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1 Supplementary webappendix This webappendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Li L, Yiin GS, Geraghty OC, et al, on behalf of the 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; published online July 28.

2 Web appendix Incidence, outcome, risk factors and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study Web appendix Title Page 1a References for hospital-based studies on aetiological subtypes of TIA and ischaemic stroke 2 1b References for population-based studies on aetiological subtypes of TIA and ischaemic stroke 3 2 Length of follow-up for recurrent stroke risks in cohort studies 4 3a Criteria for the modified TOAST classification 5 3b Criteria for diagnosis of embolic stroke of undetermined source in OXVASC 6 4 Proportions of cryptogenic vs. large artery disease aetiology in population-based studies in 7 predominantly white population in Western Europe, North America and Australia/New Zealand 5 Age-specific rates per 1,000 population per year of the first ever incident cryptogenic ischaemic stroke 8 in OXVASC 6a Diagnostic work-up for cryptogenic TIA/ischaemic stroke in OXVASC 9 6b Diagnostic work-up in other population-based studies 9 7 Sensitivity analysis of prevalence of different risk factors and comorbid atherosclerotic disease in cryptogenic events versus other subtypes excluding TIA patients 8 Prevalence of different risk factors and comorbid atherosclerotic disease in cryptogenic events versus 11 other subtypes stratified by OXVASC phases 9a Sensitivity analysis of prevalence of different risk factors and comorbid atherosclerotic disease in 12 cryptogenic events versus other subtypes in patients underwent MRI 9b Sensitivity analysis of prevalence of different risk factors and comorbid atherosclerotic disease in 12 cryptogenic events versus other subtypes in patients with acute infarct on imaging only Prevalence of different risk factors in Embolic strokes of undetermined source (ESUS) versus other 13 TIA/ischaemic stroke subtypes 11 Sensitivity analyses of long-term risks of recurrent cardioembolic events or new AF during follow-up in 14 cryptogenic TIA/ischaemic stroke versus other non-cardioembolic subtypes in OXVASC phase 1 vs. phase 2 12 Sensitivity analyses of long-term risks of vascular events in patients with embolic strokes of 15 undetermined source (ESUS) events vs. patients with TOAST defined non- ESUS cryptogenic events 13 Aetiological stroke subtypes of first recurrent ischaemic stroke by index events (ischaemic stroke vs. 16 TIA) 14 Ten-year risks of any recurrent large artery stroke and recurrent cryptogenic stroke by index event subtypes 17 1

