Semin Neurol 2021; 41(04): 348-364
DOI: 10.1055/s-0041-1726332
Review Article

Atrial Fibrillation and Ischemic Stroke: A Clinical Review

Ibrahim Migdady
1   Division of Neurocritical Care, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
,
Andrew Russman
2   Cerebrovascular Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio
,
Andrew B. Buletko
2   Cerebrovascular Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio
› Author Affiliations

Abstract

Atrial fibrillation (AF) is an important risk factor for ischemic stroke resulting in a fivefold increased stroke risk and a twofold increased mortality. Our understanding of stroke mechanisms in AF has evolved since the concept of atrial cardiopathy was introduced as an underlying pathological change, with both AF and thromboembolism being common manifestations and outcomes. Despite the strong association with stroke, there is no evidence that screening for AF in asymptomatic patients improves clinical outcomes; however, there is strong evidence that patients with embolic stroke of undetermined source may require long-term monitoring to detect silent or paroxysmal AF. Stroke prevention in patients at risk, assessed by the CHA2DS2-VASc score, was traditionally achieved with warfarin; however, direct oral anticoagulants have solidified their role as safe and effective alternatives. Additionally, left atrial appendage exclusion has emerged as a viable option in patients intolerant of anticoagulation. When patients with AF have an acute stroke, the timing of initiation or resumption of anticoagulation for secondary stroke prevention has to be balanced against the risk of hemorrhagic conversion. Multiple randomized clinical trials are currently underway to determine the best timing for administration of anticoagulants following acute ischemic stroke.



Publication History

Article published online:
13 April 2021

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  • References

  • 1 Benjamin EJ, Blaha MJ, Chiuve SE. et al. Heart Disease and Stroke Statistics-2017 Update: a report from the American Heart Association. Circulation 2017; 135 (10) e146-e603
  • 2 Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367 (9524): 1747-1757
  • 3 Katan M, Luft A. Global burden of stroke. Semin Neurol 2018; 38 (02) 208-211
  • 4 Chugh SS, Havmoeller R, Narayanan K. et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014; 129 (08) 837-847
  • 5 Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98 (10) 946-952
  • 6 Lubitz SA, Yin X, McManus DD. et al. Stroke as the initial manifestation of atrial fibrillation: the Framingham Heart Study. Stroke 2017; 48 (02) 490-492
  • 7 January CT, Wann LS, Alpert JS. et al; ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130 (23) 2071-2104
  • 8 El-Armouche A, Boknik P, Eschenhagen T. et al. Molecular determinants of altered Ca2+ handling in human chronic atrial fibrillation. Circulation 2006; 114 (07) 670-680
  • 9 Waks JW, Josephson ME. Mechanisms of atrial fibrillation - reentry, rotors and reality. Arrhythm Electrophysiol Rev 2014; 3 (02) 90-100
  • 10 Wallmüller C, Sterz F, Testori C. et al. Emergency cardio-pulmonary bypass in cardiac arrest: seventeen years of experience. Resuscitation 2013; 84 (03) 326-330
  • 11 Schnabel RB, Yin X, Gona P. et al. 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study. Lancet 2015; 386 (9989): 154-162
  • 12 Mehra R, Benjamin EJ, Shahar E. et al; Sleep Heart Health Study. Association of nocturnal arrhythmias with sleep-disordered breathing: the Sleep Heart Health Study. Am J Respir Crit Care Med 2006; 173 (08) 910-916
  • 13 Staerk L, Sherer JA, Ko D, Benjamin EJ, Helm RH. Atrial fibrillation: epidemiology, pathophysiology, and clinical outcomes. Circ Res 2017; 120 (09) 1501-1517
  • 14 Cai H, Li Z, Goette A. et al. Downregulation of endocardial nitric oxide synthase expression and nitric oxide production in atrial fibrillation: potential mechanisms for atrial thrombosis and stroke. Circulation 2002; 106 (22) 2854-2858
