Canadian Journal of Cardiology


Published:October 19, 2022DOI:


      In 2014, Hart et al. introduced the concept of “Embolic Stroke of Undetermined Source” (ESUS) to the clinical-research stroke community. The hypothesis underlying the development of the ESUS construct was that this potentially heterogenous group of stroke mechanisms were largely thromboembolic, and would thus benefit from anticoagulation over antiplatelet for secondary prevention. Since then, two large clinical trials have demonstrated that, to date, there is not a clear uniform antithrombotic strategy for secondary prevention after ESUS as it was originally broadly defined. However, this work has yielded valuable information about the patient phenotypes that experience ESUS strokes, as well as hypothesis-generating substudies that have given rise to the next generation of secondary prevention trials aimed at more personalized approaches for different suspected mechanisms of embolic stroke. In parallel with the evolution of ESUS, several studies aimed at screening for atrial fibrillation in the secondary stroke prevention population have generated additional questions about the mechanistic relevance of atrial fibrillation detected after stroke, and how this should inform post-stroke workup, and secondary prevention strategies. Here, we provide a synthesis of the current understanding surrounding the patient phenotypes that experience ESUS strokes, and previous, ongoing and anticipated clinical trials that will guide earlier and later secondary prevention strategies and post-stroke cardiac investigations.
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      1. Hart RG, Diener H-C, Coutts SB, Easton JD, Granger CB, O’Donnell MJ, Sacco RL, Connolly SJ, Cryptogenic Stroke/ESUS International Working Group. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol. 2014;13:429–438.

      2. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24:35–41.

      3. Hart RG, Sharma M, Mundl H, Kasner SE, Bangdiwala SI, Berkowitz SD, Swaminathan B, Lavados P, Wang Y, Wang Y, et al. Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source. N. Engl. J. Med. 2018;378:2191–2201.

      4. Diener H-C, Sacco RL, Easton JD, Granger CB, Bernstein RA, Uchiyama S, Kreuzer J, Cronin L, Cotton D, Grauer C, et al. Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source. N. Engl. J. Med. 2019;380:1906–1917.

      5. Mas J-L, Derumeaux G, Guillon B, Massardier E, Hosseini H, Mechtouff L, Arquizan C, Béjot Y, Vuillier F, Detante O, et al. Patent Foramen Ovale Closure or Anticoagulation vs. Antiplatelets after Stroke. N. Engl. J. Med. 2017;377:1011–1021.

      6. Søndergaard L, Kasner SE, Rhodes JF, Andersen G, Iversen HK, Nielsen-Kudsk JE, Settergren M, Sjöstrand C, Roine RO, Hildick-Smith D, et al. Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke. N. Engl. J. Med. 2017;377:1033–1042.

      7. Lee PH, Song J-K, Kim JS, Heo R, Lee S, Kim D-H, Song J-M, Kang D-H, Kwon SU, Kang D-W, et al. Cryptogenic Stroke and High-Risk Patent Foramen Ovale: The DEFENSE-PFO Trial. J. Am. Coll. Cardiol. 2018;71:2335–2342.

      8. Saver JL, Carroll JD, Thaler DE, Smalling RW, MacDonald LA, Marks DS, Tirschwell DL, RESPECT Investigators. Long-Term Outcomes of Patent Foramen Ovale Closure or Medical Therapy after Stroke. N. Engl. J. Med. 2017;377:1022–1032.

      9. Hart RG, Catanese L, Perera KS, Ntaios G, Connolly SJ. Embolic Stroke of Undetermined Source: A Systematic Review and Clinical Update. Stroke. 2017;48:867–872.

      10. Diener H-C, Easton JD, Hart RG, Kasner S, Kamel H, Ntaios G. Review and update of the concept of embolic stroke of undetermined source. Nat. Rev. Neurol. 2022;18:455–465.

      11. Perera KS, Vanassche T, Bosch J, Giruparajah M, Swaminathan B, Mattina KR, Berkowitz SD, Arauz A, O’Donnell MJ, Ameriso SF, et al. Embolic strokes of undetermined source: Prevalence and patient features in the ESUS Global Registry. Int. J. Stroke. 2016;11:526–533.

