥1 ECG and ≥3 ECGs with SR obtained during the follow-up with an interval of ≥1 wk. The control group included age- and sex-matched patients in SR who previously participated in the Copenhagen City Heart Study and considered themselves healthy.	Paroxysmal AF linked to acute MI, intoxication, trauma or alcohol; history of anticoagulant, aspirin, or alcohol abuse in case patients; history of cerebrovascular disease without normal neurologic examination in both case and control patients; history of IHD or endocrinologic disease in control patients	Paroxysmal AF diagnosed by ECG	No	SCIs were diagnosed by 2 consultant neuroradiologists blindly
Petersen et al, 1989 (32)	CT	Nonprospective study with calculable prevalence and risk estimate (comparing patients with AF with age- and sex-matched control patients in SR)	Case patients had chronic AF of >l-y duration and were selected from patients referred to the outpatient clinic by their general practitioner for routine ECG. Control patients were age- and sex-matched in SR, considered themselves healthy, and previously participated in the Copenhagen City Heart Study.	History of cerebrovascular disease, abnormal neurologic examination, anticoagulants or aspirin therapy, history of alcohol abuse, and bad-quality CT; patients with cardiovascular events were excluded from the control group	Chronic AF of >1 y duration diagnosed by ECG	No	All CT results were evaluated blindly by 2 consultant neuroradiologists*
Feinberg et al, 1990 (17)	CT	Nonprospective study reporting the prevalence of SCIs in a large group of patients with NVAF participating in SPAF study	Patients with NVAF aged >21 y participating in the SPAF study from 15 centers in the United States	Cardiac exclusions: self-limited AF, mitral stenosis, NYHA-IV CHF, idiopathic cardiomyopathy in conjunction with CHF, prosthetic heart valve, MI, percutaneous transluminal angioplasty within 1 y, unstable angina, and CABG within 3 mo. Noncardiac exclusions: dementia, renal failure, any illness reducing life expectancy to <24 mo, any condition requiring antiplatelet or anticoagulant, and history of a stroke or TIA.	NVAF diagnosed by ECG †	No	2 independent authors blinded to the clinical data read CT results using a standardized assessment form (disagreement in SCI diagnosis was seen in 8% of CT scans, and disagreement in SCI location was seen in 3%)
Guidotti et al, 1990 (18)	CT	Nonprospective study with calculable prevalence and risk estimate (comparing patients with AF with age- and sex-matched control patients without AF)	Case patients had ≥1 y ECG documented AF, without historical or instrumental evidence of rheumatic heart disease. Control patients were in SR without cardiopathy affected by muscle-tensive headache, diagnosed according to strict criteria.	Previous MI or thyroid disease, severe enlarged hearts, CHF, history of cerebrovascular events, abnormal neurologic examination, and antiaggregant or anticoagulant therapy	NRAF diagnosed by ECG	No	CT results were examined by a neuroradiologist who was blinded to the patients’ condition
Ezekowitz et al, 1995 (33)	CT	Prospective study of many patients with NRAF reporting prevalence and incidence of SCIs during 3 y of follow-up	Men of any age with AF documented by 2 ECGs ≥4 wk apart and no echocardiographic evidence of rheumatic heart disease; baseline prothrombin times had to be within the normal range; the neurologic examination taken at the entry had to be normal with no focal deficit	Previous stroke or a TIA within the 5 y before entry into the study	NRAF diagnosed by 2 ECGs ≥4 wk apart	No‡	Scans were evaluated by 6 neurologists. Each scan was read by 2 neurologists blinded to physical condition or clinical course of the patient, and their consensus interpretation was recorded. Reading pairs were rotated after every 50 scans to minimize bias. When a consensus was not reached by the 2 primary readers, the scan in question was reviewed and classified by the entire 6-member committee.
Zito et al, 1996 (34)	CT	Nonprospective study with calculable prevalence and risk estimate (comparing patients with NVAF and their age- and sex-matched control patients in SR)	Patients with chronic AF >1 y, detected by ECG and defined as NVAF by ECG, all patients were admitted to the hospital because of symptoms related to AF and other minor diseases (such as benign disease of the upper and lower GI tract, arthrosis, urinary infection, etc.). The control group included elderly patients in SR matched for age and sex and educational level with the NVAF group. All control patients were randomly selected either among patients hospitalized for minor disease or among their relatives.	