  • 15 Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 1997; 96 (04) 1180-1184
  • 16 Mihm MJ, Yu F, Carnes CA. et al. Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation 2001; 104 (02) 174-180
  • 17 Kamel H, Soliman EZ, Heckbert SR. et al. P-wave morphology and the risk of incident ischemic stroke in the Multi-Ethnic Study of Atherosclerosis. Stroke 2014; 45 (09) 2786-2788
  • 18 Yaghi S, Boehme AK, Hazan R. et al. Atrial cardiopathy and cryptogenic stroke: a cross-sectional pilot study. J Stroke Cerebrovasc Dis 2016; 25 (01) 110-114
  • 19 Sanna T, Diener HC, Passman RS. et al; CRYSTAL AF Investigators. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014; 370 (26) 2478-2486
  • 20 Kamel H, Okin PM, Longstreth Jr WT, Elkind MSV, Soliman EZ. Atrial cardiopathy: a broadened concept of left atrial thromboembolism beyond atrial fibrillation. Future Cardiol 2015; 11 (03) 323-331
  • 21 AtRial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke - Full Text View - ClinicalTrials.gov. Accessed January 3, 2020 at: https://clinicaltrials.gov/ct2/show/NCT03192215
  • 22 Fure B, Wyller TB, Thommessen B. TOAST criteria applied in acute ischemic stroke. Acta Neurol Scand 2005; 112 (04) 254-258
  • 23 Chung JW, Park SH, Kim N. et al. Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification and vascular territory of ischemic stroke lesions diagnosed by diffusion-weighted imaging. J Am Heart Assoc 2014; 3 (04) e001119
  • 24 Wessels T, Röttger C, Jauss M, Kaps M, Traupe H, Stolz E. Identification of embolic stroke patterns by diffusion-weighted MRI in clinically defined lacunar stroke syndromes. Stroke 2005; 36 (04) 757-761
  • 25 Adams Jr HP, Bendixen BH, Kappelle LJ. et al. 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 (01) 35-41
  • 26 Chen LY, Chung MK, Allen LA. et al; American Heart Association Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Quality of Care and Outcomes Research; and Stroke Council. atrial fibrillation burden: moving beyond atrial fibrillation as a binary entity: a scientific statement from the American Heart Association. Circulation 2018; 137 (20) e623-e644
  • 27 Steinberg JS, O'Connell H, Li S, Ziegler PD. Thirty-second gold standard definition of atrial fibrillation and its relationship with subsequent arrhythmia patterns: analysis of a large prospective device database. Circ Arrhythm Electrophysiol 2018; 11 (07) e006274
  • 28 Verma A, Champagne J, Sapp J. et al. Discerning the incidence of symptomatic and asymptomatic episodes of atrial fibrillation before and after catheter ablation (DISCERN AF): a prospective, multicenter study. JAMA Intern Med 2013; 173 (02) 149-156
  • 29 Steinberg JS, Varma N, Cygankiewicz I. et al. 2017 ISHNE-HRS expert consensus statement on ambulatory ECG and external cardiac monitoring/telemetry. Heart Rhythm 2017; 14 (07) e55-e96
  • 30 Curry SJ, Krist AH, Owens DK. et al; US Preventive Services Task Force. Screening for atrial fibrillation with electrocardiography: US preventive services task force recommendation statement. JAMA 2018; 320 (05) 478-484
  • 31 Steinhubl SR, Waalen J, Edwards AM. et al. Effect of a home-based wearable continuous ECG monitoring patch on detection of undiagnosed atrial fibrillation the mSToPS randomized clinical trial. JAMA 2018; 320 (02) 146-155
  • 32 Perez MV, Mahaffey KW, Hedlin H. et al; Apple Heart Study Investigators. Large-scale assessment of a smartwatch to identify atrial fibrillation. N Engl J Med 2019; 381 (20) 1909-1917
  • 33 Healey JS, Connolly SJ, Gold MR. et al; ASSERT Investigators. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012; 366 (02) 120-129
  • 34 Gladstone DJ, Spring M, Dorian P. et al; EMBRACE Investigators and Coordinators. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med 2014; 370 (26) 2467-2477