      12. Geisler T, Poli S, Meisner C, Schreieck J, Zuern CS, Nägele T, Brachmann J, Jung W, Gahn G, Schmid E, et al. Apixaban for treatment of embolic stroke of undetermined source (ATTICUS randomized trial): Rationale and study design. Int. J. Stroke. 2017;12:985–990.

      13. ESOC 2022 – Late Breaking Science, Ongoing Trials & Young Stroke Physicians and Researchers. European Stroke Journal. 2022;7:546–588.

      14. ESOC 2022 Abstract Book. European Stroke Journal. 2022;7:3–545.

      15. Rebchuk AD, O’Neill ZR, Szefer EK, Hill MD, Field TS. Health Utility Weighting of the Modified Rankin Scale: A Systematic Review and Meta-analysis. JAMA Netw Open. 2020;3:e203767.

      16. Perera, Sharma, Connolly, Wang. Stroke type and severity in patients with subclinical atrial fibrillation: an analysis from the Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients …. Am. Heart J. [Internet]. Available from:

      17. Perera KS, de Sa Boasquevisque D, Rao-Melacini P, Taylor A, Cheng A, Hankey GJ, Lee S, Fabregas JM, Ameriso SF, Field TS, et al. Evaluating Rates of Recurrent Ischemic Stroke Among Young Adults With Embolic Stroke of Undetermined Source: The Young ESUS Longitudinal Cohort Study. JAMA Neurol. 2022;79:450–458.

      18. Ntaios G, Pearce LA, Veltkamp R, Sharma M, Kasner SE, Korompoki E, Milionis H, Mundl H, Berkowitz SD, Connolly SJ, et al. Potential Embolic Sources and Outcomes in Embolic Stroke of Undetermined Source in the NAVIGATE-ESUS Trial. Stroke. 2020;51:1797–1804.

      19. Ntaios G, Perlepe K, Lambrou D, Sirimarco G, Strambo D, Eskandari A, Karagkiozi E, Vemmou A, Koroboki E, Manios E, et al. Prevalence and Overlap of Potential Embolic Sources in Patients With Embolic Stroke of Undetermined Source. J. Am. Heart Assoc. 2019;8:e012858.

      20. Hart RG, Veltkamp RC, Sheridan P, Sharma M, Kasner SE, Bangdiwala SI, Ntaios G, Shoamanesh A, Ameriso SF, Toni D, et al. Predictors of Recurrent Ischemic Stroke in Patients with Embolic Strokes of Undetermined Source and Effects of Rivaroxaban Versus Aspirin According to Risk Status: The NAVIGATE ESUS Trial. J. Stroke Cerebrovasc. Dis. 2019;28:2273–2279.

      21. Del Brutto VJ, Diener H-C, Easton JD, Granger CB, Cronin L, Kleine E, Grauer C, Brueckmann M, Toyoda K, Schellinger PD, et al. Predictors of Recurrent Stroke After Embolic Stroke of Undetermined Source in the RE-SPECT ESUS Trial. J. Am. Heart Assoc. 2022;11:e023545.

      22. Diener H-C, Chutinet A, Easton JD, Granger CB, Kleine E, Marquardt L, Meyerhoff J, Zini A, Sacco RL. Dabigatran or Aspirin After Embolic Stroke of Undetermined Source in Patients With Patent Foramen Ovale: Results From RE-SPECT ESUS. Stroke. 2021;52:1065–1068.

      23. Kamel H, Pearce LA, Ntaios G, Gladstone DJ, Perera K, Roine RO, Meseguer E, Shoamanesh A, Berkowitz SD, Mundl H, et al. Atrial Cardiopathy and Nonstenosing Large Artery Plaque in Patients With Embolic Stroke of Undetermined Source. Stroke. 2020;51:938–943.

      24. Ntaios G, Swaminathan B, Berkowitz SD, Gagliardi RJ, Lang W, Siegler JE, Lavados P, Mundl H, Bornstein N, Meseguer E, et al. Efficacy and Safety of Rivaroxaban Versus Aspirin in Embolic Stroke of Undetermined Source and Carotid Atherosclerosis. Stroke. 2019;50:2477–2485.

