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  • Review Article
  • Published:

Interventional and surgical occlusion of the left atrial appendage

Nature Reviews Cardiology volume 14, pages 727–743 (2017)Cite this article

Subjects

Key Points

  • The left atrial appendage (LAA), a site of predilection for thrombus formation, is the primary source of thromboemboli in patients with nonvalvular atrial fibrillation (NVAF) who have a stroke

  • Anticoagulation with vitamin K antagonists or non-vitamin K-dependent (direct-acting) oral anticoagulants is the gold standard for stroke prevention, but are contraindicated in some patients with NVAF, necessitating novel (nonpharmacological) strategies targeting the LAA

  • Interventional LAA occlusion devices are a valid alternative to pharmacological stroke-prevention therapies; however, use is limited by an unsatisfactory rate of periprocedural complications and the unknown long-term clinical implications of residual peri-device flow

  • The majority of studies reporting on outcomes of surgical LAA occlusion are inconclusive and had heterogeneous outcomes owing to failure to achieve occlusion

  • Whereas robust clinical data from randomized, controlled trials are still lacking for surgical techniques to exclude the LAA, epicardial, device-enabled LAA occlusion might offer a safe, durable, and efficacious surgical approach

  • An outcome-oriented collaboration between cardiologists and surgeons — the Heart Team approach — as successfully applied in the transcatheter aortic valve replacement or MitraClip experience, is imperative

Abstract

With a steadily increasing prevalence, atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide and an independent risk factor for stroke caused by thromboembolic events. The left atrial appendage (LAA) is the primary source of thromboemboli in patients with nonvalvular AF who have a stroke. Novel strategies (such as mechanical and nonpharmacological intervention) targeting the LAA in patients with AF for stroke prevention have become a major focus during the past decade. Some devices for percutaneous LAA occlusion are supported by robust clinical data obtained from randomized trials or large registries, and are a valid alternative to pharmacological stroke prevention. However, the incidence of periprocedural complications and the presence of device-related thrombi or residual LAA leaks, whose long-term clinical implications are still unknown, are limiting factors in wider acceptability of these techniques. In this Review, we discuss the available techniques for LAA occlusion in patients with nonvalvular AF at high risk of stroke. We describe the pharmacological and mechanical approaches to LAA occlusion, and provide the current clinical evidence for various strategies. We particularly focus on the current management of the LAA, and discuss the challenges and future implications of the available approaches to LAA occlusion.

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Figure 1: Anatomy and morphology of the left atrial appendage.
Figure 2: Surgical occlusion of the left atrial appendage.

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References

  1. Wolf, P. A., Abbott, R. D. & Kannel, W. B. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 22, 983–988 (1991).

    CAS  PubMed  Google Scholar 

  2. Chugh, S. S. et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 129, 837–847 (2014).

    PubMed  Google Scholar 

  3. Go, A. S. et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the anticoagulation and risk factors in atrial fibrillation (atria) study. JAMA 285, 2370–2375 (2001).

    CAS  PubMed  Google Scholar 

  4. Lip, G. Y. H., Brechin, C. M. & Lane, D. A. The global burden of atrial fibrillation and stroke: a systematic review of the epidemiology of atrial fibrillation in regions outside North America and Europe. Chest 142, 1489–1498 (2012).

    PubMed  Google Scholar 

  5. Mozaffarian, D. et al. Heart disease and stroke statistics — 2015 update: a report from the American Heart Association. Circulation 131, e29–322 (2015).

    PubMed  Google Scholar 

  6. Schnabel, R. B. et al. 50 year trends in atrial fibrillation prevalence, incidence, risk factors and mortality in the Framingham Heart Study: a cohort study. Lancet 386, 154–162 (2015).

    PubMed  PubMed Central  Google Scholar 

  7. Benjamin, E. J. et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 98, 946–952 (1998).

    CAS  PubMed  Google Scholar 

  8. Svennberg, E. et al. Mass screening for untreated atrial fibrillation: the STROKESTOP Study. Circulation 131, 2176–2184 (2015).

    PubMed  Google Scholar 

  9. National Center for Health Statistics. Health, United States, 2015: With special feature on racial and ethnic health disparities. http://www.cdc.gov/nchs/data/hus/hus15.pdf (2016).

  10. Lackland, D. T. et al. Factors influencing the decline in stroke mortality: a statement from the American Heart Association/American Stroke Association. Stroke 45, 315–353 (2014).

    PubMed  Google Scholar 

  11. Lin, H. J. et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 27, 1760–1764 (1996).

    CAS  PubMed  Google Scholar 

  12. Ferro, J. M. Cardioembolic stroke: an update. Lancet Neurol. 2, 177–188 (2003).

    PubMed  Google Scholar 

  13. Bruggenjurgen, B. et al. The impact of atrial fibrillation on the cost of stroke: the Berlin Acute Stroke Study. Value Health 10, 137–143 (2007).

    PubMed  Google Scholar 

  14. Lamassa, M. et al. Characteristics, outcome, and care of stroke associated with atrial fibrillation in Europe: data from a multicenter multinational hospital-based registry (The European Community Stroke Project). Stroke 32, 392–398 (2001).