  • 35 January CT, Wann LS, Calkins H. et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74 (01) 104-132
  • 36 Hart RG, Catanese L, Perera KS, Ntaios G, Connolly SJ. Embolic stroke of undetermined source: a systematic review and clinical update. Stroke 2017; 48 (04) 867-872
  • 37 Hart RG, Diener HC, Coutts SB. et al; Cryptogenic Stroke/ESUS International Working Group. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13 (04) 429-438
  • 38 Kirchhof P, Benussi S, Kotecha D. et al; ESC Scientific Document Group. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016; 37 (38) 2893-2962
  • 39 Lip GYH, 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 (02) 263-272
  • 40 Friberg L, Rosenqvist M, Lip GYH. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33 (12) 1500-1510
  • 41 Hijazi Z, Wallentin L, Siegbahn A. et al. N-terminal pro-B-type natriuretic peptide for risk assessment in patients with atrial fibrillation: insights from the ARISTOTLE Trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation). J Am Coll Cardiol 2013; 61 (22) 2274-2284
  • 42 Masson P, Webster AC, Hong M, Turner R, Lindley RI, Craig JC. Chronic kidney disease and the risk of stroke: a systematic review and meta-analysis. Nephrol Dial Transplant 2015; 30 (07) 1162-1169
  • 43 Anders B, Alonso A, Artemis D. et al. What does elevated high-sensitive troponin I in stroke patients mean: concomitant acute myocardial infarction or a marker for high-risk patients?. Cerebrovasc Dis 2013; 36 (03) 211-217
  • 44 Vafaie M, Giannitsis E, Mueller-Hennessen M. et al. High-sensitivity cardiac troponin T as an independent predictor of stroke in patients admitted to an emergency department with atrial fibrillation. PLoS One 2019; 14 (02) e0212278
  • 45 Go AS, Reynolds K, Yang J. et al. Association of burden of atrial fibrillation with risk of ischemic stroke in adults with paroxysmal atrial fibrillation: the KP-RHYTHM study. JAMA Cardiol 2018; 3 (07) 601-608
  • 46 Chao TF, Lip GYH, Liu CJ. et al. Relationship of aging and incident comorbidities to stroke risk in patients with atrial fibrillation. J Am Coll Cardiol 2018; 71 (02) 122-132
  • 47 Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 1994; 343 (8899): 687-691
  • 48 Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet 1989; 1 (8631): 175-179
  • 49 Ezekowitz MD, Bridgers SL, James KE. et al; Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. N Engl J Med 1992; 327 (20) 1406-1412
  • 50 Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991; 18 (02) 349-355
  • 51 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 (12) 857-867
  • 52 Granger CB, Alexander JH, McMurray JJV. et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
  • 53 Connolly SJ, Ezekowitz MD, Yusuf S. et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
  • 54 Patel MR, Mahaffey KW, Garg J. et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
  • 55 Carnicelli AP, De Caterina R, Halperin JL. et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban for the prevention of thromboembolism in patients with atrial fibrillation and bioprosthetic valves. Circulation 2017; 135 (13) 1273-1275
  • 56 Ruff CT, Giugliano RP, Braunwald E. 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): 955-962
  • 57 Connolly SJ, Eikelboom J, Joyner C. et al; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364 (09) 806-817
  • 58 Poller L, Aronow WS, Karalis DG. et al. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 1991; 325 (02) 129-132
  • 59 Connolly SJ, Pogue J, Hart RG. et al; ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009; 360 (20) 2066-2078
  • 60 Connolly S, Pogue J, Hart R. et al; ACTIVE Writing Group of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367 (9526): 1903-1912