      25. Ameriso SF, Amarenco P, Pearce LA, Perera KS, Ntaios G, Lang W, Bereczki D, Uchiyama S, Kasner SE, Yoon B-W, et al. Intracranial and systemic atherosclerosis in the NAVIGATE ESUS trial: Recurrent stroke risk and response to antithrombotic therapy. J. Stroke Cerebrovasc. Dis. 2020;29:104936.

      26. Ntaios G, Pearce LA, Meseguer E, Endres M, Amarenco P, Ozturk S, Lang W, Bornstein NM, Molina CA, Pagola J, et al. Aortic Arch Atherosclerosis in Patients With Embolic Stroke of Undetermined Source: An Exploratory Analysis of the NAVIGATE ESUS Trial. Stroke. 2019;50:3184–3190.

      27. Uchiyama S, Toyoda K, Kitagawa K, Okada Y, Ameriso S, Mundl H, Berkowitz S, Yamada T, Liu YY, Hart RG, et al. Branch atheromatous disease diagnosed as embolic stroke of undetermined source: A sub-analysis of NAVIGATE ESUS. Int. J. Stroke. 2019;14:915–922.

      28. Katsanos AH, Hart RG. New Horizons in Pharmacologic Therapy for Secondary Stroke Prevention. JAMA Neurol. 2020;77:1308–1317.

      29. Studying Anakinra to Reduce Secondary Brain Damage After Spontaneous Haemorrhagic Stroke - Full Text View - ClinicalTrials.Gov [Internet]. [cited 2022 Oct 4];Available from:

      30. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin. Proc. 1984;59:17–20.

      31. Meissner I, Whisnant JP, Khandheria BK, Spittell PC, O’Fallon WM, Pascoe RD, Enriquez-Sarano M, Seward JB, Covalt JL, Sicks JD, et al. Prevalence of Potential Risk Factors for Stroke Assessed by Transesophageal Echocardiography and Carotid Ultrasonography: The SPARC Study. Mayo Clin. Proc. 1999;74:862–869.

      32. Kent DM, Ruthazer R, Weimar C, Mas J-L, Serena J, Homma S, Di Angelantonio E, Di Tullio MR, Lutz JS, Elkind MSV, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology. 2013;81:619–625.

      33. Kasner SE, Swaminathan B, Lavados P, Sharma M, Muir K, Veltkamp R, Ameriso SF, Endres M, Lutsep H, Messé SR, et al. Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial. Lancet Neurol. 2018;17:1053–1060.

      34. Fuentes B, Gutiérrez-Zúñiga R, Díez-Tejedor E. It’s Time to Say Goodbye to the ESUS Construct. Front. Neurol. 2020;11:653.

      35. Paciaroni M, Kamel H. Do the Results of RE-SPECT ESUS Call for a Revision of the Embolic Stroke of Undetermined Source Definition? Stroke. 2019;50:1032–1033.

      36. Mazzucco S, Li L, Rothwell PM. Prognosis of Cryptogenic Stroke With Patent Foramen Ovale at Older Ages and Implications for Trials: A Population-Based Study and Systematic Review. JAMA Neurol. 2020;77:1279–1287.

      37. Abo-Salem E, Chaitman B, Helmy T, Boakye EA, Alkhawam H, Lim M. Patent foramen ovale closure versus medical therapy in cases with cryptogenic stroke, meta-analysis of randomized controlled trials. J. Neurol. 2018;265:578–585.

      38. Turc G, Calvet D, Guérin P, Sroussi M, Chatellier G, Mas J-L, CLOSE Investigators. Closure, Anticoagulation, or Antiplatelet Therapy for Cryptogenic Stroke With Patent Foramen Ovale: Systematic Review of Randomized Trials, Sequential Meta-Analysis, and New Insights From the CLOSE Study. J. Am. Heart Assoc. [Internet]. 2018;7. Available from:

      39. Navi BB, Kasner SE, Elkind MSV, Cushman M, Bang OY, DeAngelis LM. Cancer and Embolic Stroke of Undetermined Source. Stroke. 2021;52:1121–1130.