Previous stroke or TIA; lesions of large extracranial arteries; possible source of cerebral embolization (irregular fibrocalcific ulcerative plaques or stenosis >50%); significant abnormalities at neurologic examination; diseases leading to cognitive impairment or potentially interfering with cognitive functions (i.e., senile dementia [DSM III R], psychiatric diseases, or alcohol abuse); hypothyroidism; folate or vitamin B12 deficiency; advanced cardiac failure (NYHA class III and IV); and severe respiratory insufficiency renal failure (creatinine level >221 μmol/L [>2.5 mg/dL]); liver cirrhosis; anemia (hemoglobin level <10 g/dL); insulin-dependent DM; malignancy or other severe medical illness; and other conditions potentially interfering with physical abilities, such as visual impairments, deafness, and severe osteoarthritis	Chronic NVAF diagnosed by ECG	–	All CT scans were interpreted blindly by 2 consultant neuroradiologists with high levels of interobserver agreement.
Hara et al, 1995 (35)	MRI	Nonprospective study reporting the prevalence of SCIs in patients with AF at baseline (patients were followed for 2 y for incidence of symptomatic stroke)	Patients with chronic or paroxysmal AF who visited the department of internal medicine of the Health Insurance Nankai Hospital between November 1992 and January 1994	Mitral stenosis and a history of MI or dilated cardiomyopathy and patients who had been treated with anticoagulants	Chronic or paroxysmal AF diagnosed by Holter electrocardiography and heart monitoring	No	Images were evaluated by a radiologist who was blinded to the study protocol.
Longstreth et al, 2002 (14)	MRI 1.5T, or 0.35T§	Prospective cohort of CHS following patients with no stroke history for a mean of 5 y for development of clinical stroke or SCI	CHS patients with no infarctions on their initial MRI who had a second MRI during the 5-y follow-up. Patients had to be aged >65 y, able to give informed consent, and able to respond to questions without the aid of a surrogate respondent.	Patients were screened for a history of TIA or stroke before the initial MRI but were not excluded if they had such events; however, they had to be infarction-free on their initial MRI.	ECG	–	Imaging data were sent to a single reading center for interpretation by neuroradiologists trained in CHS protocol and without knowledge of the patients’ demographic or clinical profile‖
Vermeer et al, 2003 (23)	MRI 1.5T	Prospective Rotterdam Scan Study following patients for an average of 4.2 y for incident stroke but with only cross-sectional assessment of AF and SCI, reporting prevalence and age- and sex-adjusted risk estimate	Patients without dementia aged 60–90 y from 32 large ongoing, population-based studies (the Rotterdam Elderly Study)	Symptomatic infarctions on MRI and patients with a previous stroke without infarctions on MRI	ECG (MEANS software)	–	Infarctions were rated by a single rater with good intrarater agreement (κ, 0.80). A history of stroke and TIA were determined by self-report, and by checking medical records. An experienced neurologist subsequently reviewed the medical history and scans and categorized the infarctions as silent or symptomatic.
Strach et al, 2005 (29)	MRI 1.5T	Prospective study of patients with AF reporting prevalence and incidence of SCIs with ≤52 wk of follow-up (comparing patients with AF and echocardiographic evidence of atrial thrombi with AF patients with no such evidence)	Consecutive patients with the diagnosis of AF that had either occurred for the first time or was diagnosed for the first time with subsequent initiation of therapeutic anticoagulation. The study group consisted of patients with echocardiographic evidence of a left atrial thrombus. Patients with AF and no echocardiographic evidence of left atrial thrombi served as control patients.	Acute neurologic event associated with the first-time diagnosis, presence of MRI-incompatible foreign bodies, biomedical implants, as well as the existence of the following potential cardiovascular sources for emboli: left ventricular thrombi, endocarditic vegetations on cardiac valves, aortic plaques >4 mm, floating aortic plaques, and stenosis of the internal carotid artery >70%, the presence of contraindications for TEE, and intravenous or oral anticoagulation within the last 12 mo	ECG	Yes	2 experienced radiologists without knowledge of neurologic status or clinical therapy evaluated the averaged images (independent of direction) using the consensus method
Study, Year (Reference)	Diagnosis Method	Design (Comparison Groups)	Inclusion Criteria	Exclusion Criteria	AF Ascertainment Method	Anticoagulation	SCI Ascertainment Method
