Clinical Research in Cardiology

, Volume 108, Issue 2, pp 157–166 | Cite as

Interventional closure vs. medical therapy of patent foramen ovale for secondary prevention of stroke: updated meta-analysis

  • Davor VukadinovićEmail author
  • Stephan H. Schirmer
  • Aleksandra Nikolovska Vukadinović
  • Christian Ukena
  • Bruno Scheller
  • Felix Mahfoud
  • Michael Böhm
Original Paper



We aimed to explore whether interventional closure of patent foramen ovale (PFO) results in reduction of composite outcome [stroke/transitory ischemic attack (TIA), death, and thrombolysis in myocardial infarction—TIMI bleeding], stroke and stroke/TIA compared to medical treatment in patients with cryptogenic stroke.

Methods and results

Searching the PUBMED and Cochrane library database, we performed meta-analysis from all randomized controlled studies that compared effects of interventional PFO closure with medical treatment on stroke prevention. 3560 patients from six randomized trials were included. Interventional PFO closure reduced composite outcome (RR of 0.47, 0.26–0.85, p = 0.01), stroke (RR of 0.38, 0.18–0.82, p = 0.01) and stroke/TIA (RR of 0.56, 0.43–0.74, p < 0.0001). Analysis had 70.5% power to detect observed reduction of RR for the primary outcome, 70.6% for stroke and 98.7% for stroke/TIA. Bleeding rates were comparable (RR of 0.91, 0.60–1.38, p = 0.66), while there was higher burden of new AF (RR of 5.54, 3–10.2, p < 0.0001) after interventional closure. Subgroup analysis revealed that patients with large shunts had substantial less recurrent strokes over patients with small shunts (p for interaction = 0.02). Use of Amplatzer PFO device was associated with substantial less AF (RR of 2.36, p = 0.06) compared with other devices (RR of 8.93, p < 0.0001) (p for interaction = 0.04), with comparable benefit for stroke prevention (p for interaction = 0.73).


Interventional closure of PFO resulted in significant reduction of stroke and stroke/TIA compared with antiplatelets/anticoagulants with comparable bleeding rates between the groups, whereas AF occurred more frequently in the intervention group. Patients with large shunts had more benefit from interventional closure.


Patent foramen ovale Interventional PFO closure Cryptogenic stroke Meta-analysis 



This research received no specific Grant from any funding agency in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

392_2018_1334_MOESM1_ESM.docx (113 kb)
Supplementary material 1 (DOCX 113 KB)