3 Web-appendix 1a References for hospital-based studies on aetiological subtypes of TIA and ischaemic stroke r1 Vallejos J, Jaramillo A, Reyes A, et al. Prognosis of Cryptogenic Ischemic Stroke: A Prospective Single- Center Study in Chile. J Stroke Cerebrovasc 2012; 21: r2 Kim D, Lee SH, Joon Kim B, et al. Secondary prevention by stroke subtype: a nationwide follow-up study in 46 8 patients after acute ischaemic stroke. Eur Heart J 2013; 34: r3 Purroy F, Montaner J, Molina CA, Delgado P, Ribo M, Alvarez-Sabin J. Patterns and predictors of early risk of recurrence after transient ischemic attack with respect to etiologic subtypes. Stroke 2007; 38: r4 Deleu D, Inshasi J, Akhtar N, et al. Risk factors, management and outcome of subtypes of ischemic stroke: a stroke registry from the Arabian Gulf. J Neurol Sci 2011; 300: r5 Sumer MM, Erturk O. Ischemic stroke subtypes: risk factors, functional outcome and recurrence. Neurol Sci 2002; 22: r6 Markaki I, Franzen I, Talani C, Loizou L, Kostulas N. Long-term survival of ischemic cerebrovascular disease in the acute inflammatory stroke study, a hospital-based cohort described by TOAST and ASCO. Cerebrovasc Dis 2013; 35: r7 Cabral NL, Goncalves ARR, Longo AL, et al. Incidence of stroke subtypes, prognosis and prevalence of risk factors in Joinville, Brazil: a 2 year community based study. J Neurol Neurosur Ps 2009; 80: r8 Liu XF, Xu GL, Wu WT, Zhang RL, Yin Q, Zhu WS. Subtypes and one-year survival of first-ever stroke in Chinese patients: The Nanjing Stroke Registry. Cerebrovasc Dis 2006; 22: r9 Grau AJ, Weimar C, Buggle F, et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke - The German Stroke Data Bank. Stroke 2001; 32: r Bang OY, Lee PH, Yeo SH, Kim JW, Joo IS, Huh K. Non-cardioembolic mechanisms in cryptogenic stroke: clinical and diffusion-weighted imaging features. J Clin Neurol 2005; 1: r11 Karttunen V, Alfthan G, Hiltunen L, et al. Risk factors for cryptogenic ischaemic stroke. Eur J Neurol 2002; 9: r12 Ois A, Cuadrado-Godia E, Rodriguez-Campello A, et al. Relevance of stroke subtype in vascular risk prediction. Neurology 2013; 81: r13 Moroney JT, Bagiella E, Paik MC, Sacco RL, Desmond DW. Risk factors for early recurrence after ischemic stroke - The role of stroke syndrome and subtype. Stroke 1998;29: r14 Ntaios G, Papavasileiou V, Makaritsis K, Milionis H, Michel P, Vemmos K. Association of ischaemic stroke subtype with long-term cardiovascular events. Eur J Neurol 2014;21: r15 Suto Y, Kowa H, Nakayasu H, et al. Relationship between three-year survival and functional outcome at discharge from acute-care hospitals in each subtype of first-ever ischemic stroke patients. Intern Med 2011; 50:

4 Web-appendix 1b References for population-based studies on aetiological subtypes of TIA and ischaemic stroke r16 Lavados PM, Sacks C, Prina L, et al. Incidence, case-fatality rate, and prognosis of ischaemic stroke subtypes in a predominantly Hispanic-Mestizo population in Iquique, Chile (PISCIS project): a community-based incidence study. Lancet Neurol 2007; 6: r17 Schneider AT, Kissela B, Woo D, et al. Ischemic stroke subtypes: a population-based study of incidence rates among blacks and whites. Stroke 2004; 35: r18 Petty GW, Brown RD, Jr., Whisnant JP, Sicks JD, O'Fallon WM, Wiebers DO. Ischemic stroke subtypes : a population-based study of functional outcome, survival, and recurrence. Stroke 2000; 31: r19 Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B, Heuschmann PU. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke 2001; 32: r20 Alzamora MT, Sorribes M, Heras A, et al. Ischemic stroke incidence in Santa Coloma de Gramenet (ISISCOG), Spain. A community-based study. BMC Neurol 2008; 8: 5. r21 Bejot Y, Caillier M, Ben Salem D, et al. Ischaemic stroke subtypes and associated risk factors: a French population based study. J Neurol Neurosurg Psychiatry 2008; 79: r22 Feigin V, Carter K, Hackett M, et al. Ethnic disparities in incidence of stroke subtypes: Auckland Regional Community Stroke Study, Lancet Neurol 2006; 5: r23 Hajat C, Heuschmann PU, Coshall C, et al. Incidence of aetiological subtypes of stroke in a multi-ethnic population based study: the South London Stroke Register. J Neurol Neurosurg Psychiatry 2011; 82: r24 Marnane M, Duggan CA, Sheehan OC, et al. Stroke subtype classification to mechanism-specific and undetermined categories by TOAST, A-S-C-O, and causative classification system: direct comparison in the North Dublin population stroke study. Stroke 20; 41: r25 Meurer WJ, Sanchez BN, Smith MA, et al. Predicting ischaemic stroke subtype from presenting systolic blood pressure: the BASIC Project. J Intern Med 2009; 265: r26 Petty GW, Brown RD, Jr., Whisnant JP, Sicks JD, O'Fallon WM, Wiebers DO. Ischemic stroke subtypes: a population-based study of incidence and risk factors. Stroke 1999; 30: r27 Vemmos KN, Bots ML, Tsibouris PK, et al. Stroke incidence and case fatality in southern Greece: the Arcadia stroke registry. Stroke 1999; 30: r28. Ward G, Jamrozik K, Stewart-Wynne E. Incidence and outcome of cerebrovascular disease in Perth, Western Australia. Stroke 1988; 19: r29 Palm F, Urbanek C, Wolf J, et al. Etiology, risk factors and sex differences in ischemic stroke in the Ludwigshafen Stroke Study, a population-based stroke registry. Cerebrovasc Dis 2012;33: r30 Pikija S, Cvetko D, Malojcic B, et al. A population-based prospective 24-month study of stroke: incidence and 30-day case-fatality rates of first-ever strokes in Croatia. Neuroepidemiology 2012;38:

5 Web-appendix 2 Length of follow-up for recurrent stroke risks in cohort studies Study Year Study period Total (n) Cryptogenic (n) Cryptogenic definition Follow-up Population-based study Erlangen, Germany r Mixed 2 years Rochester, USA r Mixed 5 years Hospital-based study Grau r Mixed 7 days Purroy r Mixed 90 days Moroney r Not reported Cryptogenic 90 days Sumer r Mixed 180 days Bang Cryptogenic 1 year Vallejos r Cryptogenic 2 years Ntaios r Mixed years * All r-references referred to references listed in web-appendix 1. Mixed: cryptogenic definition in the study was a collapsed group including undetermined cases (real cryptogenic), cases of unknown cause and cases of several potential causes. 4

6 Web-appendix 3a Criteria for the modified TOAST classification 19 TOAST subtypes Large artery disease (LAD) Small vessel disease (SVD) Cardioembolic (CE) Unknown causes Other determined causes Severale causes Cryptogenic Definition Imaging abnormality of atherosclerosis of intra or extracranial artery supplying the ischaemic filed with either occlusive or stenosis ( 50% diameter reduction). Clinical lacunar syndromes with no cerebral cortical dysfunction and normal imaging; OR Imaging evidence of a relevant acute infarction <20 mm within the territory of basal or brainstem penetrating arteries in the absence of any other pathology in the parent artery at the site of the origin of the penetrating artery. Major-risk cardioembolic source of embolism Prosthetic cardiac valve Mitral stenosis Permanent of paroxysmal AF (>30s) Sustained atrial flutter Intracardiac thrombus Sick sinus syndrome Recent myocardial infarction (<4 weeks) Atrial myxoma or other cardiac tymours Infective endocarditis Valvular vegetations Congestive heart failure (Ejection fraction <30%) PFO and concomitant PE or DVT or long-haul flight preceding the cerebrovascular event with clinical presentation of an embolic event The absence of diagnostic tests that, under the examiner s judgment, their presence would have been essential to uncover the underlying aetiology. The presence of a specific disease process that involves clinically appropriate brain arteries and disorders that bear a clear and close temporal or spatial relationship with the acute event. Abnormalities od thrombosis and haemostasis Arterial dissection Acute disseminated intravascular coagulation Clinically relevant aneurysm Drug-induced event Fibromuscular dysplasia Hyperviscosity syndromes Hypoperfusion syndromes Iatrogenic causes Meningitis Migraine-induced event Mitochondrial myopathy encephalopathy with lactic acidosis and stroke-like episodes Moyamoya disease Primary antiphospholipid antibody syndrome Primary infection of the arterial wall Segmental vasoconstriction or vasospasm Sickle cell disease Sneddon syndrome Thrombotic thrombocytopenic purpura Other The presence of >1 evident mechanism in which there is either probable evidence for each. Patient who has had at least one type of brain imaging (CT/MR/autopsy), ECG and at least one type of vascular imaging (Carotid Doppler/MRA/CTA/DSA/TCD/autopsy) but no aetiology was identified. 5