    CAS  PubMed  Google Scholar 

  15. Sharma, S., Devine, W., Anderson, R. H. & Zuberbuhler, J. R. The determination of atrial arrangement by examination of appendage morphology in 1842 heart specimens. Br. Heart J. 60, 227–231 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Di Biase, L. et al. Does the left atrial appendage morphology correlate with the risk of stroke in patients with atrial fibrillation? Results from a multicenter study. J. Am. Coll. Cardiol. 60, 531–538 (2012).

    PubMed  Google Scholar 

  17. Lupercio, F. et al. Left atrial appendage morphology assessment for risk stratification of embolic stroke in patients with atrial fibrillation: a meta-analysis. Heart Rhythm 13, 1402–1409 (2016).

    PubMed  Google Scholar 

  18. Taina, M. et al. Morphological and volumetric analysis of left atrial appendage and left atrium: cardiac computed tomography-based reproducibility assessment. PloS ONE 9, e101580 (2014).

    PubMed  PubMed Central  Google Scholar 

  19. Wang, Y. A. N. et al. Left atrial appendage studied by computed tomography to help planning for appendage closure device placement. J. Cardiovasc. Electrophysiol. 21, 973–982 (2010).

    PubMed  Google Scholar 

  20. Tabata, T. M. D. et al. Role of left atrial appendage in left atrial reservoir function as evaluated by left atrial appendage clamping during cardiac surgery. Am. J. Cardiol. 81, 327–332 (1998).

    CAS  PubMed  Google Scholar 

  21. Chapeau, C. et al. Localization of immunoreactive synthetic atrial natriuretic factor (ANF) in the heart of various animal species. J. Histochem. Cytochem. 33, 541–550 (1985).

    CAS  PubMed  Google Scholar 

  22. Kappagoda, C. T., Linden, R. J. & Snow, H. M. The effect of distending the atrial appendages on urine flow in the dog. J. Physiol. 227, 233–242 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Massoudy, P., Beblo, S., Raschke, P., Zahler, S. & Becker, B. F. Influence of intact left atrial appendage on hemodynamic parameters of isolated guinea pig heart. Eur. J. Med. Res. 3, 470–474 (1998).

    CAS  PubMed  Google Scholar 

  24. Inoue, S.-I., Murakami, Y., Sano, K., Katoh, H. & Shimada, T. Atrium as a source of brain natriuretic polypeptide in patients with atrial fibrillation. J. Card. Fail. 6, 92–96 (2000).

    CAS  PubMed  Google Scholar 

  25. Hoit, B. D., Shao, Y. & Gabel, M. Influence of acutely altered loading conditions on left atrial appendage flow velocities. J. Am. Coll. Cardiol. 24, 1117–1123 (1994).

    CAS  PubMed  Google Scholar 

  26. Tabata, T. et al. Relationship between left atrial appendage function and plasma concentration of atrial natriuretic peptide. Eur. J. Echocardiogr. 1, 130–137 (2000).

    CAS  PubMed  Google Scholar 

  27. Frustaci, A. et al. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 96, 1180–1184 (1997).

    CAS  PubMed  Google Scholar 

  28. Takada, T., Yasaka, M., Nagatsuka, K., Minematsu, K. & Yamaguchi, T. Blood flow in the left atrial appendage and embolic stroke in nonvalvular atrial fibrillation. Eur. Neurol. 46, 148–152 (2001).

    CAS  PubMed  Google Scholar 

  29. Inoue, H. et al. Prothrombotic activity is increased in patients with nonvalvular atrial fibrillation and risk factors for embolism. Chest 126, 687–692 (2004).

    PubMed  Google Scholar 

  30. Cox, J. L. Mechanical closure of the left atrial appendage: is it time to be more aggressive? J. Thorac. Cardiovasc. Surg. 146, 1018–1027.e2 (2013).

    PubMed  Google Scholar 

  31. Lim, H. S. et al. Effect of atrial fibrillation on atrial thrombogenesis in humans: impact of rate and rhythm. J. Am. Coll. Cardiol. 61, 852–860 (2013).

    PubMed  Google Scholar 

  32. Johnson, W. D., Ganjoo, A. K., Stone, C. D., Srivyas, R. C. & Howard, M. The left atrial appendage: our most lethal human attachment! Surgical implications. Eur. J. Cardiothorac. Surg. 17, 718–722 (2000).

    CAS  PubMed  Google Scholar 

  33. Watson, T., Shantsila, E. & Lip, G. Y. H. Mechanisms of thrombogenesis in atrial fibrillation: Virchow's triad revisited. Lancet 373, 155–166 (2009).

    CAS  PubMed  Google Scholar 

  34. Al-Saady, N. M., Obel, O. A. & Camm, A. J. Left atrial appendage: structure, function, and role in thromboembolism. Heart 82, 547–554 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Blackshear, J. L. & Odell, J. A. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann. Thorac. Surg. 61, 755–759 (1996).

    CAS  PubMed  Google Scholar 

  36. Gage, B. F. et al. Validation of clinical classification schemes for predicting stroke: Results from the national registry of atrial fibrillation. JAMA 285, 2864–2870 (2001).

    CAS  PubMed  Google Scholar 

  37. Lip, G. Y., Nieuwlaat, R., Pisters, R., Lane, D. A. & Crijns, H. J. 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 137, 263–272 (2010).

    PubMed  Google Scholar 

  38. Singer, D. E. et al. A new risk scheme to predict ischemic stroke and other thromboembolism in atrial fibrillation: the ATRIA study stroke risk score. J. Am. Heart Assoc. 2, e000250 (2013).

