Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treat- ment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837 853. 231. Gerstein HC, Calhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, Probstfield J, Riesmeyer JS, Riddle MC, Ryd n L, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomized, placebo-controlled trial. Lancet. 2019;394:121 130. doi: CLINICAL STATEMENTS AND GUIDELINES Kleindorfer 232. Hernandez AF, Green JB, Janmohamed S, D Agostino RB Sr, Granger CB, Jones NP, Leiter LA, Rosenberg AE, Sigmon KN, Somerville MC, et al; Harmony Outcomes Committees and Investigators. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, ran- domised placebo-controlled trial. Lancet. 2018;392:1519 1529. doi: 233. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, J dar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834 1844. doi: 10.1056/NEJMoa1607141 234. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311 322. doi: 235. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews D; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:2099. doi: 10.1056/NEJMc1712572 236. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117 2128. doi: 237. Tuomilehto J, Lindstr m J, Eriksson JG, Valle TT, H m l inen H, Ilanne-Parikka P, Kein nen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, et al; Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343 1350. doi: 238. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle in- tervention or metformin. N Engl J Med. 2002;346:393 403. doi: 239. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 240. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, et al; VADT Investigators. Glucose con- trol and vascular complications in veterans with type 2 diabetes. N Engl J 241. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, et al. Effects of intensive glu- cose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545 2559. 242. Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B; Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643 243. Kelly TN, Bazzano LA, Fonseca VA, Thethi TK, Reynolds K, He J. Systematic review: glucose control and cardiovascular disease in type 2 diabetes. Ann Intern Med. 2009;151:394 403. doi: 10.7326/0003- 244. Ray KK, Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S, Preiss D, Erqou S, Sattar N. Effect of intensive control of glucose on cardiovas- cular outcomes and death in patients with diabetes mellitus: a meta-anal- ysis of randomised controlled trials. Lancet. 2009;373:1765 1772. doi: 245. DeFronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, Henry RR, Hodis HN, Kitabchi AE, et al; ACT NOW Study. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med. 2011;364:1104 1115. doi: 10.1056/NEJMoa1010949 246. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP- NIDDM Trial Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359:2072 247. le Roux CW, Astrup A, Fujioka K, Greenway F, Lau DCW, Van Gaal L, Ortiz RV, Wilding JPH, Skj th TV, Manning LS, et al; SCALE Obesity Prediabetes NN8022-1839 Study Group. 3 Years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet. 2017;389:1399 248. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, Guarino PD, Lovejoy AM, Peduzzi PN, Conwit R, et al; IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J 249. Bullard KM, Cowie CC, Lessem SE, Saydah SH, Menke A, Geiss LS, Orchard TJ, Rolka DB, Imperatore G. Prevalence of diagnosed diabetes in adults by diabetes type United States 2016. Morb Mortal Wkly Rep. 250. Almdal T, Scharling H, Jensen JS, Vestergaard H. The independent ef- fect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up. Arch Intern Med. 2004;164:1422 1426. doi: 251. Banerjee C, Moon YP, Paik MC, Rundek T, Mora-McLaughlin C, Vieira JR, Sacco RL, Elkind MS. Duration of diabetes and risk of ischemic stroke: the Northern Manhattan Study. Stroke. 2012;43:1212 1217. doi: 252. Mitsios JP, Ekinci EI, Mitsios GP, Churilov L, Thijs V. Relationship between glycated hemoglobin and stroke risk: a systematic review and meta-analy- sis. J Am Heart Assoc. 2018;7:e007858. doi: 10.1161/JAHA.117.00785 253. Folsom AR, Rasmussen ML, Chambless LE, Howard G, Cooper LS, Schmidt MI, Heiss G. Prospective associations of fasting insulin, body fat distribu- tion, and diabetes with risk of ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) study investigators. Diabetes Care. 1999;22:1077 254. Selvin E, Steffes MW, Zhu H, Matsushita K, Wagenknecht L, Pankow J, Coresh J, Brancati FL. Glycated hemoglobin, diabetes, and cardiovas- cular risk in nondiabetic adults. N Engl J Med. 2010;362:800 811. doi: 255. Kernan WN, Viscoli CM, Inzucchi SE, Brass LM, Bravata DM, Shulman GI, McVeety JC. Prevalence of abnormal glucose tolerance following a tran- sient ischemic attack or ischemic stroke. Arch Intern Med. 2005;165:227 256. Pan Y, Chen W, Wang Y. Prediabetes and outcome of ischemic stroke or transient ischemic attack: a systematic review and meta-analy- sis. J Stroke Cerebrovasc Dis. 2019;28:683 692. doi: 10.1016/j. 257. Hier DB, Foulkes MA, Swiontoniowski M, Sacco RL, Gorelick PB, Mohr JP, Price TR, Wolf PA. Stroke recurrence within 2 years after ischemic infarc- tion. Stroke. 1991;22:155 161. doi: 10.1161/01.str.22.2.155 258. Lean ME, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, Peters C, Zhyzhneuskaya S, Al-Mrabeh A, Hollingsworth KG, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. 2018;391:541 551. doi: 259. Dixon JB, O Brien PE, Playfair J, Chapman L, Schachter LM, Skinner S, Proietto J, Bailey M, Anderson M. Adjustable gastric banding and conven- tional therapy for type 2 diabetes: a randomized controlled trial. JAMA. 260. Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Aminian A, Brethauer SA, Navaneethan SD, Singh RP, Pothier CE, Nissen SE, et al; STAMPEDE Investigators. Bariatric surgery versus intensive medical therapy for diabetes: 5-year outcomes. N Engl J Med. 2017;376:641 651. doi: 261. Arnott C, Li Q, Kang A, Neuen BL, Bompoint S, Lam CSP, Rodgers A, Mahaffey KW, Cannon CP, Perkovic V, Jardine MJ, Neal B. Sodium-glucose cotransporter 2 inhibition for the prevention of cardiovascular events in pa- tients with type 2 diabetes mellitus: a systematic review and meta-analysis. J Am Heart Assoc. 2020;9:e014908. doi: 10.1161/JAHA.119.014908 262. American Diabetes Association. 6: Glycemic targets: standards of medical care in diabetes 2020. Diabetes Care. 2020;43 (suppl 1):S66 S76. doi: 263. Buse JB, Wexler DJ, Tsapas A, Rossing P, Mingrone G, Mathieu C, D Alessio DA, Davies MJ. 2019 Update to: management of hyperglycemia in type 2 diabetes, 2018: a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2020;43:487 493. doi: 10.2337/dci19-0066 264. Davies MJ, D Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, Rossing P, Tsapas A, Wexler DJ, Buse JB. Management of hypergly- cemia in type 2 diabetes, 2018: a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41:2669 2701. doi: CLINICAL STATEMENTS AND GUIDELINES Kleindorfer 265. American Diabetes Association. 