      40. Martinez-Majander N, Ntaios G, Liu YY, Ylikotila P, Joensuu H, Saarinen J, Perera KS, Marti-Fabregas J, Chamorro A, Rudilosso S, et al. Rivaroxaban versus aspirin for secondary prevention of ischaemic stroke in patients with cancer: a subgroup analysis of the NAVIGATE ESUS randomized trial. Eur. J. Neurol. 2020;27:841–848.

      41. Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N. Engl. J. Med. 2018;378:615–624.

      42. Agnelli G, Becattini C, Meyer G, Muñoz A, Huisman MV, Connors JM, Cohen A, Bauersachs R, Brenner B, Torbicki A, et al. Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. N. Engl. J. Med. 2020;382:1599–1607.

      43. Edoxaban for the Treatment of Coagulopathy in Patients With Active Cancer and Acute Ischemic Stroke: A Pilot Study. (ENCHASE Study) - Full Text View - ClinicalTrials.Gov [Internet]. [cited 2022 Oct 4];Available from:

      44. Hays AG, Sacco RL, Rundek T, Sciacca RR, Jin Z, Liu R, Homma S, Di Tullio MR. Left ventricular systolic dysfunction and the risk of ischemic stroke in a multiethnic population. Stroke. 2006;37:1715–1719.

      45. Ramasamy S, Yaghi S, Salehi Omran S, Lerario MP, Devereux R, Okin PM, Gupta A, Navi BB, Kamel H, Merkler AE. Association Between Left Ventricular Ejection Fraction, Wall Motion Abnormality, and Embolic Stroke of Undetermined Source. J. Am. Heart Assoc. 2019;8:e011593.

      46. Homma S, Thompson JLP, Pullicino PM, Levin B, Freudenberger RS, Teerlink JR, Ammon SE, Graham S, Sacco RL, Mann DL, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. N. Engl. J. Med. 2012;366:1859–1869.

      47. Reddin C, Judge C, Loughlin E, Murphy R, Costello M, Alvarez A, Ferguson J, Smyth A, Canavan M, O’Donnell MJ. Association of Oral Anticoagulation With Stroke in Atrial Fibrillation or Heart Failure: A Comparative Meta-Analysis. Stroke. 2021;52:3151–3162.

      48. Vanassche T, Lauw MN, Eikelboom JW, Healey JS, Hart RG, Alings M, Avezum A, Díaz R, Hohnloser SH, Lewis BS, et al. Risk of ischaemic stroke according to pattern of atrial fibrillation: analysis of 6563 aspirin-treated patients in ACTIVE-A and AVERROES. Eur. Heart J. 2015;36:281–7a.

      49. Singer DE, Ziegler PD, Koehler JL, Sarkar S, Passman RS. Temporal Association Between Episodes of Atrial Fibrillation and Risk of Ischemic Stroke. JAMA Cardiol. 2021;6:1364–1369.

      50. Kirchhof P, Camm AJ, Goette A, Brandes A, Eckardt L, Elvan A, Fetsch T, van Gelder IC, Haase D, Haegeli LM, et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N. Engl. J. Med. 2020;383:1305–1316.

      51. McIntyre WF, Wang J, Benz AP, Johnson L, Connolly SJ, Van Gelder IC, Lopes RD, Gold MR, Hohnloser SH, Lau CP, et al. Estimated incidence of previously undetected atrial fibrillation on a 14-day continuous electrocardiographic monitor and associated risk of stroke. Europace. 2022;24:1058–1064.

      52. Binici Z, Intzilakis T, Nielsen OW, Køber L, Sajadieh A. Excessive supraventricular ectopic activity and increased risk of atrial fibrillation and stroke. Circulation. 2010;121:1904–1911.

      53. Van Gelder IC, Healey JS, Crijns HJGM, Wang J, Hohnloser SH, Gold MR, Capucci A, Lau C-P, Morillo CA, Hobbelt AH, et al. Duration of device-detected subclinical atrial fibrillation and occurrence of stroke in ASSERT. Eur. Heart J. 2017;38:1339–1344.

      54. Daoud EG, Glotzer TV, Wyse DG, Ezekowitz MD, Hilker C, Koehler J, Ziegler PD, TRENDS Investigators. Temporal relationship of atrial tachyarrhythmias, cerebrovascular events, and systemic emboli based on stored device data: a subgroup analysis of TRENDS. Heart Rhythm. 2011;8:1416–1423.