    PubMed  PubMed Central  Google Scholar 

  39. January, C. T. et al. 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 practice guidelines and the Heart Rhythm Society. Circulation 130, 2071–2104 (2014).

    PubMed  Google Scholar 

  40. Kirchhof, P. et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur. Heart J. 37, 2893–2962 (2016).

    PubMed  Google Scholar 

  41. Bartolucci, A. A., Tendera, M. & Howard, G. Meta-analysis of multiple primary prevention trials of cardiovascular events using aspirin. Am. J. Cardiol. 107, 1796–1801 (2011).

    CAS  PubMed  Google Scholar 

  42. Antithrombotic Trialists' Collaboration et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 373, 1849–1860 (2009).

  43. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324, 71–86 (2002).

    PubMed Central  Google Scholar 

  44. Hennekens, C. H., Dyken, M. L. & Fuster, V. Aspirin as a therapeutic agent in cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 96, 2751–2753 (1997).

    CAS  PubMed  Google Scholar 

  45. Lip, G. Y. H. The role of aspirin for stroke prevention in atrial fibrillation. Nat. Rev. Cardiol. 8, 602–606 (2011).

    CAS  PubMed  Google Scholar 

  46. [No authors listed.] Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation 84, 527–539 (1991).

  47. [No authors listed.] Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 343, 687–691 (1994).

  48. Petersen, P., Boysen, G., Godtfredsen, J., Andersen, E. D. & Andersen, B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet 1, 175–179 (1989).

    CAS  PubMed  Google Scholar 

  49. Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N. Engl. J. Med. 323, 1505–1511 (1990).

  50. Ezekowitz, M. D. et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. N. Engl. J. Med. 327, 1406–1412 (1992).

    CAS  PubMed  Google Scholar 

  51. Connolly, S. J. et al. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J. Am. Coll. Cardiol. 18, 349–355 (1991).

    CAS  PubMed  Google Scholar 

  52. Hart, R. G., Pearce, L. A. & Aguilar, M. I. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann. Intern. Med. 146, 857–867 (2007).

    PubMed  Google Scholar 

  53. European Heart Rhythm Association et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace 12, 1360–1420 (2010).

  54. Holmes, D. R. & Reddy, V. Y. Left atrial appendage and closure: who, when, and how. Circ. Cardiovasc. Interv. 9, e002942 (2016).

    PubMed  Google Scholar 

  55. Brass, L. M., Krumholz, H. M., Scinto, J. M. & Radford, M. Warfarin use among patients with atrial fibrillation. Stroke 28, 2382–2389 (1997).

    CAS  PubMed  Google Scholar 

  56. Go, A. S. et al. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: The AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. Ann. Intern. Med. 131, 927–934 (1999).

    CAS  PubMed  Google Scholar 

  57. Gladstone, D. J. et al. Potentially preventable strokes in high-risk patients with atrial fibrillation who are not adequately anticoagulated. Stroke 40, 235–240 (2009).

    CAS  PubMed  Google Scholar 

  58. Waldo, A. L., Becker, R. C., Tapson, V. F., Colgan, K. J. & Committee, N. S. Hospitalized patients with atrial fibrillation and a high risk of stroke are not being provided with adequate anticoagulation. J. Am. Coll. Cardiol. 46, 1729–1736 (2005).

    PubMed  Google Scholar 

  59. Connolly, S. J. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 361, 1139–1151 (2009).

    CAS  PubMed  Google Scholar 

  60. Giugliano, R. P. et al. Edoxaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 369, 2093–2104 (2013).

    CAS  PubMed  Google Scholar 

  61. Granger, C. B. et al. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 365, 981–992 (2011).

    CAS  PubMed  Google Scholar 

  62. Patel, M. R. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 365, 883–891 (2011).

    CAS  PubMed  Google Scholar 

  63. Dentali, F. et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation 126, 2381–2391 (2012).

    CAS  PubMed  Google Scholar 

  64. Ruff, C. T. 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 383, 955–962 (2014).

    CAS  PubMed  Google Scholar 

  65. Heidbuchel, H. et al. Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur. Heart J. http://dx.doi.org/10.1093/eurheartj/ehw058 (2016).

  66. Hellerstein, H. K., Sinaiko, E. & Dolgin, M. Amputation of the canine atrial appendages. Proc. Soc. Exp. Biol. Med. 66, 337 (1947).

    CAS  PubMed  Google Scholar 

  67. Madden, J. L. Resection of the left auricular appendix: a prophylaxis for recurrent arterial emboli. J. Am. Med. Assoc. 140, 769–772 (1949).

    CAS  PubMed  Google Scholar 

  68. Coulshed, N., Epstein, E. J., McKendrick, C. S., Galloway, R. W. & Walker, E. Systemic embolism in mitral valve disease. Br. Heart J. 32, 26–34 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Cox, J. L. The surgical treatment of atrial fibrillation. IV. Surgical technique. J. Thorac. Cardiovasc. Surg. 101, 584–592 (1991).

    CAS  PubMed  Google Scholar 

  70. Cox, J. L. et al. The surgical treatment of atrial fibrillation. III. Development of a definitive surgical procedure. J. Thorac. Cardiovasc. Surg. 101, 569–583 (1991).

    CAS  PubMed  Google Scholar 

  71. Ad, N. & Cox, J. L. Stroke prevention as an indication for the Maze procedure in the treatment of atrial fibrillation. Semin. Thorac. Cardiovasc. Surg. 12, 56–62 (2000).

