Patent foramen ovale closure versus medical therapy for prevention of recurrent cryptogenic embolism: updated meta-analysis of randomized clinical trials
We performed an updated meta-analysis of all randomized-controlled trials (RCTs) comparing patent foramen ovale (PFO) closure with medical therapy for prevention of recurrent ischemic stroke.
Methods and results
We searched Medline, EMBASE, and Cochrane databases, and proceedings of international meetings for RCTs of patients with cryptogenic stroke and PFO comparing percutaneous PFO closure versus medical therapy for prevention of recurrent ischemic stroke. The primary outcome was a composite ischemic/embolic endpoint comprising stroke, transient ischemic attack (TIA), peripheral embolism, and early death in the intention-to-treat population. Secondary outcomes were all-cause death, stroke, TIA, atrial fibrillation (AF), and major bleeding. Of 3440 enrolled patients across five RCTs, 1829 were allocated to PFO closure and 1611 to medical therapy. The follow-up ranged from 2 to 5.9 years. PFO closure reduced the risk of the composite outcome [HR 0.52, (0.36–0.77); p < 0.01], and stroke, [HR 0.39, (0.19–0.83); p < 0.01], and increased the risk of AF [OR 3.75, (2.44–5.78); p < 0.01] as compared to medical therapy. NNT for stroke was 37 and NNH for AF 49, indicating a net clinical benefit of PFO closure. The meta-analysis had 95% power to detect a 50% relative risk reduction (RRR) in the primary outcome and 89% power to detect a 70% RRR in ischemic stroke. The risk of all-cause death (HR 1.08, p = 0.90), TIA [HR 0.73, (0.49–1.09); p = 0.12], and major bleeding [OR 0.97, (0.44–2.17); p = 0.95] was comparable between the groups.
Among patients with cryptogenic stroke and PFO, percutaneous closure of PFO is superior to medical therapy in preventing recurrent ischemic/embolic events and stroke but is associated with an increased risk of AF.
KeywordsPersistent foramen ovale Structural intervention Stroke Transcatheter intervention
Compliance with ethical standards
Conflict of interest
Dr. Colleran reports a grant from the Irish Board for Training in Cardiovascular Medicine sponsored by MSD, outside the submitted work. Prof. Lauten reports grants from Edwards Lifesciences, grants from Abbott Vascular, outside the submitted work. Prof. Meier was principal investigator of the PC trial and reports personal fees from Abbott, during the conduction of the study and Co-primary investigator of the PC trial (more than 2 years ago). Prof. Landmesser reports grants from Edwards Lifesciences, grants and personal fees from Abbott, outside the submitted work. All other authors report no relationships relevant to the contents of this paper to disclose.
- 5.Wahl A, Juni P, Mono ML, Kalesan B, Praz F, Geister L, Raber L, Nedeltchev K, Mattle HP, Windecker S, Meier B (2012) Long-term propensity score-matched comparison of percutaneous closure of patent foramen ovale with medical treatment after paradoxical embolism. Circulation 125 (6):803–812. https://doi.org/10.1161/CIRCULATIONAHA.111.030494 CrossRefPubMedGoogle Scholar
- 6.Capodanno D, Milazzo G, Vitale L, Di Stefano D, Di Salvo M, Grasso C, Tamburino C (2014) Updating the evidence on patent foramen ovale closure versus medical therapy in patients with cryptogenic stroke: a systematic review and comprehensive meta-analysis of 2,303 patients from three randomised trials and 2,231 patients from 11 observational studies. EuroIntervention 9 (11):1342–1349. https://doi.org/10.4244/EIJV9I11A225 CrossRefPubMedGoogle Scholar
- 7.Stortecky S, da Costa BR, Mattle HP, Carroll J, Hornung M, Sievert H, Trelle S, Windecker S, Meier B, Juni P (2015) Percutaneous closure of patent foramen ovale in patients with cryptogenic embolism: a network meta-analysis. Eur Heart J 36 (2):120–128. https://doi.org/10.1093/eurheartj/ehu292 CrossRefPubMedGoogle Scholar