      55. Brambatti M, Connolly SJ, Gold MR, Morillo CA, Capucci A, Muto C, Lau CP, Van Gelder IC, Hohnloser SH, Carlson M, et al. Temporal relationship between subclinical atrial fibrillation and embolic events. Circulation. 2014;129:2094–2099.

      56. Martin DT, Bersohn MM, Waldo AL, Wathen MS, Choucair WK, Lip GYH, Ip J, Holcomb R, Akar JG, Halperin JL, et al. Randomized trial of atrial arrhythmia monitoring to guide anticoagulation in patients with implanted defibrillator and cardiac resynchronization devices. Eur. Heart J. 2015;36:1660–1668.

      57. Sub-Clinical Atrial Fibrillation Biomarker Study - Full Text View - [Internet]. [cited 2022 Oct 3];Available from:

      58. Non-vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes - Full Text View - ClinicalTrials.Gov [Internet]. [cited 2022 Oct 4];Available from:

      59. MidregiOnal Proatrial Natriuretic Peptide to Guide SEcondary Stroke Prevention - Full Text View - [Internet]. [cited 2022 Oct 4];Available from:

      60. AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke - Full Text View - ClinicalTrials.Gov [Internet]. [cited 2022 Oct 4];Available from:

      61. Healey JS, Gladstone DJ, Swaminathan B, Eckstein J, Mundl H, Epstein AE, Haeusler KG, Mikulik R, Kasner SE, Toni D, et al. Recurrent Stroke With Rivaroxaban Compared With Aspirin According to Predictors of Atrial Fibrillation: Secondary Analysis of the NAVIGATE ESUS Randomized Clinical Trial. JAMA Neurol. 2019;76:764–773.

      62. Hart RG, Sharma M, Mundl H, Shoamanesh A, Kasner SE, Berkowitz SD, Pare G, Kirsch B, Pogue J, Pater C, et al. Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: Design of the NAVIGATE ESUS randomized trial. Eur Stroke J. 2016;1:146–154.

      63. Diener H-C, Easton JD, Granger CB, Cronin L, Duffy C, Cotton D, Brueckmann M, Sacco RL, RE-SPECT ESUS Investigators. Design of Randomized, double-blind, Evaluation in secondary Stroke Prevention comparing the EfficaCy and safety of the oral Thrombin inhibitor dabigatran etexilate vs. acetylsalicylic acid in patients with Embolic Stroke of Undetermined Source (RE-SPECT ESUS). Int. J. Stroke. 2015;10:1309–1312.

      64. Bahit MC, Sacco RL, Easton JD, Meyerhoff J, Cronin L, Kleine E, Grauer C, Brueckmann M, Diener H-C, Lopes RD, et al. Predictors of Atrial Fibrillation Development in Patients With Embolic Stroke of Undetermined Source: An Analysis of the RE-SPECT ESUS Trial. Circulation. 2021;144:1738–1746.

      65. Kishore AK, Hossain MJ, Cameron A, Dawson J, Vail A, Smith CJ. Use of risk scores for predicting new atrial fibrillation after ischemic stroke or transient ischemic attack-A systematic review. Int. J. Stroke. 2022;17:608–617.

      66. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann. Intern. Med. 2007;146:857–867.

      67. Gladstone DJ, Spring M, Dorian P, Panzov V, Thorpe KE, Hall J, Vaid H, O’Donnell M, Laupacis A, Côté R, et al. Atrial fibrillation in patients with cryptogenic stroke. N. Engl. J. Med. 2014;370:2467–2477.

      68. Sanna T, Diener H-C, Passman RS, Di Lazzaro V, Bernstein RA, Morillo CA, Rymer MM, Thijs V, Rogers T, Beckers F, et al. Cryptogenic stroke and underlying atrial fibrillation. N. Engl. J. Med. 2014;370:2478–2486.

      69. Bernstein RA, Kamel H, Granger CB, Piccini JP, Sethi PP, Katz JM, Vives CA, Ziegler PD, Franco NC, Schwamm LH, et al. Effect of Long-term Continuous Cardiac Monitoring vs Usual Care on Detection of Atrial Fibrillation in Patients With Stroke Attributed to Large- or Small-Vessel Disease: The STROKE-AF Randomized Clinical Trial. JAMA. 2021;325:2169–2177.