7 Web-appendix 3b Criteria for diagnosis of embolic stroke of undetermined source in OXVASC 3 1. Diagnostic assessment must include brain imaging, intra- and extracranial vascular imaging, ambulatory home cardiac monitoring (5- day R test routinely) and echocardiography 2. TIA or ischaemic stroke that is not lacunar 3. Absence of extracranial or intracranial atherosclerosis causing 50% luminal stenosis in arteries supplying the area of ischaemia 4. No major-risk cardioembolic source of embolism 5. No other specific cause of stroke identified TIA cases with acute non-lacunar infarct on Diffusion-Weighted-Imaging (DWI) were also included as TIA events. 6

8 Web-appendix 4 Proportions of cryptogenic vs. large artery disease aetiology in population-based studies in predominantly white population in Western Europe, North America and Australia/New Zealand (The bubble size represents the size of the study; high quality population-based studies with detailed risk factor documentation by all aetiological subtypes; All r-references referred to references listed in web-appendix 1b) 60 r22 Auckland r17 GCNKSS 40 r24 Dublin r19 Erlangen r26 Rochester % Cryptogenic 20 r23 SLSR OXVASC r25 BASIC OCSP r28 Perth r27 Arcadia r20 Spain r21 Dijion % Large artery disease 7

9 Web-appendix 5 Age-specific rates per 1,000 population per year of the first ever incident cryptogenic ischaemic stroke in OXVASC Age-group Men Rate per 00 per year (95%CI) Women Rate per 00 per year (95%CI) Total Rate per 00 per year (95%CI) <35 2/ ( ) 1/ ( ) 3/ ( ) / ( ) 8/ ( ) 15/ ( ) / ( ) 9/ ( ) 32/ ( ) / ( ) 21/ ( ) 56/ ( ) / ( ) 50/ ( ) 114/ ( ) / ( ) 60/ ( ) 1/ ( ) 85 16/ ( ) 27/ ( ) 43/ ( ) Total 197/ ( ) 176/ ( ) 373/ ( ) *Standardized to England and Wales population 2012; CI=confidence interval ( )* 8

10 Web-appendix 6a Diagnostic work-up for cryptogenic TIA/ischaemic stroke in OXVASC Phase 1 ( ) Phase 2 ( ) (n=524) (n=288) Brain imaging (n, %) 506 (96.6) 288 (0) Computed tomography 458 (87.4) 134 (46.5) Magnetic resonance imaging 160 (30.5) 226 (78.5) Post-mortem 2 (0.4) 1 (0.3) Vascular imaging (n, %) 524 (0) 288 (0) Extracranial only 328 (62.6) 48 (16.7) Intracranial and extracranial 196 (37.4) 240 (83.3) Echocardiography (n, %) 242 (46.2) 208 (72.2) Ambulatory home cardiac monitoring (n, %)* 79 (20.2) 186 (79.5) 24-hour ECG 63 (16.1) 20 (8.5) 5-day R test 16 (4.1) 166 (70.9) In addition, during the study period, patients aged <55 years, or patients with concomitant venous thrombosis, or patients with long-haul flight preceding the cerebrovascular event, or patients with clinical or imaging evidence of multi-territory events with undetermined aetiology were also referred to Department of Cardiology for patent foramen ovale screening.*ambulatory home cardiac monitoring was performed in outpatient setting (n=391 in phase 1 and n=234 in phase 2). TIA=Transient ischaemic attack. Web-appendix 6b Diagnostic work-up in other population-based studies Study Year Study Period Brain imaging (%) ECG (%) Echocardiog raphy (%) Vascular imaging (%) Intracranial vascular imaging (%) Rochester, USA r NR NR Erlangen, Germany r NR NR OCSP,UK NR NR NR NR GCNKSS, USA r NR NR PISCIS, Chile r Dijon, France r NR Dublin, Ireland r SLSR,UK r NR NR Ludwigshafen, Germany r Croatia r *NR: not reported. Vascular imaging: carotid Doppler, transcranial Doppler, CT-angiography, MR-angiography or DSA. All r-references referred to references listed in web-appendix 1b. 9