    CAS  PubMed  Google Scholar 

  72. Cox, J. L., Ad, N. & Palazzo, T. Impact of the maze procedure on the stroke rate in patients with atrial fibrillation. J. Thorac. Cardiovasc. Surg. 118, 833–840 (1999).

    CAS  PubMed  Google Scholar 

  73. Chatterjee, S., Alexander, J. C., Pearson, P. J. & Feldman, T. Left atrial appendage occlusion: lessons learned from surgical and transcatheter experiences. Ann. Thorac. Surg. 92, 2283–2292 (2011).

    PubMed  Google Scholar 

  74. Kanderian, A. S., Gillinov, A. M., Pettersson, G. B., Blackstone, E. & Klein, A. L. Success of surgical left atrial appendage closure: assessment by transesophageal echocardiography. J. Am. Coll. Cardiol. 52, 924–929 (2008).

    PubMed  Google Scholar 

  75. Bakhtiary, F. et al. Simplified technique for surgical ligation of the left atrial appendage in high-risk patients. J. Thorac. Cardiovasc. Surg. 135, 430–431 (2008).

    PubMed  Google Scholar 

  76. Hernandez-Estefania, R., Levy Praschker, B., Bastarrika, G. & Rabago, G. Left atrial appendage occlusion by invagination and double suture technique. Eur. J. Cardiothorac. Surg. 41, 134–136 (2012).

    PubMed  Google Scholar 

  77. Lynch, M., Shanewise, J. S., Chang, G. L., Martin, R. P. & Clements, S. D. Recanalization of the left atrial appendage demonstrated by transesophageal echocardiography. Ann. Thorac. Surg. 63, 1774–1775 (1997).

    CAS  PubMed  Google Scholar 

  78. Schneider, B., Stöllberger, C. & Sievers, H. H. Surgical closure of the left atrial appendage – a beneficial procedure? Cardiology 104, 127–132 (2005).

    PubMed  Google Scholar 

  79. Gillinov, A. M., Pettersson, G. & Cosgrove, D. M. Stapled excision of the left atrial appendage. J. Thorac. Cardiovasc. Surg. 129, 679–680 (2005).

    PubMed  Google Scholar 

  80. Landymore, R. & Kinley, C. E. Staple closure of the left atrial appendage. Can. J. Surg. 27, 144–145 (1984).

    CAS  PubMed  Google Scholar 

  81. Blackshear, J. L. et al. Thoracoscopic extracardiac obliteration of the left atrial appendage for stroke risk reduction in atrial fibrillation. J. Am. Coll. Cardiol. 42, 1249–1252 (2003).

    PubMed  Google Scholar 

  82. Jayakar, D., Gozo, F., Gomez, E. & Carlos, C. Use of tissue welding technology to obliterate left atrial appendage – novel use of Ligasure™. Interact. Cardiovasc. Thorac. Surg. 4, 372–373 (2005).

    PubMed  Google Scholar 

  83. Benussi, S. et al. Thoracoscopic appendage exclusion with an atriclip device as a solo treatment for focal atrial tachycardia. Circulation 123, 1575–1578 (2011).

    PubMed  Google Scholar 

  84. U.S. Food and Drug Administration. Class 1 Device Recall TigerPaw System II. US FDA http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRes/res.cfm?ID=135185 (2015).

  85. Katz, E. S. et al. Surgical left atrial appendage ligation is frequently incomplete: a transesophageal echocardiographic study. J. Am. Coll. Cardiol. 36, 468–471 (2000).

    CAS  PubMed  Google Scholar 

  86. García-Fernández, M. A. et al. Role of left atrial appendageobliteration in stroke reductionin patients with mitral valve prosthesis: a transesophageal echocardiographic study. J. Am. College Cardiol. 42, 1253–1258 (2003).

    Google Scholar 

  87. Healey, J. S. et al. Left Atrial Appendage Occlusion Study (LAAOS): results of a randomized controlled pilot study of left atrial appendage occlusion during coronary bypass surgery in patients at risk for stroke. Am. Heart J. 150, 288–293 (2005).

    PubMed  Google Scholar 

  88. Dawson, A. G., Asopa, S. & Dunning, J. Should patients undergoing cardiac surgery with atrial fibrillation have left atrial appendage exclusion? Interact. Cardiovasc. Thorac. Surg. 10, 306–311 (2010).

    PubMed  Google Scholar 

  89. Orszulak, T. A. et al. The risk of stroke in the early postoperative period following mitral valve replacement. Eur. J. Cardiothorac. Surg. 9, 615–619 (1995).

    CAS  PubMed  Google Scholar 

  90. Melduni, R. M. et al. Impact of left atrial appendage closure during cardiac surgery on the occurrence of early postoperative atrial fibrillation, stroke, and mortality. Circulation 135, 366–378 (2017).

    PubMed  Google Scholar 

  91. Aryana, A. et al. Association between incomplete surgical ligation of left atrial appendage and stroke and systemic embolization. Heart Rhythm 12, 1431–1437 (1995).

    Google Scholar 

  92. Emmert, M. Y. et al. Safe, effective and durable epicardial left atrial appendage clip occlusion in patients with atrial fibrillation undergoing cardiac surgery: first long-term results from a prospective device trial. Eur. J. Cardiothorac. Surg. 45, 126–131 (2014).