      70. Buck BH, Hill MD, Quinn FR, Butcher KS, Menon BK, Gulamhusein S, Siddiqui M, Coutts SB, Jeerakathil T, Smith EE, et al. Effect of Implantable vs Prolonged External Electrocardiographic Monitoring on Atrial Fibrillation Detection in Patients With Ischemic Stroke: The PER DIEM Randomized Clinical Trial. JAMA. 2021;325:2160–2168.

      71. Wein T, Lindsay MP, Côté R, Foley N, Berlingieri J, Bhogal S, Bourgoin A, Buck BH, Cox J, Davidson D, et al. Canadian stroke best practice recommendations: Secondary prevention of stroke, sixth edition practice guidelines, update 2017. Int. J. Stroke. 2018;13:420–443.

      72. Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, Fang MC, Fisher M, Furie KL, Heck DV, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:2160–2236.

      73. Yong JHE, Thavorn K, Hoch JS, Mamdani M, Thorpe KE, Dorian P, Sharma M, Laupacis A, Gladstone DJ, EMBRACE Steering Committee. Potential Cost-Effectiveness of Ambulatory Cardiac Rhythm Monitoring After Cryptogenic Stroke. Stroke. 2016;47:2380–2385.

      74. Ministry of Health. Cardiac Monitors for the Detection of Atrial Fibrillation Among Patients Diagnosed with a Cryptogenic Stroke [Internet]. [cited 2022 Oct 3];Available from:

      75. De Angelis G, Cimon K, Sinclair A, Farrah K, Cairns J, Baranchuk A, Cipriano LE, Akhtar AO, Weeks L, Rader T, et al. Monitoring for Atrial Fibrillation in Discharged Stroke and Transient Ischemic Attack Patients: Recommendations. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2016.

      76. Svendsen JH, Diederichsen SZ, Højberg S, Krieger DW, Graff C, Kronborg C, Olesen MS, Nielsen JB, Holst AG, Brandes A, et al. Implantable loop recorder detection of atrial fibrillation to prevent stroke (The LOOP Study): a randomised controlled trial. Lancet. 2021;398:1507–1516.

      77. Sposato LA, Chaturvedi S, Hsieh C-Y, Morillo CA, Kamel H. Atrial Fibrillation Detected After Stroke and Transient Ischemic Attack: A Novel Clinical Concept Challenging Current Views. Stroke. 2022;53:e94–e103.

      78. Fridman S, Jimenez-Ruiz A, Vargas-Gonzalez JC, Sposato LA. Differences between Atrial Fibrillation Detected before and after Stroke and TIA: A Systematic Review and Meta-Analysis. Cerebrovasc. Dis. 2022;51:152–157.

      79. Zhang K, Kamtchum-Tatuene J, Li M, Jickling GC. Cardiac natriuretic peptides for diagnosis of covert atrial fibrillation after acute ischaemic stroke: a meta-analysis of diagnostic accuracy studies. Stroke Vasc Neurol. 2021;6:128–132.

      80. Noubiap JJ, Agbaedeng TA, Kamtchum-Tatuene J, Fitzgerald JL, Middeldorp ME, Kleinig T, Sanders P. Rhythm monitoring strategies for atrial fibrillation detection in patients with cryptogenic stroke: A systematic review and meta-analysis. Int J Cardiol Heart Vasc. 2021;34:100780.

      81. Tao Y, Xu J, Gong X, Sun J, Yang D. Premature atrial complexes can predict atrial fibrillation in ischemic stroke patients: A systematic review and meta-analysis. Pacing Clin. Electrophysiol. 2021;44:1599–1606.

      82. Scheitz JF, Sposato LA, Schulz-Menger J, Nolte CH, Backs J, Endres M. Stroke-Heart Syndrome: Recent Advances and Challenges. J. Am. Heart Assoc. 2022;11:e026528.

      83. Tsivgoulis G, Triantafyllou S, Palaiodimou L, Grory BM, Deftereos S, Köhrmann M, Dilaveris P, Ricci B, Tsioufis K, Cutting S, et al. Prolonged Cardiac Monitoring and Stroke Recurrence: A Meta-analysis. Neurology. 2022;98:e1942–e1952.