11 Web-appendix 7 Sensitivity analysis of prevalence of different risk factors and comorbid atherosclerotic disease in cryptogenic events versus other subtypes excluding TIA patients Cryptogenic LAD Crude Age-and sex-adjusted (n=392) (n=158) OR 95%CI p OR 95%CI p Age (mean/sd) 70.6/ / Male (n,%) % % Hypertension (n,%) % % Diabetes (n,%) % % Hypercholesterolaemia (n,%) % % History of smoking (n,%) % % Myocardial infarction (n,%) % % Peripheral vascular disease (n,%) % % Asymptomatic carotid stenosis 50% (n,%) 9 2.3% % < < Cryptogenic Non-LAD Crude Age-and sex-adjusted (n=392) (n=692) OR 95%CI p OR 95%CI p Age (mean/sd) 70.6/ / < < Male (n,%) % % Hypertension (n,%) % % Diabetes (n,%) % % Hypercholesterolaemia (n,%) % % History of smoking (n,%) % % Myocardial infarction (n,%) % % Peripheral vascular disease (n,%) % % Asymptomatic carotid stenosis 50% (n,%) 9 2.3% % *OR=odds ratio, CI=confidence interval, LAD=large artery disease, non-lad=small vessel disease and cardioembolic events combined. TIA=transient ischaemic attack.

12 Web-appendix 8 Prevalence of different risk factors and comorbid atherosclerotic disease in cryptogenic events versus other subtypes stratified by OXVASC phases Phase 1 ( ) Cryptogenic LAD Crude Age-and sex-adjusted (n=524) (n=175) OR 95%CI p OR 95%CI p Age (mean/sd) 71.4/ / Male (n,%) % % Hypertension (n,%) % % < < Diabetes (n,%) % % Hypercholesterolaemia (n,%) % % History of smoking (n,%) % % Myocardial infarction (n,%) % % Peripheral vascular disease (n,%) % % < < Asymptomatic carotid stenosis 50% (n,%) % % < < Cryptogenic Non-LAD Crude Age-and sex-adjusted (n=524) (n=659) OR 95%CI p OR 95%CI p Age (mean/sd) 71.4/ / < < Male (n,%) % % Hypertension (n,%) % % < Diabetes (n,%) % % Hypercholesterolaemia (n,%) % % History of smoking (n,%) % % Myocardial infarction (n,%) % % Peripheral vascular disease (n,%) % % Asymptomatic carotid stenosis 50% (n,%) % % Phase 2 ( ) Cryptogenic LAD Crude Age-and sex-adjusted (n=288) (n=5) OR 95%CI p OR 95%CI p Age (mean/sd) 68.5/ / Male (n,%) % % Hypertension (n,%) % % Diabetes (n,%) % % Hypercholesterolaemia (n,%) % % History of smoking (n,%) % % Myocardial infarction (n,%) % % Peripheral vascular disease (n,%) 8 2.8% 11.5% Asymptomatic carotid stenosis 50% (n,%) 6 2.1% % < < Cryptogenic Non-LAD Crude Age-and sex-adjusted (n=288) (n=326) OR 95%CI p OR 95%CI p Age (mean/sd) 68.5/ / < < Male (n,%) % % Hypertension (n,%) % % Diabetes (n,%) % % Hypercholesterolaemia (n,%) % % History of smoking (n,%) % % Myocardial infarction (n,%) % % Peripheral vascular disease (n,%) 8 2.8% % Asymptomatic carotid stenosis 50% (n,%) 6 2.1% 9 3.8% *OR=odds ratio, CI=confidence interval, LAD=large artery disease, non-lad=small vessel disease and cardioembolic events combined. TIA=transient ischaemic attack. 11