  • 61 Connolly SJ, Eikelboom JW, Ng J. et al; ACTIVE (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) Steering Committee and Investigators. Net clinical benefit of adding clopidogrel to aspirin therapy in patients with atrial fibrillation for whom vitamin K antagonists are unsuitable. Ann Intern Med 2011; 155 (09) 579-586
  • 62 Mac Grory B, Flood S, Schrag M, Paciaroni M, Yaghi S. Anticoagulation resumption after stroke from atrial fibrillation. Curr Atheroscler Rep 2019; 21 (08) 29
  • 63 Paciaroni M, Agnelli G, Micheli S, Caso V. Efficacy and safety of anticoagulant treatment in acute cardioembolic stroke: a meta-analysis of randomized controlled trials. Stroke 2007; 38 (02) 423-430
  • 64 Powers WJ, Rabinstein AA, Ackerson T. et al; 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. Stroke 2018; 49 (03) e46-e110
  • 65 Paciaroni M, Agnelli G, Falocci N. et al. Early recurrence and cerebral bleeding in patients with acute ischemic stroke and atrial fibrillation: effect of anticoagulation and its timing: the RAF study. Stroke 2015; 46 (08) 2175-2182
  • 66 Kirchhof P, Benussi S, Kotecha D. et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur J Cardiothorac Surg 2016; 50 (05) e1-e88
  • 67 Steffel J, Verhamme P, Potpara TS. et al; ESC Scientific Document Group. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018; 39 (16) 1330-1393
  • 68 Seiffge DJ, Werring DJ, Paciaroni M. et al. Timing of anticoagulation after recent ischaemic stroke in patients with atrial fibrillation. Lancet Neurol 2019; 18 (01) 117-126
  • 69 Li Y-g, Lip GYH. Anticoagulation resumption after intracerebral hemorrhage. Curr Atheroscler Rep 2018; 20 (07) 32
  • 70 Murthy SB, Gupta A, Merkler AE. et al. Restarting anticoagulant therapy after intracranial hemorrhage: a systematic review and meta-analysis. Stroke 2017; 48 (06) 1594-1600
  • 71 Halperin JL, Hart RG. Atrial fibrillation and stroke: new ideas, persisting dilemmas. Stroke 1988; 19 (08) 937-941
  • 72 Salem DN, O'Gara PT, Madias C, Pauker SG. Valvular and structural heart disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008; 133 (6, Suppl): 593S-629S
  • 73 Eikelboom JW, Connolly SJ, Brueckmann M. et al; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013; 369 (13) 1206-1214
  • 74 Go AS, Fang MC, Udaltsova N. et al; ATRIA Study Investigators. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation 2009; 119 (10) 1363-1369
  • 75 Zeng W-T, Sun X-T, Tang K. et al. Risk of thromboembolic events in atrial fibrillation with chronic kidney disease. Stroke 2015; 46 (01) 157-163
  • 76 Tomura S, Nakamura Y, Doi M. et al. Fibrinogen, coagulation factor VII, tissue plasminogen activator, plasminogen activator inhibitor-1, and lipid as cardiovascular risk factors in chronic hemodialysis and continuous ambulatory peritoneal dialysis patients. Am J Kidney Dis 1996; 27 (06) 848-854
  • 77 Reinecke H, Brand E, Mesters R. et al. Dilemmas in the management of atrial fibrillation in chronic kidney disease. J Am Soc Nephrol 2009; 20 (04) 705-711
  • 78 Shlipak MG, Fried LF, Crump C. et al. Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. Circulation 2003; 107 (01) 87-92
  • 79 Marinigh R, Lane DA, Lip GYH. Severe renal impairment and stroke prevention in atrial fibrillation: implications for thromboprophylaxis and bleeding risk. J Am Coll Cardiol 2011; 57 (12) 1339-1348
  • 80 Mavrakanas TA, Samer CF, Nessim SJ, Frisch G, Lipman ML. Apixaban pharmacokinetics at steady state in hemodialysis patients. J Am Soc Nephrol 2017; 28 (07) 2241-2248
  • 81 Levine GN, Bates ER, Bittl JA. et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016; 68 (10) 1082-1115
  • 82 Dewilde WJM, Oirbans T, Verheugt FWA. et al; WOEST Study Investigators. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013; 381 (9872): 1107-1115
  • 83 Lopes RD, Vora AN, Liaw D. et al. An open-Label, 2 × 2 factorial, randomized controlled trial to evaluate the safety of apixaban vs. vitamin K antagonist and aspirin vs. placebo in patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention: Rat. Am Heart J 2018; 200: 17-23