2: Classification and diagnosis of diabe- tes: standards of medical care in diabetes 2020. Diabetes Care. 2020;43 266. American Geriatrics Society Expert Panel on Care of Older Adults With Diabetes Mellitus, Moreno G, Mangione CM, Kimbro L, Vaisberg E. Guidelines abstracted from the American Geriatrics Society guidelines for improving the care of older adults with diabetes mellitus: 2013 update. J Am Geriatr Soc. 2013;61:2020 2026. doi: 10.1111/jgs.12514 267. Qaseem A, Wilt TJ, Kansagara D, Horwitch C, Barry MJ, Forciea MA; Clinical Guidelines Committee of the American College of Physicians. Hemoglobin A1c targets for glycemic control with pharmacologic therapy for nonpregnant adults with type 2 diabetes mellitus: a guidance state- ment update from the American College of Physicians. Ann Intern Med. 268. Inzucchi SE, Docherty K, Kober L, Kosiborod MN, Martinez F. Effect of dapagliflozin on the incidence of diabetes: a prespecified exploratory anal- ysis from DAPA-HF. Paper presented at: American Diabetes Association 80th Scientific Sessions; 2020; virtual. 269. Kernan WN, Inzucchi SE, Viscoli CM, Brass LM, Bravata DM, Shulman GI, McVeety JC, Horwitz RI. Impaired insulin sensitivity among nondiabetic patients with a recent TIA or ischemic stroke. Neurology. 2003;60:1447 270. Hishinuma A, Majima M, Kurabayashi H. Insulin resistance in pa- tients with stroke is related to visceral fat obesity and adipocyto- kines. J Stroke Cerebrovasc Dis. 2008;17:175 180. doi: 10.1016/j. 271. Rundek T, Gardener H, Xu Q, Goldberg RB, Wright CB, Boden-Albala B, Disla N, Paik MC, Elkind MS, Sacco RL. Insulin resistance and risk of ischemic stroke among nondiabetic individuals from the Northern Manhattan Study. Arch Neurol. 2010;67:1195 1200. doi: 10.1001/archneurol.2010.235 272. Thacker EL, Psaty BM, McKnight B, Heckbert SR, Longstreth WT Jr, Mukamal KJ, Meigs JB, de Boer IH, Boyko EJ, Carnethon MR, et al. Fasting and post-glucose load measures of insulin resistance and risk of ischemic stroke in older adults. Stroke. 2011;42:3347 3351. doi: 273. Hyv rinen M, Tuomilehto J, M h nen M, Stehouwer CD, Py r l K, Zethelius B, Qiao Q; DECODE Study Group. Hyperglycemia and inci- dence of ischemic and hemorrhagic stroke: comparison between fast- ing and 2-hour glucose criteria. Stroke. 2009;40:1633 1637. doi: 274. Lee M, Saver JL, Hong KS, Song S, Chang KH, Ovbiagele B. Effect of pre- diabetes on future risk of stroke: meta-analysis. BMJ. 2012;344:e3564. 275. Burchfiel CM, Curb JD, Rodriguez BL, Abbott RD, Chiu D, Yano K. Glucose intolerance and 22-year stroke incidence: the Honolulu Heart Program. 276. Ikramuddin S, Korner J, Lee WJ, Connett JE, Inabnet WB, Billington CJ, Thomas AJ, Leslie DB, Chong K, Jeffery RW, et al. Roux-en-Y gas- tric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial. JAMA. 2013;309:2240 2249. doi: 277. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabe- tes. Diabetes. 2005;54:603 608. doi: 10.2337/diabetes.54.3.603 278. Schauer PR, Kashyap SR, Wolski K, Brethauer SA, Kirwan JP, Pothier CE, Thomas S, Abood B, Nissen SE, Bhatt DL. Bariatric surgery versus in- tensive medical therapy in obese patients with diabetes. N Engl J Med. 279. Wing RR, Lang W, Wadden TA, Safford M, Knowler WC, Bertoni AG, Hill JO, Brancati FL, Peters A, Wagenknecht L; Look AHEAD Research Group. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 280. Jebb SA, Ahern AL, Olson AD, Aston LM, Holzapfel C, Stoll J, Amann-Gassner U, Simpson AE, Fuller NR, Pearson S, et al. Primary care referral to a commercial provider for weight loss treatment versus standard care: a randomised controlled trial. Lancet. 2011;378:1485 1492. doi: 281. LeBlanc ES, Patnode CD, Webber EM, Redmond N, Rushkin M, O Connor EA. Behavioral and pharmacotherapy weight loss interventions to prevent obesity-related morbidity and mortality in adults: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 282. Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. Trends in obesity among adults in the United States, 2005 to 2014. JAMA. 283. Ward ZJ, Bleich SN, Cradock AL, Barrett JL, Giles CM, Flax C, Long MW, Gortmaker SL. Projected U.S. state-level prevalence of adult obe- sity and severe obesity. N Engl J Med. 2019;381:2440 2450. doi: 284. Suk SH, Sacco RL, Boden-Albala B, Cheun JF, Pittman JG, Elkind MS, Paik MC; Northern Manhattan Stroke Study. Abdominal obesity and risk of ischemic stroke: the Northern Manhattan Stroke Study. Stroke. 285. Ni Mhurchu C, Rodgers A, Pan WH, Gu DF, Woodward M; Asia Pacific Cohort Studies Collaboration. Body mass index and cardiovascular disease in the Asia-Pacific region: an overview of 33 cohorts involving 310,000 participants. Int J Epidemiol. 2004;33:751 758. doi: 10.1093/ije/dyh163 286. Bazzano LA, Gu D, Whelton MR, Wu X, Chen CS, Duan X, Chen J, Chen JC, He J. Body mass index and risk of stroke among Chinese men and women. Ann Neurol. 2010;67:11 20. doi: 10.1002/ana.21950 287. Hu G, Tuomilehto J, Silventoinen K, Sarti C, M nnist S, Jousilahti P. Body mass index, waist circumference, and waist-hip ratio on the risk of total and type-specific stroke. Arch Intern Med. 2007;167:1420 1427. doi: 288. Kurth T, Gaziano JM, Berger K, Kase CS, Rexrode KM, Cook NR, Buring JE, Manson JE. Body mass index and the risk of stroke in men. Arch Intern 289. Kurth T, Gaziano JM, Rexrode KM, Kase CS, Cook NR, Manson JE, Buring JE. Prospective study of body mass index and risk of stroke in apparently healthy women. Circulation. 2005;111:1992 1998. doi: 290. Kroll ME, Green J, Beral V, Sudlow CL, Brown A, Kirichek O, Price A, Yang TO, Reeves GK; Million Women Study Collaborators. Adiposity and ischemic and hemorrhagic stroke: prospective study in women and meta-analysis. 291. Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration (BMI Mediated Effects), Lu Y, Hajifathalian K, Ezzati M, Woodward M, Rimm EB, Danaei G. Metabolic mediators of the effects of body-mass index, overweight, and obesity on coronary heart disease and stroke: a pooled analysis of 97 prospective cohorts with 1 8 million participants. Lancet. 2014;383:970 983. 292. Look AHEAD Research Group, Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M, Crow RS, Curtis JM, Egan CM, Espeland MA, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369:145 154. doi: 10.1056/NEJMoa1212914 293. Sj str m L, Peltonen M, Jacobson P, Sj str m CD, Karason K, Wedel H, Ahlin S, Anveden , Bengtsson C, Bergmark G, et al. Bariatric surgery and long-term cardiovascular events. JAMA. 2012;307:56 65. doi: 294. Fisher DP, Johnson E, Haneuse S, Arterburn D, Coleman KJ, O Connor PJ, O Brien R, Bogart A, Theis MK, Anau J, et al. Association between bariatric surgery and macrovascular disease outcomes in patients with type 2 diabetes and severe obesity. JAMA. 2018;320:1570 1582. doi: 295. Kernan WN, Inzucchi SE, Sawan C, Macko RF, Furie KL. Obesity: a stub- bornly obvious target for stroke prevention. Stroke. 2013;44:278 286. doi: 296. Huang K, Liu F, Han X, Huang C, Huang J, Gu D, Yang X. Association of BMI with total mortality and recurrent stroke among stroke patients: a meta-analysis of cohort studies. Atherosclerosis. 2016;253:94 101. doi: 297. Aparicio HJ, Himali JJ, Beiser AS, Davis-Plourde KL, Vasan RS, Kase CS, Wolf PA, Seshadri S. Overweight, obesity, and survival after stroke in the Framingham Heart Study. J Am Heart Assoc. 