Das et al, 2008 (11)	MRI 1T	Prospective Framingham Offspring Study but with cross-sectional assessment of AF and SCIs reporting prevalence and age- and sex-adjusted risk estimate	Framingham Offspring patients who attended the sixth examination and had brain MRI at the seventh examination	Prevalent stroke or dementia or other neurologic conditions that may confound the diagnosis of SCI on MRI, claustrophobia, metal in the eyes or other body parts, valvular prosthesis, vascular clips, cardiac pacemakers, cochlear implants, or other implanted device sensitive to strong magnetic fields	Standard 12 lead ECG	–	3 different raters blinded to patient demographic and stroke risk factor data processed and analyzed the scans (κ, 0.73–0.90). The final diagnosis about the presence and absence of stroke, type, and location was made at a stroke review by ≥2 neurologists with access to all Framingham and outside records, including brain imaging.
Kim et al, 2011 (13)	MRI 1.5T	Nonprospective study with reported risk estimate and prevalence (comparing patients with and without SCIs)	Retrospective analysis of the brain MRI findings of study patients who had visited the Neurology Clinic between March 2004 and August 2009 and had no neurologic disorder but requested a medical evaluation for symptoms, such as dizziness and headache, fear of stroke, a positive family history of stroke, or the presence of vascular risk factors	History of a neurologic disorder by medical interview and neurologic examination	Presence of a past history in medical records or routine ECG	–	2 neurologists, unaware of the clinical information, evaluated the MRI, and SCI
Kobayashi et al, 2012 (36)	MRI 1.5T	Nonprospective study reporting multivariate risk estimate (comparing patients with NVAF with their age- and sex-matched control patients with SR)	Case patients had attended or were admitted to the department of neurology between 2003 and 2007 with chronic or paroxysmal AF. The control group was sex- and age-matched SR patients with subjective symptoms alone, such as headache, dizziness, tinnitus, and tingling of the hands or feet.	History of stroke or TIA, known neurologic disorders or CNS involvement, atrial fibrillation associated with valvular disease	Chronic or paroxysmal NVAF with no reported method of diagnosis	Yes	All images were shuffled before evaluation and interpreted by multiple neurologists and neuroradiologists who were blinded to the clinical data. The final diagnosis of each MRI lesion was made by consensus.
Marfella et al, 2013 (12)	MRI 1.5T	Perspective study with an average follow-up of 37 mo evaluating the association between subclinical episodes of AF with risk of SCI at baseline. Patients were followed for incident SCI and clinical stroke.	Patients were selected from a larger cohort of patients with type 2 diabetes from 4 participating institutions. The inclusion criteria were age <60 y, successful quarterly 48-h ECG, Holter monitoring, and assessment of the presence/absence of SCI by MRI of the brain.	Arrhythmia, documented persistent or permanent AF, documented stroke or TIA, anticoagulation therapy, coronary artery or valvular heart disease, cardiomyopathy, history of CHF, hypertension, carotid and peripheral vascular disease, hyperthyroidism, COPD, obstructive sleep apnea, and hepatic damage	48-h ambulatory ECG recording at 3, 6, 9, and 12 mo during the screening for AF and then annually for another 3 y	No¶	The MRI scans of the patients were randomly stored and interpreted without knowledge of the patients’ names and characteristics.
Saito et al, 2014 (37)	MRI 1.5T	Nonprospective study reporting the prevalence of SCI in patients with and without AF. Prospective assessment of predictors of new ACI in patients with AF.	AF patients: outpatients aged >45 y with AF who visited the cardiovascular, respiratory, and neurology divisions of Asahikawa Medical University Hospital. Control patients: patients without AF who had brain MRI scans for screening or diagnosing any neurologic disorders.	Patients with valvular AF or patients with any history of symptomatic cerebral infarction	NR	Yes	Trained observers who were blinded to the clinical information

AF = atrial fibrillation; CABG = coronary artery bypass grafting; CHF = congestive heart failure; CHS = Cardiovascular Health Study; COPD = chronic obstructive pulmonary disease; CT = computed tomography; CVA = cerebrovascular accident; DM = diabetes mellitus; DSM = Diagnostic and Statistical Manual of Mental Disorders; ECG = electrocardiography; GI = gastrointestinal; IHD = ischemic heart disease; MI = myocardial infarction; MRI = magnetic resonance imaging; NRAF = nonrheumatic atrial fibrillation; NVAF = nonvalvular atrial fibrillation; NYHA = New York Heart Association; SCI = silent cerebral infarction; SPAF = Stroke Prevention in Atrial Fibrillation; SR = sinus rhythm; TEE = transesophageal echocardiography; TIA = transient ischemic attack.

^*From reference 45.

^†From reference 46.

^‡Patients were randomly assigned to warfarin and placebo at entry (they were not on any anticoagulants before entry).

^§From reference 38.

^‖From reference 20.

^¶All patients were treated with aspirin, 75 to 325 mg/day. If the CHADS₂ score was 2, antiaggregant therapy was switched to oral anticoagulation therapy.