13 Web-appendix 9a Sensitivity analysis of prevalence of different risk factors and comorbid atherosclerotic disease in cryptogenic events versus other subtypes in patients underwent MRI Cryptogenic vs. LAD Cryptogenic vs. non-lad OR 95%CI p OR 95%CI p Male Hypertension < Diabetes Hypercholesterolaemia < History of smoking Asymptomatic carotid stenosis < Myocardial infarction Peripheral vascular disease < *OR=odds ratio, CI=confidence interval, LAD=large artery disease, non-lad=small vessel disease and cardioembolic events combined. Web appendix 9b Sensitivity analysis of prevalence of different risk factors and comorbid atherosclerotic disease in cryptogenic events versus other subtypes in patients with acute infarct on imaging only Cryptogenic vs. LAD Cryptogenic vs. non-lad OR 95%CI p OR 95%CI p Male Hypertension < < Diabetes Hypercholesterolaemia History of smoking Asymptomatic carotid stenosis < Myocardial infarction Peripheral vascular disease *OR=odds ratio, CI=confidence interval, LAD=large artery disease, non-lad=small vessel disease and cardioembolic events combined. 12

14 Web-appendix Prevalence of different risk factors in Embolic strokes of undetermined source (ESUS) versus other TIA/ischaemic stroke subtypes ESUS LAD Crude Age-and sex-adjusted (n=189) (n=280) OR 95%CI p OR 95%CI p Age (mean/sd) 65.2/ / < < Male (n,%) % % Hypertension (n,%) % % < Diabetes (n,%) % % Hypercholesterolaemia (n,%) % % < History of smoking (n,%) % % Myocardial infarction (n,%) % % Peripheral vascular disease (n,%) 5 2.6% % < Asymptomatic carotid stenosis 50% (n,%) 3 1.6% % < < ESUS Non-LAD Crude Age-and sex-adjusted (n=189) (n=985) OR 95%CI p OR 95%CI p Age (mean/sd) 65.2/ / < < Male (n,%) % % Hypertension (n,%) % % < Diabetes (n,%) % % Hypercholesterolaemia (n,%) % % History of smoking (n,%) % % Myocardial infarction (n,%) % % Peripheral vascular disease (n,%) 5 2.6% % Asymptomatic carotid stenosis 50% (n,%) 3 1.6% % *OR=odds ratio, CI=confidence interval, LAD=large artery disease, non-lad=small vessel disease and cardioembolic events combined. TIA= transient ischaemic attack, ESUS=embolic strokes of undetermined source. 13

15 Web-appendix 11 Sensitivity analyses of long-term risks of recurrent cardioembolic events or new AF during follow-up in cryptogenic TIA/ischaemic stroke versus other non-cardioembolic subtypes in OXVASC phase 1 vs. phase 2 Cryptogenic vs. non-cardioembolic New atrial fibrillation Cardioembolic events Age-/sex-adjusted HR (95%CI) p Age-/sex-adjusted HR (95%CI) p Phase 1 ( ) 1.22 ( ) ( ) 0.69 Phase 2 ( ) 1.03 ( ) ( ) 0.93 * HR=hazard ratio, CI=confidence interval. Non-cardioembolic: large artery disease and small vessel disease subtypes combined. cardioembolic events included recurrent cardioembolic stroke, acute embolic limb ischaemia and acute embolic visceral embolization caused by presumed cardioembolism. 14