2017;6:e004721. doi: 298. Lajous M, Banack HR, Kaufman JS, Hernan MA. Should patients with chronic disease be told to gain weight? The obesity paradox and selection bias. Am J Med. 2015;128:334 336. doi: 10.1016/j.amjmed.2014.10.043 299. Garvey WT, Mechanick JI, Brett EM, Garber AJ, Hurley DL, Jastreboff AM, Nadolsky K, Pessah-Pollack R, Plodkowski R; Reviewers of the AACE/ ACE Obesity Clinical Practice Guidelines. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr 300. US Preventive Services Task Force, Curry SJ, Krist AH, Owens DK, Barry MJ, Caughey AB, Davidson KW, Doubeni CA, Epling JW Jr, Grossman DC, Kemper AR, et al. Behavioral weight loss interventions to prevent CLINICAL STATEMENTS AND GUIDELINES Kleindorfer obesity-related morbidity and mortality in adults: US Preventive Services Task Force recommendation statement. JAMA. 2018;320:1163 1171. 301. Moyer VA; U.S. Preventive Services Task Force. Screening for and man- agement of obesity in adults: U.S. Preventive Services Task Force rec- ommendation statement. Ann Intern Med. 2012;157:373 378. doi: 302. Jonas DE, Amick HR, Feltner C, Weber RP, Arvanitis M, Stine A, Lux L, Harris RP. Screening for obstructive sleep apnea in adults: evidence report and systematic review for the US Preventive Services Task Force. JAMA. 303. McEvoy RD, Antic NA, Heeley E, Luo Y, Ou Q, Zhang X, Mediano O, Chen R, Drager LF, Liu Z, et al; SAVE Investigators and Coordinators. CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Engl J 304. Tsivgoulis G, Alexandrov AV, Katsanos AH, Barlinn K, Mikulik R, Lambadiari V, Bonakis A, Alexandrov AW. Noninvasive ventilatory correction in patients with acute ischemic stroke: a systematic review and meta-analysis. Stroke. 305. Parra O, Sanchez-Armengol A, Bonnin M, Arboix A, Campos-Rodriguez F, Perez-Ronchel J, Duran-Cantolla J, de la Torre G, Gonzalez Marcos JR, de la Pena M, et al. Early treatment of obstructive apnoea and stroke out- come: a randomized controlled trial. Eur Respir J. 2011;37:1128 1136. 306. Bravata DM, Sico J, Vaz Fragoso CA, Miech EJ, Matthias MS, Lampert R, Williams LS, Concato J, Ivan CS, Fleck JD, et al. Diagnosing and treating sleep apnea in patients with acute cerebrovascular disease. J Am Heart 307. Gupta A, Shukla G, Afsar M, Poornima S, Pandey RM, Goyal V, Srivastava A, Vibha D, Behari M. Role of positive airway pressure therapy for obstructive sleep apnea in patients with stroke: a randomized controlled trial. J Clin Sleep Med. 2018;14:511 521. doi: 10.5664/jcsm.7034 308. Minnerup J, Ritter MA, Wersching H, Kemmling A, Okegwo A, Schmidt A, Schilling M, Ringelstein EB, Sch bitz WR, Young P, et al. Continuous positive airway pressure ventilation for acute ischemic stroke: a randomized feasibility study. Stroke. 2012;43:1137 1139. doi: 309. Ryan CM, Bayley M, Green R, Murray BJ, Bradley TD. Influence of con- tinuous positive airway pressure on outcomes of rehabilitation in stroke patients with obstructive sleep apnea. Stroke. 2011;42:1062 1067. doi: 310. Wessendorf TE, Wang YM, Thilmann AF, Sorgenfrei U, Konietzko N, Teschler H. Treatment of obstructive sleep apnoea with nasal continuous positive airway pressure in stroke. Eur Respir J. 2001;18:623 629. doi: 311. Sandberg O, Franklin KA, Bucht G, Eriksson S, Gustafson Y. Nasal con- tinuous positive airway pressure in stroke patients with sleep apnoea: a randomized treatment study. Eur Respir J. 2001;18:630 634. doi: 312. Bravata DM, Concato J, Fried T, Ranjbar N, Sadarangani T, McClain V, Struve F, Zygmunt L, Knight HJ, Lo A, et al. Continuous positive airway pressure: evaluation of a novel therapy for patients with acute ischemic stroke. Sleep. 2011;34:1271 1277. doi: 10.5665/SLEEP.1254 313. Brill AK, Horvath T, Seiler A, Camilo M, Haynes AG, Ott SR, Egger M, Bassetti CL. CPAP as treatment of sleep apnea after stroke: a meta- analysis of randomized trials. Neurology. 2018;90:e1222 e1230. doi: 314. Sandberg O, Franklin KA, Bucht G, Gustafson Y. Sleep apnea, delirium, depressed mood, cognition, and ADL ability after stroke. J Am Geriatr Soc. 315. Bravata DM, McClain V, Austin C, Ferguson J, Burrus N, Miech EJ, Matthias MS, Chumbler N, Ofner S, Foresman B, et al. Diagnosing and managing sleep apnea in patients with chronic cerebrovascular disease: a random- ized trial of a home-based strategy. Sleep Breath. 2017;21:713 725. doi: 316. Saletu MT, Kotzian ST, Schwarzinger A, Haider S, Spatt J, Saletu B. Sleep apnea testing is a feasible and accurate method to diagnose obstructive sleep apnea in stroke patients during in-hospital rehabilitation. J Clin Sleep 317. Qaseem A, Dallas P, Owens DK, Starkey M, Holty JE, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Diagnosis of obstructive sleep apnea in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2014;161:210 220. doi: 318. Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 319. Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J 320. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto FJ, O Connor GT, Boland LL, Schwartz JE, Samet JM. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med. 2001;163:19 25. doi: 321. Redline S, Yenokyan G, Gottlieb DJ, Shahar E, O Connor GT, Resnick HE, Diener-West M, Sanders MH, Wolf PA, Geraghty EM, et al. Obstructive sleep apnea-hypopnea and incident stroke: the Sleep Heart Health Study. Am J Respir Crit Care Med. 2010;182:269 277. doi: 322. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the associa- tion between sleep-disordered breathing and hypertension. N Engl J Med. 323. Johnson KG, Johnson DC. Frequency of sleep apnea in stroke and TIA patients: a meta-analysis. J Clin Sleep Med. 2010;6:131 137. 324. Mohsenin V. Obstructive sleep apnea: a new preventive and therapeutic target for stroke: a new kid on the block. Am J Med. 2015;128:811 816. 325. Seiler A, Camilo M, Korostovtseva L, Haynes AG, Brill AK, Horvath T, Egger M, Bassetti CL. Prevalence of sleep-disordered breathing after stroke and TIA: a meta-analysis. Neurology. 2019;92:e648 e654. doi: 326. Parra O, Arboix A, Bechich S, Garc a-Eroles L, Montserrat JM, L pez JA, Ballester E, Guerra JM, Sope a JJ. Time course of sleep-related breathing disorders in first-ever stroke or transient ischemic attack. Am J Respir Crit 327. Sahlin C, Sandberg O, Gustafson Y, Bucht G, Carlberg B, Stenlund H, Franklin KA. Obstructive sleep apnea is a risk factor for death in patients with stroke: a 10-year follow-up. Arch Intern Med. 2008;168:297 301. 328. Birkbak J, Clark AJ, Rod NH. The effect of sleep disordered breathing on the outcome of stroke and transient ischemic attack: a systematic review. J Clin Sleep Med. 2014;10:103 108. doi: 10.5664/jcsm.3376 329. Turkington PM, Allgar V, Bamford J, Wanklyn P, Elliott MW. Effect of up- per airway obstruction in acute stroke on functional outcome at 6 months. 330. Qaseem A, Holty JE, Owens DK, Dallas P, Starkey M, Shekelle P; Clinical Guidelines Committee of the American College of Physicians. Management of obstructive sleep apnea in adults: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2013;159:471 483. doi: 331. Deleted in proofs. 332. Takala M, Puustinen J, Rauhala E, Holm A. Pre-screening of sleep- disordered breathing after stroke: a systematic review. Brain Behav. 