  • 84 Vranckx P, Valgimigli M, Eckardt L. et al. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial. Lancet 2019; 394 (10206): 1335-1343
  • 85 Cannon CP, Bhatt DL, Oldgren J. et al; RE-DUAL PCI Steering Committee and Investigators. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med 2017; 377 (16) 1513-1524
  • 86 Kerneis M, Gibson CM, Chi G. et al. Effect of procedure and coronary lesion characteristics on clinical outcomes among atrial fibrillation patients undergoing percutaneous coronary intervention: insights from the PIONEER AF-PCI trial. JACC Cardiovasc Interv 2018; 11 (07) 626-634
  • 87 Gibson CM, Mehran R, Bode C. et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016; 375 (25) 2423-2434
  • 88 Stoddard MF, Dawkins PR, Prince CR, Ammash NM. Left atrial appendage thrombus is not uncommon in patients with acute atrial fibrillation and a recent embolic event: a transesophageal echocardiographic study. J Am Coll Cardiol 1995; 25 (02) 452-459
  • 89 Klein AL, Grimm RA, Murray RD. et al; Assessment of Cardioversion Using Transesophageal Echocardiography Investigators. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001; 344 (19) 1411-1420
  • 90 Airaksinen KE, Grönberg T, Nuotio I. et al. Thromboembolic complications after cardioversion of acute atrial fibrillation: the FinCV (Finnish CardioVersion) study. J Am Coll Cardiol 2013; 62 (13) 1187-1192
  • 91 Garg A, Khunger M, Seicean S, Chung MK, Tchou PJ. Incidence of thromboembolic complications within 30 days of electrical cardioversion performed within 48 hours of atrial fibrillation onset. JACC Clin Electrophysiol 2016; 2 (04) 487-494
  • 92 Ezekowitz MD, Pollack Jr CV, Halperin JL. et al. Apixaban compared to heparin/vitamin K antagonist in patients with atrial fibrillation scheduled for cardioversion: the EMANATE trial. Eur Heart J 2018; 39 (32) 2959-2971
  • 93 Cappato R, Ezekowitz MD, Klein AL. et al; X-VeRT Investigators. Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation. Eur Heart J 2014; 35 (47) 3346-3355
  • 94 Goette A, Merino JL, Ezekowitz MD. et al; ENSURE-AF Investigators. Edoxaban versus enoxaparin-warfarin in patients undergoing cardioversion of atrial fibrillation (ENSURE-AF): a randomised, open-label, phase 3b trial. Lancet 2016; 388 (10055): 1995-2003
  • 95 Nagarakanti R, Ezekowitz MD, Oldgren J. et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation 2011; 123 (02) 131-136
  • 96 Liu Y, Zhan X, Xue Y. et al. Incidence and outcomes of cerebrovascular events complicating catheter ablation for atrial fibrillation. Europace 2016; 18 (09) 1357-1365
  • 97 Noseworthy PA, Kapa S, Deshmukh AJ. et al. Risk of stroke after catheter ablation versus cardioversion for atrial fibrillation: a propensity-matched study of 24,244 patients. Heart Rhythm 2015; 12 (06) 1154-1161
  • 98 Ren JF, Marchlinski FE, Callans DJ. Left atrial thrombus associated with ablation for atrial fibrillation: identification with intracardiac echocardiography. J Am Coll Cardiol 2004; 43 (10) 1861-1867
  • 99 Sparks PB, Jayaprakash S, Vohra JK. et al. Left atrial “stunning” following radiofrequency catheter ablation of chronic atrial flutter. J Am Coll Cardiol 1998; 32 (02) 468-475
  • 100 Medi C, Evered L, Silbert B. et al. Subtle post-procedural cognitive dysfunction after atrial fibrillation ablation. J Am Coll Cardiol 2013; 62 (06) 531-539
  • 101 Calkins H, Hindricks G, Cappato R. et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2017; 14 (10) e275-e444
  • 102 Puwanant S, Varr BC, Shrestha K. et al. Role of the CHADS2 score in the evaluation of thromboembolic risk in patients with atrial fibrillation undergoing transesophageal echocardiography before pulmonary vein isolation. J Am Coll Cardiol 2009; 54 (22) 2032-2039