16 Web-appendix 12 Sensitivity analyses of long-term risks of vascular events in patients with embolic strokes of undetermined source (ESUS) events vs. patients with TOAST defined non- ESUS cryptogenic events A. Acute coronary events 20 Log rank p= Risk (%) 5 TOAST defined non-esus cryptogenic Number at risk TOAST definied non-esus cryptogenic 0 ESUS cryptogenic ESUS cryptogenic B. Cardioembolic events 20 Log rank p= Risk (%) Number at risk TOAST definied non-esus cryptogenic TOASTdefinied non-esus cryptogenic ESUS cryptogenic ESUS cryptogenic C. Recurrent ischaemic stroke 20 Log rank p=0.29 TOAST defined non-esus cryptogenic 15 Risk (%) ESUS cryptogenic 5 Number at risk TOAST definied non-esus cryptogenic ESUS cryptogenic Years

17 Web-appendix 13 Aetiological stroke subtypes of first recurrent ischaemic stroke by index events (ischaemic stroke vs. TIA) First recurrent ischaemic stroke after stroke N (%) Index stroke CE LAD SVD Cryptogenic UNK MULT OTHER Total Presumed PVE New AF related IS or PVE 472 (29.4) CE 69 (86.2) (16.9) (1.1) 1 (0.2) 158 (9.8) LAD 1 25 (78.1) (20.3) (1.3) 3 (1.9) 220 (13.7) SVD (54.3) (20.9) (0) 5 (2.3) 392 (24.4) Cryptogenic (62.0) (20.2) (0.8) 16 (4.1) 267 (16.6) UNK (81.2) (12.0) (0.4) 3 (1.1) 63 (3.9) MULT (44.4) 0 9 (14.3) (0) 0 (0) 35 (2.2) OTHER (80.0) 5 (14.3) (2.9) 0 (0) 1607 Total 97 (34.3) 32 (11.3) 31 (11.0) 61 (21.6) 49 (17.3) 6 (2.1) 7 (2.5) New AF Known AF No AF Total First recurrent ischaemic stroke after TIA N (%) Index TIA CE LAD SVD Cryptogenic UNK MULT OTHER Total Presumed PVE New AF related IS or PVE 196 (20.7) CE 32 (97.0) (16.8) (3.1) 0 (0) 122 (12.9) LAD 3 16 (72.7) (18.0) (0.8) 4 (3.3) 97 (.2) SVD (66.7) (18.6) (2.1) 0 (0) 420 (44.3) Cryptogenic (63.6) (7.9) (0.7) 5 (1.2) 64 (6.8) UNK (83.3) (18.8) (1.6) 2 (3.1) 27 (2.8) MULT (62.5) 0 8 (29.6) (3.7) 0 (0) 22 (2.3) OTHER (66.7) 3 (13.6) (0) 0 (0) 948 Total 42 (32.6) 19 (14.7) 14 (.9) 26 (20.2) 16 (12.4) 8 (6.2) 4 (3.1) *CE=cardioembolic, LAD=large artery disease, SVD=small vessel disease, UNK=unknown cause, MULT=more than one cause, AF=atrial fibrillation. PVE=peripheral vascular embolism, IS=ischaemic stroke. New AF Known AF No AF Total 16

18 Web-appendix 14 Ten-year risks of any recurrent large artery stroke and recurrent cryptogenic stroke by index event subtypes (CE=cardioembolic, LAD=large artery disease, SVD=small vessel disease) 25 Ischaemic stroke only Log rank p< TIA and ischaemic stroke A. Any recurrent large artery stroke Log rank p< LAD 20 LAD risk (%) 15 risk (%) 15 Number at risk 5 SVD CE Cryptogenic Years LAD SVD CE Cryptogenic Number at risk Years LAD SVD CE Cryptogenic SVD CE Cryptogenic B. Any recurrent cryptogenic stroke 25 Log rank p< Log rank p< risk (%) 15 Cryptogenic risk (%) 15 Cryptogenic 5 SVD 5 SVD Number at risk Years Cryptogenic SVD LAD CE LAD CE Number at risk Years Cryptogenic SVD LAD CE LAD CE 17

Supplementary webappendix

Supplementary webappendix This webappendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Hart RG, Diener H-C, Coutts SB, et al,