333. Senaratna CV, Perret JL, Matheson MC, Lodge CJ, Lowe AJ, Cassim R, Russell MA, Burgess JA, Hamilton GS, Dharmage SC. Validity of the Berlin questionnaire in detecting obstructive sleep apnea: a system- atic review and meta-analysis. Sleep Med Rev. 2017;36:116 124. doi: 334. Kapur VK, Auckley DH, Chowdhuri S, Kuhlmann DC, Mehra R, Ramar K, Harrod CG. Clinical practice guideline for diagnostic testing for adult obstructive sleep apnea: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13:479 504. doi: 335. Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, Frankel MR, Levine SR, Chaturvedi S, Kasner SE, Benesch CG, et al; Warfarin- Aspirin Symptomatic Intracranial Disease Trial Investigators. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med. 2005;352:1305 1316. doi: 10.1056/NEJMoa043033 336. Chimowitz MI, Lynn MJ, Derdeyn CP, Turan TN, Fiorella D, Lane BF, Janis LS, Lutsep HL, Barnwell SL, Waters MF, et al; SAMMPRIS Trial Investigators. Stenting versus aggressive medical therapy for intracranial arterial steno- sis. N Engl J Med. 2011;365:993 1003. doi: 10.1056/NEJMoa1105335 337. Chaturvedi S, Turan TN, Lynn MJ, Kasner SE, Romano J, Cotsonis G, Frankel M, Chimowitz MI; WASID Study Group. Risk factor status and vas- cular events in patients with symptomatic intracranial stenosis. Neurology. CLINICAL STATEMENTS AND GUIDELINES Kleindorfer 338. Liu L, Wong KS, Leng X, Pu Y, Wang Y, Jing J, Zou X, Pan Y, Wang A, Meng X, et al; CHANCE Investigators. Dual antiplatelet therapy in stroke and ICAS: subgroup analysis of CHANCE. Neurology. 2015;85:1154 1162. 339. Wong KS, Chen C, Fu J, Chang HM, Suwanwela NC, Huang YN, Han Z, Tan KS, Ratanakorn D, Chollate P, et al; CLAIR Study Investigators. Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): a ran- domised, open-label, blinded-endpoint trial. Lancet Neurol. 2010;9:489 340. Amarenco P, Denison H, Evans SR, Himmelmann A, James S, Knutsson M, Ladenvall P, Molina CA, Wang Y, Johnston SC; THALES Steering Committee and Investigators. Ticagrelor added to aspirin in acute nonse- vere ischemic stroke or transient ischemic attack of atherosclerotic origin. 341. Kwon SU, Cho YJ, Koo JS, Bae HJ, Lee YS, Hong KS, Lee JH, Kim JS. Cilostazol prevents the progression of the symptomatic intracranial arterial stenosis: the multicenter double-blind placebo-controlled trial of cilostazol in symptomatic intracranial arterial stenosis. Stroke. 2005;36:782 786. 342. Kwon SU, Hong KS, Kang DW, Park JM, Lee JH, Cho YJ, Yu KH, Koo JS, Wong KS, Lee SH, et al. Efficacy and safety of combination antiplatelet therapies in patients with symptomatic intracranial atherosclerotic stenosis. 343. Uchiyama S, Sakai N, Toi S, Ezura M, Okada Y, Takagi M, Nagai Y, Matsubara Y, Minematsu K, Suzuki N, et al; CATHARSIS Study Group. Final results of Cilostazol-Aspirin Therapy against Recurrent Stroke with Intracranial Artery Stenosis (CATHARSIS). Cerebrovasc Dis Extra. 2015;5:1 13. doi: 344. Toyoda K, Uchiyama S, Yamaguchi T, Easton JD, Kimura K, Hoshino H, Sakai N, Okada Y, Tanaka K, Origasa H, et al; CSPS.com Trial Investigators. Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high-risk ischaemic stroke in Japan: a multicentre, open- label, randomised controlled trial. Lancet Neurol. 2019;18:539 548. doi: 345. Turan TN, Cotsonis G, Lynn MJ, Chaturvedi S, Chimowitz M; Warfarin- Aspirin Symptomatic Intracranial Disease (WASID) Trial Investigators. Relationship between blood pressure and stroke recurrence in patients with intracranial arterial stenosis. Circulation. 2007;115:2969 2975. doi: 346. Yu DD, Pu YH, Pan YS, Zou XY, Soo Y, Leung T, Liu LP, Wang DZ, Wong KS, Wang YL, et al; Chinese Intracranial Atherosclerosis (CICAS) Study Group. High blood pressure increases the risk of poor outcome at dis- charge and 12-month follow-up in patients with symptomatic intracranial large artery stenosis and occlusions: subgroup analysis of the CICAS Study. CNS Neurosci Ther. 2015;21:530 535. doi: 10.1111/cns.12400 347. Amin-Hanjani S, Turan TN, Du X, Pandey DK, Rose-Finnell L, Richardson D, Elkind MS, Zipfel GJ, Liebeskind DS, Silver FL, et al; VERiTAS Study Group. Higher stroke risk with lower blood pressure in hemodynamic vertebro- basilar disease: analysis from the VERiTAS study. J Stroke Cerebrovasc Dis. 348. Park JM, Kim BJ, Kwon SU, Hwang YH, Heo SH, Rha JH, Lee J, Park MS, Kim JT, Song HJ, et al. Intensive blood pressure control may not be safe in subacute ischemic stroke by intracranial atherosclerosis: a result of randomized trial. J Hypertens. 2018;36:1936 1941. doi: 349. Zhou P, Lu Z, Gao P, Wang P, Cao Z, Zhang G, Wang S, Feng Y, Wang P. Efficacy and safety of intensive statin therapy in Chinese patients with atherosclerotic intracranial arterial stenosis: a single-center, randomized, single-blind, parallel-group study with one-year follow-up. Clin Neurol 350. Alexander MJ, Zauner A, Chaloupka JC, Baxter B, Callison RC, Gupta R, Song SS, Yu W; WEAVE Trial Sites and Interventionalists. WEAVE trial: final results in 152 on-label patients. Stroke. 2019;50:889 894. doi: 351. Aghaebrahim A, Agnoletto GJ, Aguilar-Salinas P, Granja MF, Monteiro A, Siddiqui AH, Levy EI, Shallwani H, Kim SJ, Haussen DC, et al. Endovascular recanalization of symptomatic intracranial arterial stenosis despite aggres- sive medical management. World Neurosurg. 2019;123:e693 e699. doi: 352. Lutsep HL, Barnwell SL, Larsen DT, Lynn MJ, Hong M, Turan TN, Derdeyn CP, Fiorella D, Janis LS, Chimowitz MI; SAMMPRIS Investigators. Outcome in patients previously on antithrombotic therapy in the SAMMPRIS trial: subgroup analysis. Stroke. 2015;46:775 779. doi: 353. Derdeyn CP, Chimowitz MI, Lynn MJ, Fiorella D, Turan TN, Janis LS, Montgomery J, Nizam A, Lane BF, Lutsep HL, et al; Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis Trial Investigators. Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results of a randomised trial. Lancet. 2014;383:333 341. doi: 354. Miao Z, Jiang L, Wu H, Bao Y, Jiao L, Li S, Wu J, Hua Y, Li Y, Zhu J, et al. Randomized controlled trial of symptomatic middle cerebral artery steno- sis: endovascular versus medical therapy in a Chinese population. Stroke. 355. Zaidat OO, Fitzsimmons BF, Woodward BK, Wang Z, Killer-Oberpfalzer M, Wakhloo A, Gupta R, Kirshner H, Megerian JT, Lesko J, et al; VISSIT Trial Investigators. Effect of a balloon-expandable intracranial stent vs medical therapy on risk of stroke in patients with symptomatic intracranial stenosis: the VISSIT randomized clinical trial. JAMA. 2015;313:1240 1248. doi: 356. Lutsep HL, Lynn MJ, Cotsonis GA, Derdeyn CP, Turan TN, Fiorella D, Janis LS, Lane BF, Montgomery J, Chimowitz MI; SAMMPRIS Investigators. Does the stenting versus aggressive medical therapy trial support stenting for subgroups with intracranial stenosis? Stroke. 2015;46:3282 3284. 357. Wabnitz AM, Derdeyn CP, Fiorella DJ, Lynn MJ, Cotsonis GA, Liebeskind DS, Waters MF, Lutsep H, Lopez-Cancio E, Turan TN, et al; SAMMPRIS Investigators. Hemodynamic markers in the ante- rior circulation as predictors of recurrent stroke in patients with intra- cranial stenosis [published online December 11, 2018]. Stroke. doi: 358. Compter A, van der Worp HB, Schonewille WJ, Vos JA, Boiten J, Nederkoorn PJ, Uyttenboogaart M, Lo RT, Algra A, Kappelle LJ; VAST Investigators. Stenting versus medical treatment in patients with symptom- atic vertebral artery stenosis: a randomised open-label phase 2 trial. Lancet 359. Markus HS, Larsson SC, Kuker W, Schulz UG, Ford I, Rothwell PM, Clifton A; VIST Investigators. Stenting for symptomatic vertebral artery stenosis: the Vertebral Artery Ischaemia Stenting Trial. Neurology. 