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Management of Embolic Stroke of Undetermined Source (ESUS)

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Abstract

According to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification, embolic stroke of undetermined source (ESUS) has refined the old definition of cryptogenic stroke. More sophisticated criteria and a well-defined diagnostic workup point out the embolic nature of this disease. Because ESUS is associated with a high stroke recurrence, a clear risk prediction and management is of utmost importance to improve prognosis. To date, standard pharmacotherapy consists of antiplatelet drugs and statins. This review attempts to provide an overview on the diagnostic criteria, prognosis, and current clinical trials evaluating the value of direct oral anticoagulants for secondary prevention after ESUS.

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References

  1. Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O’Donnell MJ, Cryptogenic Stroke/ESUS International Working Group, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol. 2014;13:429–38.

    Article  PubMed  Google Scholar 

  2. Perera KS, Vanassche T, Bosch J, Giruparajah M, Swaminathan B, Mattina KR, ESUS Global Registry Investigators, et al. Embolic strokes of undetermined source: prevalence and patient features in the ESUS Global Registry. Int J Stroke. 2016;11(5):526–33.

    Article  PubMed  Google Scholar 

  3. Hart RG, Catanese L, Perera KS, Ntaios G, Connolly SJ. Embolic stroke of undetermined source: a systematic review and clinical update. Stroke. 2017;48(4):867–72.

    Article  PubMed  Google Scholar 

  4. Martinez-Majander N, Aarnio K, Pirinen J, Lumikari T, Nieminen T, Lehto M, et al. Embolic strokes of undetermined source in young adults: baseline characteristics and long-term outcome. Eur J Neurol. 2018;25(3):535–41.

    Article  PubMed  CAS  Google Scholar 

  5. Perera KS, Swaminathan B, Veltkamp R, Arauz A, Ameriso S, Marti-Fabregas J, et al. Frequency and features of embolic stroke of undetermined source in young adults. Eur Stroke J. 2018;3(2):110–6.

    Article  Google Scholar 

  6. Grau AJ, Weimar C, Buggle F, Heinrich A, Goertler M, Neumaier S, et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke. 2001;32(11):2559–66.

    Article  PubMed  CAS  Google Scholar 

  7. Ntaios G, Vemmos K, Lip GY, Koroboki E, Manios E, Vemmou A, et al. Risk stratification for recurrence and mortality in embolic stroke of undetermined source. Stroke. 2016;47(9):2278–85.

    Article  PubMed  Google Scholar 

  8. Bal S, Patel SK, Almekhlafi M, Modi J, Demchuk AM, Coutts SB. High rate of magnetic resonance imaging stroke recurrence in cryptogenic transient ischemic attack and minor stroke patients. Stroke. 2012;43(12):3387–8.

    Article  PubMed  Google Scholar 

  9. Kang DW, Lattimore SU, Latour LL, Warach S. Silent ischemic lesion recurrence on magnetic resonance imaging predicts subsequent clinical vascular events. Arch Neurol. 2006;63(12):1730–3.

    Article  PubMed  Google Scholar 

  10. Gioia LC, Tollard É, Dubuc V, Lanthier S, Deschaintre Y, Chagnon M, et al. Silent ischemic lesions in young adults with first stroke are associated with recurrent stroke. Neurology. 2012;79(12):1208–14.

    Article  PubMed  Google Scholar 

  11. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med. 2003;348(13):1215–22.

    Article  PubMed  Google Scholar 

  12. Friberg L, Rosenqvist M, Lindgren A, Terént A, Norrving B, Asplund K. High prevalence of atrial fibrillation among patients with ischemic stroke. Stroke. 2014;45(9):2599–605.

    Article  PubMed  CAS  Google Scholar 

  13. Seet RC, Zhang Y, Wijdicks EF, Rabinstein AA. Relationship between chronic atrial fibrillation and worse outcomes in stroke patients after intravenous thrombolysis. Arch Neurol. 2011;68(11):1454–8.

    Article  PubMed  Google Scholar 

  14. Yoo J, Song D, Baek JH, Kim YD, Nam HS, Hong GR, et al. Poor outcome of stroke patients with atrial fibrillation in the presence of coexisting spontaneous echo contrast. Stroke. 2016;47(7):1920–2.