    PubMed  Google Scholar 

  93. Salzberg, S. P. et al. Left atrial appendage clip occlusion: early clinical results. J. Thorac. Cardiovasc. Surg. 139, 1269–1274 (2010).

    PubMed  Google Scholar 

  94. Ailawadi, G. et al. Exclusion of the left atrial appendage with a novel device: early results of a multicenter trial. J. Thorac. Cardiovasc. Surg. 142, 1002–1009 (2011).

    PubMed  Google Scholar 

  95. Caliskan, E. et al. Epicardial left atrial appendage AtriClip occlusion reduces the incidence of stroke in patients with atrial fibrillation undergoing cardiac surgery. Europace http://dx.doi.org/10.1093/europace/eux211 (2017).

  96. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01997905 (2013).

  97. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01561651 (2012).

  98. Nakai, T. et al. Percutaneous left atrial appendage occlusion (PLAATO) for preventing cardioembolism. Circulation 105, 2217–2222 (2002).

    PubMed  Google Scholar 

  99. Ostermayer, S. H. 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. 46, 9–14 (2005).

    PubMed  Google Scholar 

  100. Bayard, Y.-L. 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 6, 220–226 (2010).

    PubMed  Google Scholar 

  101. Meier, B. et al. Transcatheter left atrial appendage occlusion with Amplatzer devices to obviate anticoagulation in patients with atrial fibrillation. Catheter. Cardiovasc. Interv. 60, 417–422 (2003).

    PubMed  Google Scholar 

  102. Park, J.-W. et al. Left atrial appendage closure with Amplatzer cardiac plug in atrial fibrillation: initial European experience. Catheter. Cardiovasc. Interv. 77, 700–706 (2011).

    PubMed  Google Scholar 

  103. Lam, Y.-Y. et al. Left atrial appendage closure with Amplatzer cardiac plug for stroke prevention in atrial fibrillation: Initial Asia-Pacific experience. Catheter. Cardiovasc. Interv. 79, 794–800 (2012).

    PubMed  Google Scholar 

  104. Nietlispach, F. et al. Amplatzer left atrial appendage occlusion: single center 10-year experience. Catheter. Cardiovasc. Interv. 82, 283–289 (2013).

    PubMed  Google Scholar 

  105. López-Mínguez, J. R. et al. Immediate and one-year results in 35 consecutive patients after closure of left atrial appendage with the Amplatzer cardiac plug. Rev. Esp. Cardiol. (Engl. Ed.) 66, 90–97 (2013).

    Google Scholar 

  106. Urena, M. 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. 62, 96–102 (2013).

    PubMed  Google Scholar 

  107. Guerios, E. E. et al. Left atrial appendage closure with the Amplatzer cardiac plug in patients with atrial fibrillation. Arq. Bras. Cardiol. 98, 528–536 (2012).

    PubMed  Google Scholar 

  108. Tzikas, A. et al. Left atrial appendage occlusion for stroke prevention in atrial fibrillation: multicentre experience with the AMPLATZER cardiac plug. EuroIntervention 11, 1170–1179 (2016).

    PubMed  Google Scholar 

  109. Freixa, X. et al. Left atrial appendage occlusion: initial experience with the Amplatzer Amulet. Int. J. Cardiol. 174, 492–496 (2014).

    PubMed  Google Scholar 

  110. Lam, S. C. et al. Left atrial appendage closure using the Amulet device: an initial experience with the second generation Amplatzer cardiac plug. Catheter. Cardiovasc. Interv. 85, 297–303 (2015).

    PubMed  Google Scholar 

  111. Gloekler, S. et al. Early results of first versus second generation Amplatzer occluders for left atrial appendage closure in patients with atrial fibrillation. Clin. Res. Cardiol. 104, 656–665 (2015).

    PubMed  Google Scholar 

  112. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02879448 (2016).

  113. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02954237 (2016).

  114. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02964208 (2016).

  115. Holmes, D. R. et al. 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 374, 534–542 (2009).

    CAS  PubMed  Google Scholar 

  116. Sick, P. B. et al. Initial worldwide experience with the WATCHMAN left atrial appendage system for stroke prevention in atrial fibrillation. J. Am. Coll. Cardiol. 49, 1490–1495 (2007).

    PubMed  Google Scholar 

  117. Reddy, V. Y., Holmes, D., Doshi, S. K., 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 123, 417–424 (2011).

    PubMed  Google Scholar 

  118. Masoudi, F. A. et al. 2015 ACC/HRS/SCAI Left Atrial Appendage Occlusion Device Societal Overview. J. Am. Coll. Cardiol. 66, 1497–1513 (2015).

    PubMed  Google Scholar 

  119. Holmes, D. R. Jr. 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. 64, 1–12 (2014).

    PubMed  Google Scholar 

  120. U.S. Food and Drug Administration. Premarket Approval: WATCHMAN Left Atrial Appendage (LAA) Closure Technology. US FDA http://www.accessdata.fda.gov/cdrh_docs/pdf13/p130013a.pdf (2015).

  121. Holmes, D. R. Jr. et al. Left atrial appendage closure as an alternative to warfarin for stroke prevention in atrial fibrillation: a patient-level meta-analysis. J. Am. Coll. Cardiol. 65, 2614–2623 (2015).