2017;89:1229 360. Kasner SE, Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, Frankel MR, Levine SR, Chaturvedi S, Benesch CG, et al; Warfarin Aspirin Symptomatic Intracranial Disease Trial Investigators. Predictors of ischemic stroke in the territory of a symptomatic intracra- nial arterial stenosis. Circulation. 2006;113:555 563. doi: 10.1161/ 361. EC/IC Bypass Study Group. Failure of extracranial-intracranial arterial bypass to reduce the risk of ischemic stroke. results of an international randomized trial. N Engl J Med. 1985;313:1191 1200. doi: 10.1056/ 362. Gorelick PB, Wong KS, Bae HJ, Pandey DK. Large artery intracranial oc- clusive disease: a large worldwide burden but a relatively neglected frontier. 363. Amin-Hanjani S, Pandey DK, Rose-Finnell L, Du X, Richardson D, Thulborn KR, Elkind MS, Zipfel GJ, Liebeskind DS, Silver FL, et al; Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke Study Group. Effect of hemodynamics on stroke risk in symptomatic atheroscle- rotic vertebrobasilar occlusive disease. JAMA Neurol. 2016;73:178 185. 364. L pez-Cancio E, Matheus MG, Romano JG, Liebeskind DS, Prabhakaran S, Turan TN, Cotsonis GA, Lynn MJ, Rumboldt Z, Chimowitz MI. Infarct patterns, collaterals and likely causative mechanisms of stroke in symp- tomatic intracranial atherosclerosis. Cerebrovasc Dis. 2014;37:417 422. 365. Johnston SC, Elm JJ, Easton JD, Farrant M, Barsan WG, Kim AS, Lindblad AS, Palesch YY, Zurita KG, Albers GW, et al; POINT and Neurological Emergencies Treatment Trials Network Investigators. Time course for benefit and risk of clopidogrel and aspirin after acute transient ischemic attack and minor ischemic stroke. Circulation. 2019;140:658 664. doi: 366. US Food and Drug Administration. Use of the Stryker Wingspan stent sys- tem outside of approved indications leads to an increased risk of stroke or death: FDA Safety Communication. 2019. Accessed December 3, 2020. https://www.fda.gov/medical-devices/medical-device-safety/use-stryker- wingspan-stent-system-outside-approved-indications-leads-increased- risk-stroke-or-death CLINICAL STATEMENTS AND GUIDELINES Kleindorfer 367. US Food and Drug Administration. Rates of stroke and death: 522 post- market surveillance studies database. 2013. Accessed December 3, 2020. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pss. 368. Gr schel K, Schnaudigel S, Pilgram SM, Wasser K, Kastrup A. A systematic review on outcome after stenting for intracranial atherosclerosis. Stroke. 369. Rothwell PM, Eliasziw M, Gutnikov SA, Fox AJ, Taylor DW, Mayberg MR, Warlow CP, Barnett HJ; Carotid Endarterectomy Trialists Collaboration. Analysis of pooled data from the randomised controlled trials of endarter- ectomy for symptomatic carotid stenosis. Lancet. 2003;361:107 116. doi: 370. Barnett HJM, Taylor DW, Haynes RB, Sackett DL, Peerless SJ, Ferguson GG, Fox AJ, Rankin RN, Hachinski VC, Wiebers DO, et al. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991;325:445 453. 371. Howard G, Roubin GS, Jansen O, Hendrikse J, Halliday A, Fraedrich G, Eckstein HH, Calvet D, Bulbulia R, Bonati LH, et al; Carotid Stenting Trialists Collaboration. Association between age and risk of stroke or death from carotid endarterectomy and carotid stenting: a meta-analysis of pooled patient data from four randomised trials. Lancet. 2016;387:1305 372. Rantner B, Kollerits B, Roubin GS, Ringleb PA, Jansen O, Howard G, Hendrikse J, Halliday A, Gregson J, Eckstein HH, et al; Carotid Stenosis Trialists Collaboration. Early endarterectomy carries a lower procedural risk than early stenting in patients with symptomatic stenosis of the in- ternal carotid artery: results from 4 randomized controlled trials. Stroke. 373. Rothwell PM, Eliasziw M, Gutnikov SA, Warlow CP, Barnett HJ; Carotid Endarterectomy Trialists Collaboration. Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery. 374. Yadav JS, Wholey MH, Kuntz RE, Fayad P, Katzen BT, Mishkel GJ, Bajwa TK, Whitlow P, Strickman NE, Jaff MR, et al; Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy Investigators. Protected carotid-artery stenting versus endarterec- tomy in high-risk patients. N Engl J Med. 2004;351:1493 1501. doi: 375. Brott TG, Hobson RW 2nd, Howard G, Roubin GS, Clark WM, Brooks W, Mackey A, Hill MD, Leimgruber PP, Sheffet AJ, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med. 2010;363:11 23. doi: 10.1056/NEJMoa0912321 376. Schermerhorn ML, Liang P, Eldrup-Jorgensen J, Cronenwett JL, Nolan BW, Kashyap VS, Wang GJ, Motaganahalli RL, Malas MB. Association of transcarotid artery revascularization vs transfemoral carotid artery stenting with stroke or death among patients with carotid artery stenosis. JAMA. 377. Powers WJ, Clarke WR, Grubb RL Jr, Videen TO, Adams HP Jr, Derdeyn CP; COSS Investigators. Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial. JAMA. 2011;306:1983 1992. doi: 377a. Amarenco P, Kim JS, Labreuche J, Charles H, Abtan J, B jot Y, Cabrejo L, Cha JK, Ducrocq G, Giroud M, et al; Treat Stroke to Target Investigators. A comparison of two LDL cholesterol targets after ischemic stroke. N Engl J 378. Markus HS, Harshfield EL, Compter A, Kuker W, Kappelle LJ, Clifton A, van der Worp HB, Rothwell P, Algra A; Vertebral Stenosis Trialists Collaboration. Stenting for symptomatic vertebral artery stenosis: a preplanned pooled individual patient data analysis. Lancet Neurol. 379. Hanel RA, Brasiliense LB, Spetzler RF. Microsurgical revasculariza- tion of proximal vertebral artery: a single-center, single-operator analy- sis. Neurosurgery. 2009;64:1043 1050. doi: 10.1227/01.NEU. 380. Amarenco P, Davis S, Jones EF, Cohen AA, Heiss WD, Kaste M, Laou nan C, Young D, Macleod M, Donnan GA; Aortic Arch Related Cerebral Hazard Trial Investigators. Clopidogrel plus aspirin versus warfarin in patients with stroke and aortic arch plaques. Stroke. 2014;45:1248 1257. doi: 381. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, Leys D, Matias-Guiu J, Rupprecht HJ; MATCH Investigators. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331 337. doi: 382. SPS3 Investigators; Benavente OR, Hart RG, McClure LA, Szychowski JM, Coffey CS, Pearce LA. Effects of clopidogrel added to aspirin in pa- tients with recent lacunar stroke. N Engl J Med. 2012;367:817 825. doi: 383. Antithrombotic Trialists Collaboration; Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual partici- pant data from randomised trials. Lancet. 2009;373:1849 1860. doi: 384. Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, Kim AS, Lindblad AS, Palesch YY; Clinical Research Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379:215 225. doi: 10.1056/NEJMoa1800410 385. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of ran- domised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71 86. doi: 386. Amarenco P, Duyckaerts C, Tzourio C, H nin D, Bousser MG, Hauw JJ. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N 387. Amarenco P, Cohen A, Tzourio C, Bertrand B, Hommel M, Besson G, Chauvel C, Touboul PJ, Bousser MG. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med. 1994;331:1474 1479. 388. Di Tullio MR, Russo C, Jin Z, Sacco RL, Mohr JP, Homma S; Patent Foramen Ovale in Cryptogenic Stroke Study Investigators. Aortic arch plaques and risk of recurrent stroke and death. Circulation. 2009;119:2376 2382. doi: 389. Cohen A, Tzourio C, Bertrand B, Chauvel C, Bousser MG, Amarenco P. Aortic plaque morphology and vascular events: a follow-up study in patients with ischemic stroke: FAPS Investigators: French Study of Aortic Plaques in Stroke. Circulation. 1997;96:3838 3841. doi: 10.1161/01.cir.96.11.3838 390. Amarenco P, Cohen A, Hommel M, Moulin T, Leys D, Bousser MG. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. N Engl J Med. 1996;334:1216 1221. 391. Deng X, Gao F, Zhang D, Zhang Y, Wang R, Wang S, Cao Y, Zhao Y, Pan Y, Liu X, et al. Direct versus indirect bypasses for adult ischemic-type moyamoya disease: a propensity score-matched analysis. J Neurosurg. 392. Deng X, Gao F, Zhang D, Zhang Y, Wang R, Wang S, Cao Y, Zhao Y, Pan Y, Ye X, et al. Effects of different surgical modalities on the clinical out- come of patients with moyamoya disease: a prospective cohort study. J 393. Jeon JP, Kim JE, Cho WS, Bang JS, Son YJ, Oh CW. Meta-analysis of the surgical outcomes of symptomatic moyamoya disease in adults. J 394. Li Q, Gao Y, Xin W, Zhou Z, Rong H, Qin Y, Li K, Zhou Y, Wang J, Xiong J, et al. Meta-analysis of prognosis of different treatments for symptom- atic moyamoya disease. World Neurosurg. 2019;127:354 361. doi: 395. Sun H, Wilson C, Ozpinar A, Safavi-Abbasi S, Zhao Y, Nakaji P, Wanebo JE, Spetzler RF. Perioperative complications and long-term outcomes after bypasses in adults with moyamoya disease: a systematic re- view and meta-analysis. World Neurosurg. 2016;92:179 188. doi: 396. Kim H, Jang DK, Han YM, Sung JH, Park IS, Lee KS, Yang JH, Huh PW, Park YS, Kim DS, et al. Direct bypass versus indirect bypass in adult moy- amoya angiopathy with symptoms or hemodynamic instability: a meta- analysis of comparative studies. World Neurosurg. 2016;94:273 284. doi: 397. Jang DK, Lee KS, Rha HK, Huh PW, Yang JH, Park IS, Ahn JG, Sung JH, Han YM. Bypass surgery versus medical treatment for symptom- atic moyamoya disease in adults. J Neurosurg. 2017;127:492 502. doi: 398. Yamada S, Oki K, Itoh Y, Kuroda S, Houkin K, Tominaga T, Miyamoto S, Hashimoto N, Suzuki N; Research Committee on Spontaneous Occlusion of Circle of Willis (Moyamoya Disease). Effects of surgery and antiplate- let therapy in ten-year follow-up from the registry study of Research Committee on Moyamoya Disease in Japan. J Stroke Cerebrovasc Dis. CLINICAL STATEMENTS AND GUIDELINES Kleindorfer 399. Qian C, Yu X, Li J, Chen J, Wang L, Chen G. The efficacy of surgical treat- ment for the secondary prevention of stroke in symptomatic moyamoya disease: a meta-analysis. Medicine (Baltimore). 2015;94:e2218. doi: 400. Onozuka D, Hagihara A, Nishimura K, Kada A, Nakagawara J, Ogasawara K, Ono J, Shiokawa Y, Aruga T, Miyachi S, et al; J-ASPECT Study Collaborators. Prehospital antiplatelet use and functional status on ad- mission of patients with non-haemorrhagic moyamoya disease: a na- tionwide retrospective cohort study (J-ASPECT study). BMJ Open. 401. Zhao Y, Zhang Q, Zhang D, Zhao Y. Effect of aspirin in postoperative management of adult ischemic moyamoya disease. World Neurosurg. 402. Acker G, Goerdes S, Schneider UC, Schmiedek P, Czabanka M, Vajkoczy P. Distinct clinical and radiographic characteristics of moyamoya disease amongst European Caucasians. Eur J Neurol. 2015;22:1012 1017. doi: 403. Baba T, Houkin K, Kuroda S. Novel epidemiological features of moy- amoya disease. J Neurol Neurosurg Psychiatry. 2008;79:900 904. doi: 404. Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis. Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Med Chir (Tokyo). 2012;52:245 266. doi: 10.2176/nmc.52.245 405. Miyamoto S, Yoshimoto T, Hashimoto N, Okada Y, Tsuji I, Tominaga T, Nakagawara J, Takahashi JC; JAM Trial Investigators. Effects of extracra- nial-intracranial bypass for patients with hemorrhagic moyamoya disease: results of the Japan Adult Moyamoya Trial. Stroke. 2014;45:1415 1421. 406. Kim DY, Son JP, Yeon JY, Kim GM, Kim JS, Hong SC, Bang OY. Infarct pattern and collateral status in adult moyamoya disease: a multimodal magnetic resonance imaging study. Stroke. 2017;48:111 116. doi: 407. Kraemer M, Berlit P, Diesner F, Khan N. What is the expert s option on an- tiplatelet therapy in moyamoya disease? Results of a worldwide survey. Eur J Neurol. 2012;19:163 167. doi: 10.1111/j.1468-1331.2011.03481.x 408. Benavente OR, White CL, Pearce L, Pergola P, Roldan A, Benavente MF, Coffey C, McClure LA, Szychowski JM, Conwit R, et al; SPS3 Investigators. The Secondary Prevention of Small Subcortical Strokes (SPS3) study. Int J 409. Pan Y, Elm JJ, Li H, Easton JD, Wang Y, Farrant M, Meng X, Kim AS, Zhao X, Meurer WJ, et al. Outcomes associated with clopidogrel-aspirin use in minor stroke or transient ischemic attack: a pooled analysis of Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) and Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trials. JAMA Neurol. 2019;76:1466 1473. doi: 410. Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X, Cui L, et al; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369:11 19. doi: 411. Deleted in proofs. 412. Bamford J, Sandercock P, Jones L, Warlow C. The natural history of la- cunar infarction: the Oxfordshire Community Stroke Project. Stroke. 413. Jackson C, Sudlow C. Comparing risks of death and recurrent vascular events between lacunar and non-lacunar infarction. Brain. 2005;128(pt 414. Jacova C, Pearce LA, Costello R, McClure LA, Holliday SL, Hart RG, Benavente OR. Cognitive impairment in lacunar strokes: the SPS3 trial. Ann Neurol. 2012;72:351 362. doi: 10.1002/ana.23733 415. Makin SD, Turpin S, Dennis MS, Wardlaw JM. Cognitive impairment after lacunar stroke: systematic review and meta-analysis of incidence, prev- alence and comparison with other stroke subtypes. J Neurol Neurosurg 416. Gotoh F, Tohgi H, Hirai S, Terashi A, Fukuuchi Y, Otomo E, Shinohara Y, Itoh E, Matsuda T, Sawada T, et al. Cilostazol stroke prevention study: a placebo-controlled double-blind trial for secondary prevention of ce- rebral infarction. J Stroke Cerebrovasc Dis. 2000;9:147 157. doi: 417. Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S, Matsuoka K, Ohashi Y, Tanahashi N, Yamamoto H, Genka C, et al; CSPS 2 Group. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin- controlled, double-blind, randomised non-inferiority trial. Lancet Neurol. 418. Smith EE, Saposnik G, Biessels GJ, Doubal FN, Fornage M, Gorelick PB, Greenberg SM, Higashida RT, Kasner SE, Seshadri S; on be- half of the American Heart Association Stroke Council; Council on Cardiovascular Radiology and Intervention; Council on Functional Genomics and Translational Biology; and Council on Hypertension. Prevention of stroke in patients with silent cerebrovascular disease: a sci- entific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2017;48:e44 e71. doi: 419. Stroke Prevention in Atrial Fibrillation Investigators. Stroke Prevention in Atrial Fibrillation study: final results. Circulation. 