    Article  PubMed  Google Scholar 

  15. Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA, Morillo CA, CRYSTAL AF Investigators, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. 2014;370(26):2478–86.

    Article  PubMed  CAS  Google Scholar 

  16. Gladstone DJ, Spring M, Dorian P, et al. Cryptogenic stroke and atrial fibrillation. N Engl J Med. 2014;370:2467–77.

    Article  PubMed  CAS  Google Scholar 

  17. Sposato LA, Cipriano LE, Saposnik G, Ruíz Vargas E, Riccio PM, Hachinski V. Diagnosis of atrial fibrillation after stroke and transient ischaemic attack: a systematic review and meta-analysis. Lancet Neurol. 2015;14(4):377–87.

    Article  PubMed  Google Scholar 

  18. Wachter R, Gröschel K, Gelbrich G, Hamann GF, Kermer P, Liman J, Find-AF(randomised) Investigators and Coordinators, et al. Holter-electrocardiogram-monitoring in patients with acute ischaemic stroke (Find-AFRANDOMISED): an open-label randomised controlled trial. Lancet Neurol. 2017;16(4):282–90.

    Article  PubMed  Google Scholar 

  19. Haeusler KG, Kirchhof P, Heuschmann PU, Laufs U, Busse O, Kunze C, et al. Impact of standardized MONitoring for Detection of Atrial Fibrillation in Ischemic Stroke (MonDAFIS): rationale and design of a prospective randomized multicenter study. Am Heart J. 2016;172:19–25.

    Article  PubMed  Google Scholar 

  20. Thijs VN, Brachmann J, Morillo CA, Passman RS, Sanna T, Bernstein RA, et al. Predictors for atrial fibrillation detection after cryptogenic stroke: results from CRYSTAL AF. Neurology. 2016;86(3):261–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Hoshino T, Nagao T, Shiga T, Maruyama K, Toi S, Mizuno S, et al. Prolonged QTc interval predicts poststroke paroxysmal atrial fibrillation. Stroke. 2015;46(1):71–6.

    Article  PubMed  Google Scholar 

  22. Gladstone DJ, Dorian P, Spring M, Panzov V, Mamdani M, Healey JS, et al. Atrial premature beats predict atrial fibrillation in cryptogenic stroke: results from the EMBRACE trial. Stroke. 2015;46(4):936–41.

    Article  PubMed  Google Scholar 

  23. Poli S, Diedler J, Härtig F, Götz N, Bauer A, Sachse T, et al. Insertable cardiac monitors after cryptogenic stroke—a risk factor based approach to enhance the detection rate for paroxysmal atrial fibrillation. Eur J Neurol. 2016;23(2):375–81.

    Article  PubMed  CAS  Google Scholar 

  24. Kamel H, O’Neal WT, Okin PM, Loehr LR, Alonso A, Soliman EZ. Electrocardiographic left atrial abnormality and stroke subtype in the atherosclerosis risk in communities study. Ann Neurol. 2015;78(5):670–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Yaghi S, Song C, Gray WA, Furie KL, Elkind MS, Kamel H. Left atrial appendage function and stroke risk. Stroke. 2015;46(12):3554–9.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Van Gelder IC, Healey JS, Crijns HJGM, Wang J, Hohnloser SH, Gold MR, et al. Duration of device-detected subclinical atrial fibrillation and occurrence of stroke in ASSERT. Eur Heart J. 2017;38(17):1339–44.

    Article  PubMed  Google Scholar 

  27. Geisler T, Poli S, Meisner C, Schreieck J, Zuern CS, Nägele T, et al. Apixaban for treatment of embolic stroke of undetermined source (ATTICUS randomized trial): rationale and study design. Int J Stroke. 2017;12(9):985–90.

    Article  PubMed  Google Scholar 

  28. SPS3 Investigators, Benavente OR, Hart RG, McClure LA, Szychowski JM, Coffey CS, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012;367(9):817–25.

  29. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, et al. 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(9431):331–7.

    Article  PubMed  CAS  Google Scholar 

  30. Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369(1):11–9.

    Article  PubMed  CAS  Google Scholar 

  31. Pan Y, Jing J, Chen W, Meng X, Li H, Zhao X, et al. CHANCE investigators. Risks and benefits of clopidogrel-aspirin in minor stroke or TIA: time course analysis of CHANCE. Neurology. 2017;88(20):1906–11.