    PubMed  Google Scholar 

  122. Boersma, L. V. et al. Implant success and safety of left atrial appendage closure with the WATCHMAN device: peri-procedural outcomes from the EWOLUTION registry. Eur. Heart J. 37, 2465–2474 (2016).

    PubMed  PubMed Central  Google Scholar 

  123. Pison, L. et al. Left atrial appendage closure-indications, techniques, and outcomes: results of the European Heart Rhythm Association Survey. Europace 17, 642–646 (2015).

    PubMed  Google Scholar 

  124. Reddy, V. Y. et al. Post-approval U.S. experience with left atrial appendage closure for stroke prevention in atrial fibrillation. J. Am. Coll. Cardiol. 69, 253–261 (2017).

    PubMed  Google Scholar 

  125. Tereshchenko, L. G., Henrikson, C. A., Cigarroa, J. & Steinberg, J. S. Comparative effectiveness of interventions for stroke prevention in atrial fibrillation: a network meta-analysis. J. Am. Heart Assoc. 5, e003206 (2016).

    PubMed  PubMed Central  Google Scholar 

  126. Bartus, K. et al. Feasibility of closed-chest ligation of the left atrial appendage in humans. Heart Rhythm 8, 188–193 (2011).

    PubMed  Google Scholar 

  127. Lee, R. J., Bartus, K. & Yakubov, S. J. Catheter-based left atrial appendage (LAA) ligation for the prevention of embolic events arising from the LAA: initial experience in a canine model. Circ. Cardiovasc. Interv. 3, 224–229 (2010).

    PubMed  Google Scholar 

  128. Bartus, K. et al. Percutaneous left atrial appendage suture ligation using the LARIAT device in patients with atrial fibrillation: initial clinical experience. J. Am. Coll. Cardiol. 62, 108–118 (2013).

    PubMed  Google Scholar 

  129. Price, M. J. et al. Early safety and efficacy of percutaneous left atrial appendage suture ligation: results from the U.S. transcatheter LAA ligation consortium. J. Am. Coll. Cardiol. 64, 565–572 (2014).

    PubMed  PubMed Central  Google Scholar 

  130. Chatterjee, S. et al. Safety and procedural success of left atrial appendage exclusion with the lariat device: a systematic review of published reports and analytic review of the FDA MAUDE database. JAMA Intern. Med. 175, 1104–1109 (2015).

    PubMed  Google Scholar 

  131. Nagaraj, H., Wilber, D. & Lakkireddy, D. R. The lariat for left atrial appendage closure: rehash of known literature or a true analysis? JAMA Intern. Med. 175, 1867–1868 (2015).

    PubMed  Google Scholar 

  132. U.S. Food and Drug Administration. Use of LARIAT suture delivery device for left atrial appendage closure: FDA safety communication. US FDA http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm454501.htm (2015).

  133. Lakkireddy, D. et al. Short and long-term outcomes of percutaneous left atrial appendage suture ligation: results from a US multicenter evaluation. Heart Rhythm 13, 1030–1036 (2016).

    PubMed  Google Scholar 

  134. Bartus, K. et al. Left atrial appendage ligation with the next generation LARIAT+ suture delivery device: Early clinical experience. Int. J. Cardiol. 215, 244–247 (2016).

    PubMed  Google Scholar 

  135. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02239887 (2014).

  136. Reddy, V. Y. et al. Clinical experience with the Wavecrest LA appendage occlusion device for stroke prevention in AF: acute results of the WAVECREST I trial [abstract PO01–112]. Presented at The Heart Rhythm Society's 35th Annual Scientific Sessions (2014).

  137. Toumanides, S., Sideris, E. B., Agricola, T. & Moulopoulos, S. Transcatheter patch occlusion of the left atrial appendage using surgical adhesives in high-risk patients with atrial fibrillation. J. Am. Coll. Cardiol. 58, 2236–2240 (2011).

    PubMed  Google Scholar 

  138. Kim, J. S. et al. Preclinical assessment of a modified Occlutech left atrial appendage closure device in a canine model. Int. J. Cardiol. 221, 413–418 (2016).

    PubMed  Google Scholar 

  139. Park, J. W. et al. Percutaneous left atrial appendage closure with a novel self-modelizing device: a pre-clinical feasibility study. Int. J. Cardiol. 177, 957–963 (2014).

    PubMed  Google Scholar 

  140. Bellmann, B. et al. Left atrial appendage closure with the new Occlutech® device: first in man experience and neurological outcome. J. Cardiovasc. Electrophysiol. 28, 315–320 (2016).

    PubMed  Google Scholar 

  141. Cheng, Y. et al. First in vivo evaluation of a flexible self-apposing left atrial appendage closure device in the canine model. Catheter. Cardiovasc. Interv. 86, 173–181 (2015).

    PubMed  Google Scholar 

  142. Regueiro, A. et al. Left atrial appendage closure: Initial experience with the ultraseal device. Catheter. Cardiovasc. Interv. http://dx.doi.org/10.1002/ccd.26870 (2016).

  143. Friedman, P. A. et al. Percutaneous epicardial left atrial appendage closure: preliminary results of an electrogram guided approach. J. Cardiovasc. Electrophysiol. 20, 908–915 (2009).

    PubMed  Google Scholar 

  144. Lam, Y.-Y. et al. Preclinical evaluation of a new left atrial appendage occluder (Lifetech LAmbre™ device) in a canine model. Int. J. Cardiol. 168, 3996–4001 (2013).