      84. Aguilar M, Macle L, Deyell MW, Yao R, Hawkins NM, Khairy P, Andrade JG. Influence of Monitoring Strategy on Assessment of Ablation Success and Postablation Atrial Fibrillation Burden Assessment: Implications for Practice and Clinical Trial Design. Circulation. 2022;145:21–30.

      85. Piccini JP, Caso V, Connolly SJ, Fox KAA, Oldgren J, Jones WS, Gorog DA, Durdil V, Viethen T, Neumann C, et al. Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study. Lancet. 2022;399:1383–1390.

      86. Gladstone DJ, Lindsay MP, Douketis J, Smith EE, Dowlatshahi D, Wein T, Bourgoin A, Cox J, Falconer JB, Graham BR, et al. Canadian Stroke Best Practice Recommendations: Secondary Prevention of Stroke Update 2020. Can. J. Neurol. Sci. 2022;49:315–337.

      87. Boulanger JM, Lindsay MP, Gubitz G, Smith EE, Stotts G, Foley N, Bhogal S, Boyle K, Braun L, Goddard T, et al. Canadian Stroke Best Practice Recommendations for Acute Stroke Management: Prehospital, Emergency Department, and Acute Inpatient Stroke Care, 6th Edition, Update 2018. Int. J. Stroke. 2018;13:949–984.

      88. Teasell R, Salbach NM, Foley N, Mountain A, Cameron JI, Jong A de, Acerra NE, Bastasi D, Carter SL, Fung J, et al. Canadian Stroke Best Practice Recommendations: Rehabilitation, Recovery, and Community Participation following Stroke. Part One: Rehabilitation and Recovery Following Stroke; 6th Edition Update 2019. Int. J. Stroke. 2020;15:763–788.

      89. Spence JD, Eliasziw M, DiCicco M, Hackam DG, Galil R, Lohmann T. Carotid plaque area: a tool for targeting and evaluating vascular preventive therapy. Stroke. 2002;33:2916–2922.

      90. Baradaran H, Eisenmenger LB, Hinckley PJ, de Havenon AH, Stoddard GJ, Treiman LS, Treiman GS, Parker DL, Scott McNally J. Optimal Carotid Plaque Features on Computed Tomography Angiography Associated With Ischemic Stroke. J. Am. Heart Assoc. 2021;10:e019462.

      91. Gao S, Wong KS, Hansberg T, Lam WWM, Droste DW, Ringelstein EB. Microembolic signal predicts recurrent cerebral ischemic events in acute stroke patients with middle cerebral artery stenosis. Stroke. 2004;35:2832–2836.

      92. Markus HS, King A, Shipley M, Topakian R, Cullinane M, Reihill S, Bornstein NM, Schaafsma A. Asymptomatic embolisation for prediction of stroke in the Asymptomatic Carotid Emboli Study (ACES): a prospective observational study. Lancet Neurol. 2010;9:663–671.

      93. Bhat A, Mahajan V, Chen HHL, Gan GCH, Pontes-Neto OM, Tan TC. Embolic Stroke of Undetermined Source: Approaches in Risk Stratification for Cardioembolism. Stroke. 2021;52:e820–e836.

      94. Romero J, Husain SA, Kelesidis I, Sanz J, Medina HM, Garcia MJ. Detection of Left Atrial Appendage Thrombus by Cardiac Computed Tomography in Patients With Atrial Fibrillation. Circ. Cardiovasc. Imaging. 2013;6:185–194.

      95. Barnea R, Agmon IN, Shafir G, Peretz S, Mendel R, Naftali J, Shiyovich A, Kornowski R, Auriel E, Hamdan A, et al. Cardiac CT for intra-cardiac thrombus detection in embolic stroke of undetermined source (ESUS). Eur Stroke J. 2022;7:212–220.

      96. Rinkel LA, Guglielmi V, Beemsterboer CFP, Groeneveld N-S, Lobé NHJ, Boekholdt SM, Bouma BJ, Muller FF, Beenen LFM, Marquering HA, et al. Diagnostic Yield of ECG-Gated Cardiac CT in theAcute Phase of Ischemic Stroke vsTransthoracic Echocardiography. Neurology. 2022;99:e1456–e1464.