  • 103 Di Biase L, Burkhardt JD, Santangeli P. et al. Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management: results from the Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation (COMPARE) randomized trial. Circulation 2014; 129 (25) 2638-2644
  • 104 Schmidt M, Segerson NM, Marschang H. et al. Atrial fibrillation ablation in patients with therapeutic international normalized ratios. Pacing Clin Electrophysiol 2009; 32 (08) 995-999
  • 105 Cappato R, Marchlinski FE, Hohnloser SH. et al; VENTURE-AF Investigators. Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation. Eur Heart J 2015; 36 (28) 1805-1811
  • 106 Calkins H, Willems S, Gerstenfeld EP. et al; RE-CIRCUIT Investigators. Uninterrupted dabigatran versus warfarin for ablation in atrial fibrillation. N Engl J Med 2017; 376 (17) 1627-1636
  • 107 Kirchhof P, Haeusler KG, Blank B. et al. Apixaban in patients at risk of stroke undergoing atrial fibrillation ablation. Eur Heart J 2018; 39 (32) 2942-2955
  • 108 Hohnloser SH, Camm J, Cappato R. et al. Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial. Eur Heart J 2019; 40 (36) 3013-3021
  • 109 Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996; 61 (02) 755-759
  • 110 WATCHMAN for Physicians. . Accessed January 3, 2020 at: https://www.watchman.com/en-us-hcp/home.html
  • 111 Holmes DR, Reddy VY, Turi ZG. et al; 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 2009; 374 (9689): 534-542
  • 112 Holmes Jr DRJ, Kar S, Price MJ. et al. 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 (01) 1-12
  • 113 Reddy VY, Doshi SK, Kar S. et al; PREVAIL and PROTECT AF Investigators. 5-Year outcomes after left atrial appendage closure: from the PREVAIL and PROTECT AF trials. J Am Coll Cardiol 2017; 70 (24) 2964-2975
  • 114 Reddy VY, Holmes D, Doshi SK, Neuzil P, Kar S. Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry. Circulation 2011; 123 (04) 417-424
  • 115 Holmes Jr DR, Reddy VY, Gordon NT. et al. Long-term safety and efficacy in continued access left atrial appendage closure registries. J Am Coll Cardiol 2019; 74 (23) 2878-2889
  • 116 Fauchier L, Cinaud A, Brigadeau F. et al. Device-related thrombosis after percutaneous left atrial appendage occlusion for atrial fibrillation. J Am Coll Cardiol 2018; 71 (14) 1528-1536
  • 117 Dukkipati SR, Kar S, Holmes DR. et al. Device-related thrombus after left atrial appendage closure: incidence, predictors, and outcomes. Circulation 2018; 138 (09) 874-885
  • 118 Reddy VY, Möbius-Winkler S, Miller MA. et al. Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology). J Am Coll Cardiol 2013; 61 (25) 2551-2556
  • 119 Sharma D, Reddy VY, Sandri M. et al. Left atrial appendage closure in patients with contraindications to oral anticoagulation. J Am Coll Cardiol 2016; 67 (18) 2190-2192
  • 120 Boersma LV, Ince H, Kische S. et al; EWOLUTION Investigators. Efficacy and safety of left atrial appendage closure with WATCHMAN in patients with or without contraindication to oral anticoagulation: 1-Year follow-up outcome data of the EWOLUTION trial. Heart Rhythm 2017; 14 (09) 1302-1308
  • 121 Boersma LV, Ince H, Kische S. et al; Following Investigators and Institutions Participated in the EWOLUTION Study. Evaluating real-world clinical outcomes in atrial fibrillation patients receiving the WATCHMAN left atrial appendage closure technology: final 2-year outcome data of the EWOLUTION trial focusing on history of stroke and hemorrhage. Circ Arrhythm Electrophysiol 2019; 12 (04) e006841
  • 122 Tilz RR, Potpara T, Chen J. et al. Left atrial appendage occluder implantation in Europe: indications and anticoagulation post-implantation. Results of the European Heart Rhythm Association Survey. Europace 2017; 19 (10) 1737-1742
  • 123 Glikson M, Wolff R, Hindricks G. et al; ESC Scientific Document Group. EHRA/EAPCI expert consensus statement on catheter-based left atrial appendage occlusion - an update. Europace 2019; ; (epub ahead of print) doi: DOI: 10.1093/europace/euz258.