    PubMed  Google Scholar 

  145. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02583178 (2017).

  146. Meier, B. et al. EHRA/EAPCI expert consensus statement on catheter-based left atrial appendage occlusion. EuroIntervention 10, 1109–1125 (2015).

    PubMed  Google Scholar 

  147. Coylewright, M., Mack, M. J., Holmes, D. R. Jr & O'Gara, P. T. A call for an evidence-based approach to the Heart Team for patients with severe aortic stenosis. J. Am. Coll. Cardiol. 65, 1472–1480 (2015).

    PubMed  Google Scholar 

  148. Emmert, M. Y. & Salzberg, S. P. Left atrial appendage occlusion device societal overview: the surgeon's comment. J. Am. Coll. Cardiol. 67, 124 (2016).

    PubMed  Google Scholar 

  149. Holmes, D. R. Jr., Mohr, F., Hamm, C. W. & Mack, M. J. Venn diagrams in cardiovascular disease: the Heart Team concept. Eur. Heart J. 35, 66–68 (2014).

    PubMed  Google Scholar 

  150. Holmes, D. R. Jr, Rich, J. B., Zoghbi, W. A. & Mack, M. J. The heart team of cardiovascular care. J. Am. Coll. Cardiol. 61, 903–907 (2013).

    PubMed  Google Scholar 

  151. Salzberg, S. P., Grunenfelder, J. & Emmert, M. Y. Left atrial appendage closure to prevent stroke in patients with atrial fibrillation: a call for the heart team approach. Europace 17, 1880–1881 (2015).

    PubMed  Google Scholar 

  152. Viles-Gonzalez, J. F. et al. The clinical impact of incomplete left atrial appendage closure with the Watchman Device in patients with atrial fibrillation: a PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation) substudy. J. Am. Coll. Cardiol. 59, 923–929 (2012).

    PubMed  Google Scholar 

  153. Freixa, X. et al. Characterization of cerebrovascular events after left atrial appendage occlusion. Am. J. Cardiol. 118, 1836–1841 (2016).

    PubMed  Google Scholar 

  154. Reddy, V. et al. TCT-26 long-term event rates for left atrial appendage closure with WATCHMAN: PROTECT AF 5 year and PREVAIL 3 year follow-up. J. Am. Coll. Cardiol. 68, B11 (2016).

    Google Scholar 

  155. Reddy, V. Y. 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. 61, 2551–2556 (2013).

    PubMed  Google Scholar 

  156. Cruz-Gonzalez, I., Martín Moreiras, J. & García, E. Thrombus formation after left atrial appendage exclusion using an Amplatzer cardiac plug device. Catheter. Cardiovasc. Interv. 78, 970–973 (2011).

    PubMed  Google Scholar 

  157. Aznaurov, S. G., Ball, S. K. & Ellis, C. R. Thoracoscopic atriclip closure of left atrial appendage after failed ligation via LARIAT. JACC Cardiovasc. Interv. 8, e265–e267 (2015).

    PubMed  Google Scholar 

  158. Guérios, Ê. E. et al. Double device left atrial appendage closure. EuroIntervention 11, 470–476 (2015).

    PubMed  Google Scholar 

  159. Hornung, M. et al. Catheter-based closure of residual leaks after percutaneous occlusion of the left atrial appendage. Catheter. Cardiovasc Interv. 87, 1324–1330 (2016).

    PubMed  Google Scholar 

  160. Pillai, A. M. et al. Initial experience with post Lariat left atrial appendage leak closure with Amplatzer septal occluder device and repeat Lariat application. Heart Rhythm 11, 1877–1883 (2014).

    PubMed  Google Scholar 

  161. Masoudi, F. A. et al. Most hospitalized older persons do not meet the enrollment criteria for clinical trials in heart failure. Am. Heart J. 146, 250–257 (2003).

    PubMed  Google Scholar 

  162. Wennberg, D. E., Lucas, F. L., Birkmeyer, J. D., Bredenberg, C. E. & Fisher, E. S. Variation in carotid endarterectomy mortality in the medicare population: Trial hospitals, volume, and patient characteristics. JAMA 279, 1278–1281 (1998).

    CAS  PubMed  Google Scholar 

  163. Masoudi, F. A. The evolution of left atrial appendage occlusion: EWOLUTION and the WATCHMAN in practice. Eur. Heart J. 37, 2475–2477 (2016).

    PubMed  Google Scholar 

  164. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02699957 (2016).

  165. Reddy, V. Y. et al. Time to cost-effectiveness following stroke reduction strategies in AF: warfarin versus NOACs versus LAA closure. J. Am. Coll. Cardiol. 66, 2728–2739 (2015).

    PubMed  Google Scholar 

  166. Reddy, V. Y. et al. Cost effectiveness of left atrial appendage closure with the Watchman device for atrial fibrillation patients with absolute contraindications to warfarin. Europace 18, 979–986 (2016).

    PubMed  PubMed Central  Google Scholar 

  167. Cruz-Gonzalez, I. et al. Brain natriuretic peptide levels variation after left atrial appendage occlusion. Catheter. Cardiovasc. Interv. 87, E39–E43 (2016).

    PubMed  Google Scholar 

  168. Majunke, N. et al. Atrial and brain natriuretic peptide secretion after percutaneous closure of the left atrial appendage with the watchman device. J. Invasive Cardiol. 27, 448–452 (2015).