1991;84:527 39. 420. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation. Chest. 2010;137:263 272. doi: 10.1378/chest.09-1584 421. Mason PK, Lake DE, DiMarco JP, Ferguson JD, Mangrum JM, Bilchick K, Moorman LP, Moorman JR. Impact of the CHA2DS2-VASc score on anticoagulation recommendations for atrial fibrillation. Am J Med. 422. Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. The value of the CHA2DS2-VASc score for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0-1: a nationwide cohort study. Thromb Haemost. 2012;107:1172 1179. doi: 10.1160/TH12-03-0175 423. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139 1151. doi: 424. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 425. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrilla- tion. N Engl J Med. 2011;365:981 992. doi: 10.1056/NEJMoa1107039 426. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, pinar J, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093 2104. doi: 10.1056/NEJMoa1310907 427. Healey JS, Connolly SJ, Gold MR, Israel CW, Van Gelder IC, Capucci A, Lau CP, Fain E, Yang S, Bailleul C, et al; ASSERT Investigators. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med. 2012;366:120 129. doi: 428. Hart RG, Coull BM, Hart D. Early recurrent embolism associated with non- valvular atrial fibrillation: a retrospective study. Stroke. 1983;14:688 693. 429. Seiffge DJ, Werring DJ, Paciaroni M, Dawson J, Warach S, Milling TJ, Engelter ST, Fischer U, Norrving B. Timing of anticoagulation after re- cent ischaemic stroke in patients with atrial fibrillation. Lancet Neurol. 430. Paciaroni M, Agnelli G, Corea F, Ageno W, Alberti A, Lanari A, Caso V, Micheli S, Bertolani L, Venti M, et al. Early hemorrhagic transformation of brain infarction: rate, predictive factors, and influence on clinical outcome: results of a prospective multicenter study. Stroke. 2008;39:2249 2256. 431. Ahmed N, Steiner T, Caso V, Wahlgren N; ESO-KSU Session Participants. Recommendations from the ESO-Karolinska Stroke Update Conference, Stockholm 13-15 November 2016. Eur Stroke J. 2017;2:95 102. doi: 432. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardi- ac surgical patients with atrial fibrillation. Ann Thorac Surg. 1996;61:755 433. Holmes DR Jr, Kar S, Price MJ, Whisenant B, Sievert H, Doshi SK, Huber K, Reddy VY. Prospective randomized evaluation of the Watchman left atrial appendage closure device in patients with atrial fibrillation versus long- term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol. 2014;64:1 12. 434. Holmes DR, Reddy VY, Turi ZG, Doshi SK, Sievert H, Buchbinder M, Mullin CM, Sick P; PROTECT AF Investigators. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet. 435. Reddy VY, Doshi SK, Kar S, Gibson DN, Price MJ, Huber K, Horton RP, Buchbinder M, Neuzil P, Gordon NT, et al; PREVAIL and PROTECT AF CLINICAL STATEMENTS AND GUIDELINES Kleindorfer Investigators. 5-Year outcomes after left atrial appendage closure: from the PREVAIL and PROTECT AF trials. J Am Coll Cardiol. 2017;70:2964 436. Reddy VY, Sievert H, Halperin J, Doshi SK, Buchbinder M, Neuzil P, Huber K, Whisenant B, Kar S, Swarup V, et al; PROTECT AF Steering Committee and Investigators. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA. 2014;312:1988 437. Abdul-Rahim AH, Fulton RL, Frank B, Tatlisumak T, Paciaroni M, Caso V, Diener HC, Lees KR; VISTA Collaborators. Association of improved outcome in acute ischaemic stroke patients with atrial fibrillation who receive early antithrombotic therapy: analysis from VISTA. Eur J Neurol. 438. Siontis KC, Zhang X, Eckard A, Bhave N, Schaubel DE, He K, Tilea A, Stack AG, Balkrishnan R, Yao X, et al. Outcomes associated with apix- aban use in patients with end-stage kidney disease and atrial fibril- lation in the United States. Circulation. 2018;138:1519 1529. doi: 439. Gage BF, van Walraven C, Pearce L, Hart RG, Koudstaal PJ, Boode BS, Petersen P. Selecting patients with atrial fibrillation for antico- agulation: stroke risk stratification in patients taking aspirin. Circulation. 440. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285:2864 441. G rdo an M, Ari H, Tenekecio lu E, Ari S, Bozat T, Koca V, Melek M. Predictors of atrial fibrillation recurrence in hyperthyroid and euthyroid pa- tients. Arq Bras Cardiol. 2016;106:84 91. doi: 10.5935/abc.20160013 442. Lowres N, Mulcahy G, Jin K, Gallagher R, Neubeck L, Freedman B. Incidence of postoperative atrial fibrillation recurrence in patients dis- charged in sinus rhythm after cardiac surgery: a systematic review and meta-analysis. Interact Cardiovasc Thorac Surg. 2018;26:504 511. doi: 443. Park-Hansen J, Greve AM, Clausen J, Holme SJ, Carranza CL, Irmukhamedov A, Sabah L, Lin Q, Madsen AS, Dom nguez H. New- onset of postoperative atrial fibrillation is likely to recur in the absence of other triggers. Ther Clin Risk Manag. 2018;14:1641 1647. doi: 444. Siu CW, Jim MH, Zhang X, Chan YH, Pong V, Kwok J, Kung AW, Lau CP, Tse HF. Comparison of atrial fibrillation recurrence rates after success- ful electrical cardioversion in patients with hyperthyroidism-induced ver- sus non-hyperthyroidism-induced persistent atrial fibrillation. Am J Cardiol. 445. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, et al. Comparison of the efficacy and safety of new oral anticoagulants with war- farin in patients with atrial fibrillation: a meta-analysis of randomised trials. 446. Brembilla-Perrot B, Girerd N, Sellal JM, Olivier A, Manenti V, Villemin T, Beurrier D, DE Chillou C, Louis P, Selton O, et al. Risk of atrial fibrillation after atrial flutter ablation: impact of AF history, gender, and antiarrhyth- mic drug medication. J Cardiovasc Electrophysiol. 2014;25:813 820. doi: 447. Active Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, Pfeffer M, Hohnloser S, Yusuf S. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibril- lation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for preven- tion of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 448. Jaillard A, Cornu C, Durieux A, Moulin T, Boutitie F, Lees KR, Hommel M. Hemorrhagic transformation in acute ischemic stroke: the MAST-E study: MAST-E group. Stroke. 1999;30:1326 1332. doi: 449. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, et al; on behalf of the American Heart Association Stroke Council. 2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association [published correction appears in Stroke. 2018;49:e138 and Stroke. 2018;49:e233 e234]. Stroke. 2018;49:e46 e110. doi: 450. Steffel J, Verhamme P, Potpara TS, Albaladejo P, Antz M, Desteghe L, Georg Haeusler K, Oldgren J, Reinecke H, Roldan-Schilling V, et al; ESC Scientific Document Group. The 2018 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral an- ticoagulants in patients with atrial fibrillation: executive summary. Europace. 451. Muscari A, Faccioli L, Lega MV, Lorusso A, Masetti M, Pastore Trossello M, Puddu GM, Spinardi L, Zoli M. Predicting hemorrhagic transformation and its timing from maximum cerebral lesion diameter in nonlacunar ischemic strokes. Brain Behav. 2020;10:e01497. doi: 10.1002/brb3.1497 452. Pan KL, Singer DE, Ovbiagele B, Wu YL, Ahmed MA, Lee M. Effects of non-vitamin K antagonist oral anticoagulants versus warfarin in patients with atrial fibrillation and valvular heart disease: a system- atic review and meta-analysis. J Am Heart Assoc. 