    Article  PubMed  CAS  Google Scholar 

  32. Johnston SC, Amarenco P, Albers GW, Denison H, Easton JD, Evans SR, SOCRATES Steering Committee and Investigators, et al. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J Med. 2016;375(1):35–43.

    Article  PubMed  CAS  Google Scholar 

  33. Amarenco P, Albers GW, Denison H, Easton JD, Evans SR, Held P, SOCRATES Steering Committee and Investigators, et al. Ticagrelor versus aspirin in acute embolic stroke of undetermined source. Stroke. 2017;48(9):2480–7.

    Article  PubMed  CAS  Google Scholar 

  34. Kim SK, Yoon W, Kim TS, Kim HS, Heo TW, Park MS. Histologic analysis of retrieved clots in acute ischemic stroke: correlation with stroke etiology and gradient-echo MRI. AJNR. 2015;36(9):1756–62.

    Article  PubMed  CAS  Google Scholar 

  35. Sacco RL, Prabhakaran S, Thompson JL, Murphy A, Sciacca RR, Levin B, WARSS Investigators, et al. Comparison of warfarin versus aspirin for the prevention of recurrent stroke or death: subgroup analyses from the Warfarin-Aspirin Recurrent Stroke Study. Cerebrovasc Dis. 2006;22(1):4–12.

    Article  PubMed  CAS  Google Scholar 

  36. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955–62.

    Article  PubMed  CAS  Google Scholar 

  37. Ntaios G, Papavasileiou V, Makaritsis K, Vemmos K, Michel P, Lip GYH. Real-world setting comparison of nonvitamin-K antagonist oral anticoagulants versus vitamin-k antagonists for stroke prevention in atrial fibrillation: a systematic review and meta-analysis. Stroke. 2017;48(9):2494–503.

    Article  PubMed  CAS  Google Scholar 

  38. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, ESC Scientific Document Group. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37(38):2893–962.

    Article  PubMed  Google Scholar 

  39. Diener HC, Eikelboom J, Connolly SJ, Joyner CD, Hart RG, Lip GY, AVERROES Steering Committee and Investigators, et al. Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial. Lancet Neurol. 2012;11(3):225–31.

    Article  PubMed  CAS  Google Scholar 

  40. Hankey GJ, Patel MR, Stevens SR, Becker RC, Breithardt G, Carolei A, ROCKET AF Steering Committee Investigators, et al. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol. 2012;11(4):315–22.

    Article  PubMed  CAS  Google Scholar 

  41. Diener HC, Connolly SJ, Ezekowitz MD, Wallentin L, Reilly PA, Yang S, RE-LY study group, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol. 2010;9(12):1157–63.

    Article  PubMed  CAS  Google Scholar 

  42. Easton JD, Lopes RD, Bahit MC, Wojdyla DM, Granger CB, Wallentin L, ARISTOTLE Committees and Investigators, et al. Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. Lancet Neurol. 2012;11(6):503–11.

    Article  PubMed  CAS  Google Scholar 

  43. Rost NS, Giugliano RP, Ruff CT, Murphy SA, Crompton AE, Norden AD, ENGAGE AF-TIMI 48 Investigators, et al. Outcomes with edoxaban versus warfarin in patients with previous cerebrovascular events: findings from ENGAGE AF-TIMI 48 (Effective anticoagulation with factor Xa next generation in atrial fibrillation thrombolysis in myocardial infarction 48). Stroke. 2016;47(8):2075–82.

    Article  PubMed  CAS  Google Scholar 

  44. Diener HC, Easton JD, Granger CB, Cronin L, Duffy C, Cotton D, RE-SPECT ESUS Investigators, et al. 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(8):1309–12.

    Article  PubMed  Google Scholar 

  45. Hart RG, Sharma M, Mundl H, Shoamanesh A, Kasner SE, Berkowitz SD, 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(3):146–54.

    Article  Google Scholar 

  46. O’Donnell MJ, Eikelboom JW, Yusuf S, Diener HC, Hart RG, Smith EE, et al. Effect of apixaban on brain infarction and microbleeds: AVERROES-MRI assessment study. Am Heart J. 2016;178:145–50.