    PubMed  Google Scholar 

  169. Zois, N. E. et al. Natriuretic peptides in cardiometabolic regulation and disease. Nat. Rev. Cardiol. 11, 403–412 (2014).

    CAS  PubMed  Google Scholar 

  170. Tzikas, A. et al. Percutaneous left atrial appendage occlusion: the Munich consensus document on definitions, endpoints and data collection requirements for clinical studies. EuroIntervention 12, 103–111 (2016).

    PubMed  Google Scholar 

  171. Li, X. et al. Over 1-year efficacy and safety of left atrial appendage occlusion versus novel oral anticoagulants for stroke prevention in atrial fibrillation: A systematic review and meta-analysis of randomized controlled trials and observational studies. Heart Rhythm 13, 1203–1214 (2016).

    PubMed  Google Scholar 

  172. Ho, S. Y., Cabrera, J. A. & Sanchez-Quintana, D. Left atrial anatomy revisited. Circ. Arrhythm. Electrophysiol. 5, 220–228 (2012).

    PubMed  Google Scholar 

  173. Su, P., McCarthy, K. P. & Ho, S. Y. Occluding the left atrial appendage: anatomical considerations. Heart 94, 1166–1170 (2008).

    CAS  PubMed  Google Scholar 

  174. Veinot, J. P. et al. Anatomy of the normal left atrial appendage: a quantitative study of age-related changes in 500 autopsy hearts: implications for echocardiographic examination. Circulation 96, 3112–3115 (1997).

    CAS  PubMed  Google Scholar 

  175. Fountain, R. B. et al. The PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients with Atrial Fibrillation) trial. Am. Heart J. 151, 956–961 (2006).

    PubMed  Google Scholar 

  176. Freixa, X. et al. The Amplatzer™ Cardiac Plug 2 for left atrial appendage occlusion: novel features and first-in-man experience. EuroIntervention 8, 1094–1098 (2013).

    PubMed  Google Scholar 

  177. Lam, Y.-Y. A new left atrial appendage occluder (Lifetech LAmbreTM Device) for stroke prevention in atrial fibrillation. Cardiovasc. Revasc. Med. 14, 134–136 (2013).

    PubMed  Google Scholar 

  178. Block, P. C. et al. Percutaneous left atrial appendage occlusion for patients in atrial fibrillation suboptimal for warfarin therapy: 5-year results of the PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion) Study. JACC Cardiovasc. Interv. 2, 594–600 (2009).

    PubMed  Google Scholar 

  179. Reddy, V. Y. et al. Percutaneous left atrial appendage closure versus warfarin for atrial fibrillation: a randomized clinical trial. JAMA 312, 1988–1998 (2014).

    PubMed  Google Scholar 

  180. Hildick-Smith, D. et al. The AMULET study: a multicenter, prospective registry of the Amulet left atrial appendage closure device for stroke prevention in patients with atrial fibrillation. Presented at the Transcatheter Cardiovascular Therapeutics 2016 https://www.tctmd.com/sites/default/files/efs/public/2016-11/4442653.pdf (2016).

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Authors and Affiliations

  1. Department of Cardiovascular Surgery, Charité Universitätsmedizin Berlin, Charitéplatz 1, Berlin, 10117, Germany

    Etem Caliskan & Volkmar Falk

  2. Department of Cardiothoracic and Vascular Surgery, German Heart Institute Berlin, Augustenburger Platz 1, Berlin, 13353, Germany

    Etem Caliskan & Volkmar Falk

  3. Feinberg School of Medicine, Northwestern University, Arthur J. Rubloff Building, 420 East Superior Street, Chicago, 60611, Illinois, USA

    James L. Cox

  4. Department of Cardiology, Mayo Clinic, 200 First Street SW, Rochester, 55905, Minnesota, USA

    David R. Holmes Jr

  5. Department of Cardiology, University Hospital of Bern, Freiburgstrasse 8, Bern, 3010, Switzerland

    Bernhard Meier

  6. Section of Electrophysiology, University of Kansas Hospital, 3901 Rainbow Boulevard, Kansas City, 66160, Kansas, USA

    Dhanunjaya R. Lakkireddy

  7. HeartClinic, Hirslanden Hospital, Witellikerstrasse 40, Zurich, 8032, Switzerland

    Sacha P. Salzberg

  8. University Heart Center, Clinic for Cardiovascular Surgery, University Hospital Zurich, University of Zurich, Raemistrasse 100, Zurich, 8091, Switzerland

    Maximilian Y. Emmert

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  1. Etem Caliskan
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E.C. and M.Y.E. researched the data for the article and wrote the manuscript. All the authors made substantial contributions to discussion of content, and edited/reviewed the manuscript before submission.

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Correspondence to Maximilian Y. Emmert.

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Competing interests

J.L.C. is a consultant for and holds shares in Atricure, Inc. and SentreHEART, Inc. B.M. has received speaker fees from Abbott. D.R.L. is the steering committee chair for the AMULET IDE and AMAZE IDE trials. S.P.S. and M.Y.E. have received speaker fees from Atricure and Maquet. E.C., D.R.H., and V.F. declare no competing interests.

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Caliskan, E., Cox, J., Holmes, D. et al. Interventional and surgical occlusion of the left atrial appendage. Nat Rev Cardiol 14, 727–743 (2017). https://doi.org/10.1038/nrcardio.2017.107

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