  • 124 Holmes DR, Reddy VY, Buchbinder M. et al. The Assessment of the Watchman Device in Patients Unsuitable for Oral Anticoagulation (ASAP-TOO) trial. Am Heart J 2017; 189: 68-74
  • 125 Bayard Y-L, Omran H, Neuzil P. et al. PLAATO (percutaneous left atrial appendage transcatheter occlusion) for prevention of cardioembolic stroke in non-anticoagulation eligible atrial fibrillation patients: results from the European PLAATO study. EuroIntervention 2010; 6 (02) 220-226
  • 126 Ostermayer SH, Reisman M, Kramer PH. et al. Percutaneous left atrial appendage transcatheter occlusion (PLAATO system) to prevent stroke in high-risk patients with non-rheumatic atrial fibrillation: results from the international multi-center feasibility trials. J Am Coll Cardiol 2005; 46 (01) 9-14
  • 127 Park JW, Leithäuser B, Gerk U, Vršansky M, Jung F. Percutaneous left atrial appendage transcatheter occlusion (PLAATO) for stroke prevention in atrial fibrillation: 2-year outcomes. J Invasive Cardiol 2009; 21 (09) 446-450
  • 128 Left Atrial Appendage Closure vs. Novel Anticoagulation Agents in Atrial Fibrillation - Full Text View - ClinicalTrials.gov. Accessed January 1, 2020 at: https://clinicaltrials.gov/ct2/show/NCT02426944
  • 129 Urena M, Rodés-Cabau J, Freixa X. et al. Percutaneous left atrial appendage closure with the AMPLATZER cardiac plug device in patients with nonvalvular atrial fibrillation and contraindications to anticoagulation therapy. J Am Coll Cardiol 2013; 62 (02) 96-102
  • 130 Gloekler S, Shakir S, Doblies J. et al. Early results of first versus second generation Amplatzer occluders for left atrial appendage closure in patients with atrial fibrillation. Clin Res Cardiol 2015; 104 (08) 656-665
  • 131 Abualsaud A, Freixa X, Tzikas A. et al. Side-by-side comparison of LAA occlusion performance with the Amplatzer cardiac plug and Amplatzer amulet. J Invasive Cardiol 2016; 28 (01) 34-38
  • 132 Giedrimas E, Lin AC, Knight BP. Left atrial thrombus after appendage closure using LARIAT. Circ Arrhythm Electrophysiol 2013; 6 (04) e52-e53
  • 133 Briceno DF, Fernando RR, Laing ST. Left atrial appendage thrombus post LARIAT closure device. Heart Rhythm 2014; 11 (09) 1600-1601
  • 134 Truesdell AG, Patel CP, Maini BS. Late-occurring left atrial appendage thrombus after ligation using LARIAT. J Interv Card Electrophysiol 2014; 41 (01) 101
  • 135 Pillai AM, Kanmanthareddy A, Earnest M. et al. Initial experience with post Lariat left atrial appendage leak closure with Amplatzer septal occluder device and repeat Lariat application. Heart Rhythm 2014; 11 (11) 1877-1883
  • 136 Lee RJ, Lakkireddy D, Mittal S. et al. Percutaneous alternative to the Maze procedure for the treatment of persistent or long-standing persistent atrial fibrillation (aMAZE trial): rationale and design. Am Heart J 2015; 170 (06) 1184-1194
  • 137 aMAZE Study: LAA Ligation Adjunctive to PVI for Persistent or Longstanding Persistent Atrial Fibrillation - Full Text View - ClinicalTrials.gov. Accessed January 1, 2020 at: https://clinicaltrials.gov/ct2/show/NCT02513797
  • 138 WAveCrest Vs. Watchman TranssEptal LAA Closure to REduce AF-Mediated STroke 2 - Full Text View - ClinicalTrials.gov. Accessed January 1, 2020 at: https://clinicaltrials.gov/ct2/show/NCT03302494
  • 139 Coherex WAVECREST I Left Atrial Appendage Occlusion Study - Full Text View - ClinicalTrials.gov. Accessed January 1, 2020 at: https://clinicaltrials.gov/ct2/show/NCT02239887
  • 140 Cruz-González I, Freixa X, Fernández-Díaz JA, Moreno-Samos JC, Martín-Yuste V, Goicolea J. Left atrial appendage occlusion with the Lambre device: initial experience. Rev Esp Cardiol (Engl Ed) 2018; 71 (09) 755-756