    Article  PubMed  CAS  Google Scholar 

  47. Kent DM, Dahabreh IJ, Ruthazer R, Furlan AJ, Weimar C, Serena J, et al. Anticoagulant vs. antiplatelet therapy in patients with cryptogenic stroke and patent foramen ovale: an individual participant data meta-analysis. Eur Heart J. 2015;36(35):2381–9.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, 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;45:2160–236.

    Article  PubMed  Google Scholar 

  49. Mas JL, Arquizan C, Lamy C, Zuber M, Cabanes L, Derumeaux G, Patent Foramen Ovale and Atrial Septal Aneurysm Study Group, et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med. 2001;345(24):1740–6.

    Article  PubMed  CAS  Google Scholar 

  50. Mas JL, Derumeaux G, Guillon B, CLOSE Investigators. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med. 2017;377(11):1011–21.

    Article  PubMed  CAS  Google Scholar 

  51. Søndergaard L, Kasner SE, Rhodes JF, Andersen G, Iversen HK, Nielsen-Kudsk JE, Gore REDUCE Clinical Study Investigators, et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med. 2017;377(11):1033–42.

    Article  PubMed  Google Scholar 

  52. Saver JL, Carroll JD, Thaler DE, Smalling RW, MacDonald LA, Marks DS, RESPECT Investigators, et al. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med. 2017;377(11):1022–32.

    Article  PubMed  Google Scholar 

  53. Amarenco P, Bogousslavsky J, Caplan LR, Donnan GA, Wolf ME, Hennerici MG. The ASCOD phenotyping of ischemic stroke (updated ASCO phenotyping). Cerebrovasc Dis. 2013;36:1–5.

    Article  PubMed  CAS  Google Scholar 

  54. Ay H, Benner T, Arsava EM, Furie KL, Singhal AB, Jensen MB, et al. A computerized algorithm for etiologic classification of ischemic stroke: the Causative Classification of Stroke System. Stroke. 2007;38:2979–84.

    Article  PubMed  Google Scholar 

  55. Eckerle B, Massaro A. Lumpers or splitters: evaluation and management of embolic stroke of undetermined source. Neurology. 2016;87:972–3.

    Article  PubMed  Google Scholar 

  56. Dennis M. Embolic stroke of undetermined source: a therapeutic target? Lancet Neurol. 2014;13:344–6.

    Article  PubMed  Google Scholar 

  57. Katsanos AH, Bhole R, Frogoudaki A, Giannopoulos S, Goyal N, Vrettou AR, et al. The value of transesophageal echocardiography for embolic strokes of undetermined source. Neurology. 2016;87:988–95.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Cardiology, University Hospital Tübingen, Otfried-Müller-Straße 10, 72076, Tübingen, Germany

    Tobias Geisler

  2. Department of Neurology and Stroke, University Hospital Tübingen, Hoppe-Seyler-Straße 3, 72076, Tübingen, Germany

    Annerose Mengel, Ulf Ziemann & Sven Poli

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  1. Tobias Geisler
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Correspondence to Tobias Geisler.

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No external funding was used in the preparation of this manuscript.

Conflicts of interest

Tobias Geisler reports personal fees from AstraZeneca, Boehringer Ingelheim, Pfizer, and MSD; grants and personal fees from Bayer Healthcare, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, and The Medicines Company; and grants from Siemens Healthcare and Spartan Bioscience, outside the submitted work. Annerose Mengel has no conflicts of interest relevant to the presented work. Ulf Ziemann has received speaker honoraria and/or travel compensation from Bayer Vital GmbH, Biogen Idec GmbH, Bristol Myers Squibb GmbH, Medtronic GmbH, and Pfizer GmbH; and grants from Biogen Idec GmbH, Servier, and Janssen Pharmaceuticals NV. He serves on the advisory board of CorTec GmbH. None of the above are related to the submitted work. Sven Poli has received speaker’s honoraria and consulting honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo and Werfen; reimbursement for congress traveling and accommodation from Bayer and Boehringer Ingelheim; and research support from Bristol-Myers Squibb/Pfizer, Boehringer-Ingelheim, Daiichi Sankyo and Helena Laboratories. None of the above are related to the submitted work.

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Geisler, T., Mengel, A., Ziemann, U. et al. Management of Embolic Stroke of Undetermined Source (ESUS). Drugs 78, 823–831 (2018). https://doi.org/10.1007/s40265-018-0912-8

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