  1. 1.
    Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O’Donnell MJ, Sacco RL, Connolly SJ (2014) Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 13(4):429–438. CrossRefGoogle Scholar
  2. 2.
    Alsheikh-Ali AA, Thaler DE, Kent DM (2009) Patent foramen ovale in cryptogenic stroke: incidental or pathogenic? Stroke 40(7):2349–2355. CrossRefGoogle Scholar
  3. 3.
    Handke M, Harloff A, Olschewski M, Hetzel A, Geibel A (2007) Patent foramen ovale and cryptogenic stroke in older patients. N Engl J Med 357(22):2262–2268. CrossRefGoogle Scholar
  4. 4.
    Meier B, Kalesan B, Mattle HP, Khattab AA, Hildick-Smith D, Dudek D, Andersen G, Ibrahim R, Schuler G, Walton AS, Wahl A, Windecker S, Juni P (2013) Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 368(12):1083–1091. CrossRefGoogle Scholar
  5. 5.
    Furlan AJ, Reisman M, Massaro J, Mauri L, Adams H, Albers GW, Felberg R, Herrmann H, Kar S, Landzberg M, Raizner A, Wechsler L (2012) Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med 366(11):991–999. CrossRefGoogle Scholar
  6. 6.
    Carroll JD, Saver JL, Thaler DE, Smalling RW, Berry S, MacDonald LA, Marks DS, Tirschwell DL (2013) Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med 368(12):1092–1100. CrossRefGoogle Scholar
  7. 7.
    Saver JL, Carroll JD, Thaler DE, Smalling RW, MacDonald LA, Marks DS, Tirschwell DL (2017) Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med 377(11):1022–1032. CrossRefGoogle Scholar
  8. 8.
    Mas JL, Derumeaux G, Guillon B, Massardier E, Hosseini H, Mechtouff L, Arquizan C, Bejot Y, Vuillier F, Detante O, Guidoux C, Canaple S, Vaduva C, Dequatre-Ponchelle N, Sibon I, Garnier P, Ferrier A, Timsit S, Robinet-Borgomano E, Sablot D, Lacour JC, Zuber M, Favrole P, Pinel JF, Apoil M, Reiner P, Lefebvre C, Guerin P, Piot C, Rossi R, Dubois-Rande JL, Eicher JC, Meneveau N, Lusson JR, Bertrand B, Schleich JM, Godart F, Thambo JB, Leborgne L, Michel P, Pierard L, Turc G, Barthelet M, Charles-Nelson A, Weimar C, Moulin T, Juliard JM, Chatellier G (2017) Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med 377(11):1011–1021. CrossRefGoogle Scholar
  9. 9.
    Sondergaard L, Kasner SE, Rhodes JF, Andersen G, Iversen HK, Nielsen-Kudsk JE, Settergren M, Sjostrand C, Roine RO, Hildick-Smith D, Spence JD, Thomassen L (2017) Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med 377(11):1033–1042. CrossRefGoogle Scholar
  10. 10.
    Lee PH, Song JK, Kim JS, Heo R, Lee S, Kim DH, Song JM, Kang DH, Kwon SU, Kang DW, Lee D, Kwon HS, Yun SC, Sun BJ, Park JH, Lee JH, Jeong HS, Song HJ, Kim J, Park SJ (2018) Cryptogenic stroke and high-risk patent foramen ovale: The DEFENSE-PFO Trial. J Am Coll Cardiol 71(20):2335–2342. CrossRefGoogle Scholar
  11. 11.
    Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151(4):264–269, W264CrossRefGoogle Scholar
  12. 12.
    Rao G, Lopez-Jimenez F, Boyd J, D’Amico F, Durant NH, Hlatky MA, Howard G, Kirley K, Masi C, Powell-Wiley TM, Solomonides AE, West CP, Wessel J (2017) Methodological standards for meta-analyses and qualitative systematic reviews of cardiac prevention and treatment studies: a scientific statement from the American Heart Association. Circulation 136(10):e172–e194. CrossRefGoogle Scholar
  13. 13.
    Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17(1):1–12CrossRefGoogle Scholar
  14. 14.
    Olivo SA, Macedo LG, Gadotti IC, Fuentes J, Stanton T, Magee DJ (2008) Scales to assess the quality of randomized controlled trials: a systematic review. Phys Ther 88(2):156–175. CrossRefGoogle Scholar
  15. 15.
    Altman DG, Bland JM (2003) Interaction revisited: the difference between two estimates. BMJ 326(7382):219CrossRefGoogle Scholar
  16. 16.
    Turner RM, Bird SM, Higgins JP (2013) The impact of study size on meta-analyses: examination of underpowered studies in Cochrane reviews. PloS One 8(3):e59202. CrossRefGoogle Scholar
  17. 17.
    Schulze V, Lin Y, Karathanos A, Brockmeyer M, Zeus T, Polzin A, Perings S, Kelm M, Wolff G (2018) Patent foramen ovale closure or medical therapy for cryptogenic ischemic stroke: an updated meta-analysis of randomized controlled trials. Clin Res Cardiol. Google Scholar
  18. 18.
    Alushi B, Lauten A, Cassese S, Colleran R, Schupke S, Rai H, Schunkert H, Meier B, Landmesser U, Kastrati A (2018) Patent foramen ovale closure versus medical therapy for prevention of recurrent cryptogenic embolism: updated meta-analysis of randomized clinical trials. Clin Res Cardiol. Google Scholar
  19. 19.
    Kent DM, Ruthazer R, Weimar C, Mas JL, Serena J, Homma S, Di Angelantonio E, Di Tullio MR, Lutz JS, Elkind MS, Griffith J, Jaigobin C, Mattle HP, Michel P, Mono ML, Nedeltchev K, Papetti F, Thaler DE (2013) An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 81(7):619–625. CrossRefGoogle Scholar
  20. 20.
    Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA, Morillo CA, Rymer MM, Thijs V, Rogers T, Beckers F, Lindborg K, Brachmann J (2014) Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 370(26):2478–2486. CrossRefGoogle Scholar
  21. 21.
    Gladstone DJ, Spring M, Dorian P, Panzov V, Thorpe KE, Hall J, Vaid H, O’Donnell M, Laupacis A, Cote R, Sharma M, Blakely JA, Shuaib A, Hachinski V, Coutts SB, Sahlas DJ, Teal P, Yip S, Spence JD, Buck B, Verreault S, Casaubon LK, Penn A, Selchen D, Jin A, Howse D, Mehdiratta M, Boyle K, Aviv R, Kapral MK, Mamdani M (2014) Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med 370(26):2467–2477. CrossRefGoogle Scholar
  22. 22.
    Overell JR, Bone I, Lees KR (2000) Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 55(8):1172–1179CrossRefGoogle Scholar
  23. 23.
    Mas JL, Arquizan C, Lamy C, Zuber M, Cabanes L, Derumeaux G, Coste J (2001) Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 345(24):1740–1746. CrossRefGoogle Scholar
  24. 24.
    Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP (2002) Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation 105(22):2625–2631CrossRefGoogle Scholar
  25. 25.
    Hart RG, Sharma M, Mundl H, Shoamanesh A, Kasner SE, Berkowitz SD, Pare G, Kirsch B, Pogue J, Pater C (2016) Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: design of the NAVIGATE ESUS randomized trial. Eur Stroke J 1(3):146–154CrossRefGoogle Scholar
  26. 26.
    Baumgartner H, Bonhoeffer P, De Groot NM, de Haan F, Deanfield JE, Galie N, Gatzoulis MA, Gohlke-Baerwolf C, Kaemmerer H, Kilner P, Meijboom F, Mulder BJ, Oechslin E, Oliver JM, Serraf A, Szatmari A, Thaulow E, Vouhe PR, Walma E (2010) ESC Guidelines for the management of grown-up congenital heart disease (new version 2010). Eur Heart J 31(23):2915–2957. CrossRefGoogle Scholar
  27. 27.
    Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, Fang MC, Fisher M, Furie KL, Heck DV, Johnston SC, Kasner SE, Kittner SJ, Mitchell PH, Rich MW, Richardson D, Schwamm LH, Wilson JA (2014) 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 45(7):2160–2236. CrossRefGoogle Scholar
  28. 28.
    Messe SR, Gronseth G, Kent DM, Kizer JR, Homma S, Rosterman L, Kasner SE (2016) Practice advisory: recurrent stroke with patent foramen ovale (update of practice parameter): report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology. Neurology 87(8):815–821. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Universität des Saarlandes, Klinik für Innere Medizin III, Kardiologie, Angiologie und internistische IntensivmedizinHomburgGermany

Personalised recommendations