  • 141 Bellmann B, Schnupp S, Kühnlein P. et al. Left atrial appendage closure with the new Occlutech® device: first in man experience and neurological outcome. J Cardiovasc Electrophysiol 2017; 28 (03) 315-320
  • 142 Ali M, Rigopoulos AG, Mammadov M. et al. Systematic review on left atrial appendage closure with the LAmbre device in patients with non-valvular atrial fibrillation. BMC Cardiovasc Disord 2020; 20 (01) 78
  • 143 Schellinger PD, Tsivgoulis G, Steiner T, Köhrmann M. Percutaneous left atrial appendage occlusion for the prevention of stroke in patients with atrial fibrillation: Review and critical appraisal. J Stroke 2018; 20 (03) 281-291
  • 144 Caliskan E, Sahin A, Yilmaz M. et al. Epicardial left atrial appendage AtriClip occlusion reduces the incidence of stroke in patients with atrial fibrillation undergoing cardiac surgery. Europace 2018; 20 (07) e105-e114
  • 145 Hernandez-Estefania R, Levy Praschker B, Bastarrika G, Rabago G. Left atrial appendage occlusion by invagination and double suture technique. Eur J Cardiothorac Surg 2012; 41 (01) 134-136
  • 146 Kim R, Baumgartner N, Clements J. Routine left atrial appendage ligation during cardiac surgery may prevent postoperative atrial fibrillation-related cerebrovascular accident. J Thorac Cardiovasc Surg 2013; 145 (02) 582-589 , discussion 589
  • 147 Yao X, Gersh BJ, Holmes Jr DR. et al. Association of surgical left atrial appendage occlusion with subsequent stroke and mortality among patients undergoing cardiac surgery. JAMA 2018; 319 (20) 2116-2126
  • 148 Melduni RM, Schaff HV, Lee H-C. et al. Impact of left atrial appendage closure during cardiac surgery on the occurrence of early postoperative atrial fibrillation, stroke, and mortality: a propensity score-matched analysis of 10 633 patients. Circulation 2017; 135 (04) 366-378
  • 149 Kanderian AS, Gillinov AM, Pettersson GB, Blackstone E, Klein AL. Success of surgical left atrial appendage closure: assessment by transesophageal echocardiography. J Am Coll Cardiol 2008; 52 (11) 924-929
  • 150 Lee R, Vassallo P, Kruse J. et al. A randomized, prospective pilot comparison of 3 atrial appendage elimination techniques: Internal ligation, stapled excision, and surgical excision. J Thorac Cardiovasc Surg 2016; 152 (04) 1075-1080
  • 151 Katz ES, Tsiamtsiouris T, Applebaum RM, Schwartzbard A, Tunick PA, Kronzon I. Surgical left atrial appendage ligation is frequently incomplete: a transesophageal echocardiograhic study. J Am Coll Cardiol 2000; 36 (02) 468-471
  • 152 García-Fernández MÁ, Pérez-David E, Quiles J. et al. Role of left atrial appendage obliteration in stroke reduction in patients with mitral valve prosthesis: a transesophageal echocardiographic study. J Am Coll Cardiol 2003; 42 (07) 1253-1258
  • 153 Ntaios G, Lip GYH, Makaritsis K. et al. CHADS2, CHA2S2DS2-VASc, and long-term stroke outcome in patients without atrial fibrillation. Neurology 2013; 80 (11) 1009-1017
  • 154 Giugliano RP, Ruff CT, Braunwald E. et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
  • 155 Ezekowitz MD, Eikelboom J, Oldgren J. et al. Long-term evaluation of dabigatran 150 vs. 110 mg twice a day in patients with non-valvular atrial fibrillation. Europace 2016; 18 (07) 973-978
  • 156 Agarwal S, Hachamovitch R, Menon V. Current trial-associated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation: a meta-analysis. Arch Intern Med 2012; 172 (08) 623-631 , discussion 631–633
  • 157 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 (22) 2864-2870