      97. Stafford MB, Bagley JE, DiGiacinto D. Comparison of Transthoracic Echocardiography, Transesophageal Echocardiography, and Transcranial Doppler in the Detection of Patent Foramen Ovale as the Etiology for Cryptogenic Stroke. J. Diagn. Med. Sonogr. 2019;35:127–133.

      98. Field TS, Hill MD. Prevention of deep vein thrombosis and pulmonary embolism in patients with stroke. Clin. Appl. Thromb. Hemost. 2012;18:5–19.

      99. Berthet K, Lavergne T, Cohen A, Guize L, Bousser MG, Le Heuzey JY, Amarenco P. Significant association of atrial vulnerability with atrial septal abnormalities in young patients with ischemic stroke of unknown cause. Stroke. 2000;31:398–403.

      100. Rioux B, Keezer MR, Gioia LC. Occult cancer diagnosed following acute ischemic stroke. CMAJ. 2020;192:E1037–E1039.

      101. Rioux B, Touma L, Nehme A, Gore G, Keezer MR, Gioia LC. Frequency and predictors of occult cancer in ischemic stroke: A systematic review and meta-analysis. Int. J. Stroke. 2021;16:12–19.

      102. Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X, Cui L, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N. Engl. J. Med. 2013;369:11–19.

      103. 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.

      104. Johnston SC, Amarenco P, Denison H, Evans SR, Himmelmann A, James S, Knutsson M, Ladenvall P, Molina CA, Wang Y, et al. Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA. N. Engl. J. Med. 2020;383:207–217.

      105. Wang Y, Meng X, Wang A, Xie X, Pan Y, Johnston SC, Li H, Bath PM, Dong Q, Xu A, et al. Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA. N. Engl. J. Med. 2021;385:2520–2530.

      106. Johnston SC, Elm JJ, Easton JD, Farrant M, Barsan WG, Kim AS, Lindblad AS, Palesch YY, Zurita KG, Albers GW, et al. Time Course for Benefit and Risk of Clopidogrel and Aspirin After Acute Transient Ischemic Attack and Minor Ischemic Stroke. Circulation. 2019;140:658–664.

      107. Andrade JG, Aguilar M, Atzema C, Bell A, Cairns JA, Cheung CC, Cox JL, Dorian P, Gladstone DJ, Healey JS, et al. The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society Comprehensive Guidelines for the Management of Atrial Fibrillation. Can. J. Cardiol. 2020;36:1847–1948.

      108. Paciaroni M, Caso V, Agnelli G, Mosconi MG, Giustozzi M, Seiffge DJ, Engelter ST, Lyrer P, Polymeris AA, Kriemler L, et al. Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study. Stroke. 2022;53:2620–2627.

      109. Yaghi S, Henninger N, Giles JA, Leon Guerrero C, Mistry E, Liberman AL, Asad D, Liu A, Nagy M, Kaushal A, et al. Ischaemic stroke on anticoagulation therapy and early recurrence in acute cardioembolic stroke: the IAC study. J. Neurol. Neurosurg. Psychiatry. 2021;92:1062–1067.

      110. Tanaka K, Koga M, Lee K-J, Kim BJ, Park EL, Lee J, Mizoguchi T, Yoshimura S, Cha J-K, Lee B-C, et al. Atrial Fibrillation-Associated Ischemic Stroke Patients With Prior Anticoagulation Have Higher Risk for Recurrent Stroke. Stroke. 2020;51:1150–1157.

      111. Seiffge DJ, De Marchis GM, Koga M, Paciaroni M, Wilson D, Cappellari M, Macha Md K, Tsivgoulis G, Ambler G, Arihiro S, et al. Ischemic Stroke despite Oral Anticoagulant Therapy in Patients with Atrial Fibrillation. Ann. Neurol. [Internet]. 2020;Available from:

      112. Correction to: Atrial Fibrillation-Associated Ischemic Stroke Patients With Prior Anticoagulation Have Higher Risk for Recurrent Stroke. Stroke. 2020;51:e99.

      113. Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol. 2013;12:483–497.