2017;6:e005835. doi: 453. Avezum A, Lopes RD, Schulte PJ, Lanas F, Gersh BJ, Hanna M, Pais P, Erol C, Diaz R, Bahit MC, et al. Apixaban in comparison with warfarin in patients with atrial fibrillation and valvular heart disease: findings from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. Circulation. 2015;132:624 632. doi: 454. Breithardt G, Baumgartner H, Berkowitz SD, Hellkamp AS, Piccini JP, Stevens SR, Lokhnygina Y, Patel MR, Halperin JL, Singer DE, et al; ROCKET AF Steering Committee & Investigators. Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease par- ticipating in the ROCKET AF trial. Eur Heart J. 2014;35:3377 3385. doi: 455. P rez-G mez F, Alegr a E, Berj n J, Iriarte JA, Zumalde J, Salvador A, Mataix L; NASPEAF Investigators. Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and nonval- vular atrial fibrillation: a randomized multicenter study. J Am Coll Cardiol. 456. Ezekowitz MD, Nagarakanti R, Noack H, Brueckmann M, Litherland C, Jacobs M, Clemens A, Reilly PA, Connolly SJ, Yusuf S, et al. Comparison of dabigatran and warfarin in patients with atrial fibrillation and val- vular heart disease: the RE-LY Trial (Randomized Evaluation of Long- Term Anticoagulant Therapy). Circulation. 2016;134:589 598. doi: 457. Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, Blatchford J, Devenny K, Friedman J, Guiver K, et al; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369:1206 1214. doi: 458. Hering D, Piper C, Bergemann R, Hillenbach C, Dahm M, Huth C, Horstkotte D. Thromboembolic and bleeding complications following St. Jude Medical valve replacement: results of the German Experience With Low-Intensity Anticoagulation study. Chest. 2005;127:53 59. doi: 459. Massel DR, Little SH. Antiplatelet and anticoagulation for patients with prosthetic heart valves. Cochrane Database Syst Rev. 2013:CD003464. 460. Garc a-Cabrera E, Fern ndez-Hidalgo N, Almirante B, Ivanova-Georgieva R, Noureddine M, Plata A, Lomas JM, G lvez-Acebal J, Hidalgo-Tenorio C, Ru z-Morales J, et al; Group for the Study of Cardiovascular Infections of the Andalusian Society of Infectious Diseases; Spanish Network for Research in Infectious Diseases. Neurological complications of infec- tive endocarditis: risk factors, outcome, and impact of cardiac surgery: a multicenter observational study. Circulation. 2013;127:2272 2284. doi: 461. Heiro M, Nikoskelainen J, Engblom E, Kotilainen E, Marttila R, Kotilainen P. Neurologic manifestations of infective endocarditis: a 17-year experience in a teaching hospital in Finland. Arch Intern Med. 2000;160:2781 2787. 462. Durante Mangoni E, Adinolfi LE, Tripodi MF, Andreana A, Gambardella M, Ragone E, Precone DF, Utili R, Ruggiero G. Risk factors for major em- bolic events in hospitalized patients with infective endocarditis. Am Heart 463. Baddour LM, Wilson WR, Bayer AS, Fowler VG Jr, Bolger AF, Levison ME, Ferrieri P, Gerber MA, Tani LY, Gewitz MH, et al; on behalf of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease; Council on Cardiovascular Disease in the Young; Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia; American Heart Association; Infectious Diseases Society of America. Infective endocardi- tis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and CLINICAL STATEMENTS AND GUIDELINES Kleindorfer Cardiovascular Surgery and Anesthesia, American Heart Association: en- dorsed by the Infectious Diseases Society of America [published correc- tion appears in Circulation. 2005;112:2373, Circulation. 2007;115:e408, Circulation. 2007;116:e547, and Circulation. 2008;118:e497]. Circulation. 464. Kang DH, Kim YJ, Kim SH, Sun BJ, Kim DH, Yun SC, Song JM, Choo SJ, Chung CH, Song JK, et al. Early surgery versus conventional treat- ment for infective endocarditis. N Engl J Med. 2012;366:2466 2473. doi: 465. Thuny F, Di Salvo G, Disalvo G, Belliard O, Avierinos JF, Pergola V, Rosenberg V, Casalta JP, Gouvernet J, Derumeaux G, et al. Risk of embo- lism and death in infective endocarditis: prognostic value of echocardiog- raphy: a prospective multicenter study. Circulation. 2005;112:69 75. doi: 466. Eishi K, Kawazoe K, Kuriyama Y, Kitoh Y, Kawashima Y, Omae T. Surgical management of infective endocarditis associated with cerebral complica- tions: multi-center retrospective study in Japan. J Thorac Cardiovasc Surg. 467. Barsic B, Dickerman S, Krajinovic V, Pappas P, Altclas J, Carosi G, Casab JH, Chu VH, Delahaye F, Edathodu J, et al; International Collaboration on Endocarditis Prospective Cohort Study Investigators. Influence of the timing of cardiac surgery on the outcome of patients with infec- tive endocarditis and stroke. Clin Infect Dis. 2013;56:209 217. doi: 468. John S, Walsh KM, Hui FK, Sundararajan S, Silverman S, Bain M. Dynamic angiographic nature of cerebral mycotic aneurysms in patients with infective endocarditis. Stroke. 2016;47:e8 e10. doi: 10.1161/ 469. Acar J, Iung B, Boissel JP, Samama MM, Michel PL, Teppe JP, Pony JC, Breton HL, Thomas D, Isnard R, et al. AREVA: multicenter randomized comparison of low-dose versus standard-dose anticoagulation in patients with mechanical prosthetic heart valves. Circulation. 1996;94:2107 2112. 470. M rie C, K ber L, Skov Olsen P, Andersson C, Gislason G, Skov Jensen J, Torp-Pedersen C. Association of warfarin therapy duration after bio- prosthetic aortic valve replacement with risk of mortality, thromboem- bolic complications, and bleeding. JAMA. 2012;308:2118 2125. doi: 471. Puskas J, Gerdisch M, Nichols D, Quinn R, Anderson C, Rhenman B, Fermin L, McGrath M, Kong B, Hughes C, et al; PROACT Investigators. Reduced anticoagulation after mechanical aortic valve replacement: in- terim results from the prospective randomized On-X Valve Anticoagulation Clinical Trial randomized Food and Drug Administration investigational de- vice exemption trial. J Thorac Cardiovasc Surg. 2014;147:1202 1210. doi: 472. Torella M, Torella D, Chiodini P, Franciulli M, Romano G, De Santo L, De Feo M, Amarelli C, Sasso FC, Salvatore T, et al. LOWERing the INtensity of oral anticoaGulant Therapy in patients with bileaflet mechanical aortic valve replacement: results from the LOWERING-IT Trial. Am Heart J. 473. Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 474. Barnett HJ, Boughner DR, Taylor DW, Cooper PE, Kostuk WJ, Nichol PM. Further evidence relating mitral-valve prolapse to cerebral isch- emic events. N Engl J Med. 1980;302:139 144. doi: 10.1056/ 475. Freed LA, Levy D, Levine RA, Larson MG, Evans JC, Fuller DL, Lehman B, Benjamin EJ. Prevalence and clinical outcome of mitral-valve prolapse. N Engl J Med. 1999;341:1 7. doi: 10.1056/NEJM199907013410101 476. Gilon D, Buonanno FS, Joffe MM, Leavitt M, Marshall JE, Kistler JP, Levine RA. Lack of evidence of an association between mitral-valve pro- lapse and stroke in young patients. N Engl J Med. 1999;341:8 13. doi: 477. Orencia AJ, Petty GW, Khandheria BK, Annegers JF, Ballard DJ, Sicks JD, O Fallon WM, Whisnant JP. Risk of stroke with mitral valve pro- lapse in population-based cohort study. Stroke. 1995;26:7 13. doi: 478. Rodriguez CJ, Bartz TM, Longstreth WT Jr, Kizer JR, Barasch E, Lloyd-Jones DM, Gottdiener JS. 