- 8.Kent DM, Dahabreh IJ, Ruthazer R, Furlan AJ, Reisman M, Carroll JD, Saver JL, Smalling RW, Juni P, Mattle HP, Meier B, Thaler DE (2016) Device closure of patent foramen ovale after stroke: pooled analysis of completed randomized trials. J Am Coll Cardiol 67 (8):907–917. https://doi.org/10.1016/j.jacc.2015.12.023 CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Furlan AJ, Reisman M, Massaro J, Mauri L, Adams H, Albers GW, Felberg R, Herrmann H, Kar S, Landzberg M, Raizner A, Wechsler L, Investigators CI (2012) Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med 366 (11):991–999. https://doi.org/10.1056/NEJMoa1009639 CrossRefPubMedGoogle Scholar
- 10.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, Investigators PCT (2013) Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 368 (12):1083–1091. https://doi.org/10.1056/NEJMoa1211716 CrossRefPubMedGoogle Scholar
- 12.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, Investigators C (2017) Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med 377 (11):1011–1021. https://doi.org/10.1056/NEJMoa1705915 CrossRefPubMedGoogle Scholar
- 14.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, Gore RCSI (2017) Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med 377 (11):1033–1042. https://doi.org/10.1056/NEJMoa1707404 CrossRefPubMedGoogle Scholar
- 21.Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 6 (7):e1000100. https://doi.org/10.1371/journal.pmed.1000100 CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Sacco RL, Adams R, Albers G, Alberts MJ, Benavente O, Furie K, Goldstein LB, Gorelick P, Halperin J, Harbaugh R, Johnston SC, Katzan I, Kelly-Hayes M, Kenton EJ, Marks M, Schwamm LH, Tomsick T, American Heart A, American Stroke Association Council on S, Council on Cardiovascular R, Intervention, American Academy of N (2006) Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Stroke 37 (2):577–617. https://doi.org/10.1161/01.STR.0000199147.30016.74 CrossRefPubMedGoogle Scholar
- 23.Goel SS, Tuzcu EM, Shishehbor MH, de Oliveira EI, Borek PP, Krasuski RA, Rodriguez LL, Kapadia SR (2009) Morphology of the patent foramen ovale in asymptomatic versus symptomatic (stroke or transient ischemic attack) patients. Am J Cardiol 103 (1):124–129. https://doi.org/10.1016/j.amjcard.2008.08.036 CrossRefPubMedGoogle Scholar
- 26.Alushi B, Biasco L, Orzan F, Omede P, Sciuto F, Moretti C, Belli R, Defilippi G, Barisone G, Cerrato P, Gaita F (2014) Patent foramen ovale treatment strategy: an Italian large prospective study. J Cardiovasc Med (Hagerstown) 15 (10):761–768. https://doi.org/10.2459/JCM.0000000000000138 CrossRefGoogle Scholar
- 27.Wessler BS, Thaler DE, Ruthazer R, Weimar C, Di Tullio MR, Elkind MS, Homma S, Lutz JS, Mas JL, Mattle HP, Meier B, Nedeltchev K, Papetti F, Di Angelantonio E, Reisman M, Serena J, Kent DM (2014) Transesophageal echocardiography in cryptogenic stroke and patent foramen ovale: analysis of putative high-risk features from the risk of paradoxical embolism database. Circ Cardiovasc Imaging 7 (1):125–131. https://doi.org/10.1161/CIRCIMAGING.113.000807 CrossRefPubMedGoogle Scholar
- 28.Ahmad Y, Howard JP, Arnold A, Shin MS, Cook C, Petraco R, Demir O, Williams L, Iglesias JF, Sutaria N, Malik I, Davies J, Mayet J, Francis D, Sen S (2018) Patent foramen ovale closure vs. medical therapy for cryptogenic stroke: a meta-analysis of randomized controlled trials. Eur Heart J. https://doi.org/10.1093/eurheartj/ehy121 PubMedGoogle Scholar
- 29.Ando T, Holmes AA, Pahuja M, Javed A, Briasoulis A, Telila T, Takagi H, Schreiber T, Afonso L, Grines CL, Bangalore S (2017) Meta-analysis comparing patent foramen ovale closure versus medical therapy to prevent recurrent cryptogenic stroke. Am J Cardiol. https://doi.org/10.1016/j.amjcard.2017.11.037 Google Scholar
- 31.Ntaios G, Papavasileiou V, Sagris D, Makaritsis K, Vemmos K, Steiner T, Michel P (2018) Closure of patent foramen ovale versus medical therapy in patients with cryptogenic stroke or transient ischemic attack: updated systematic review and meta-analysis. Stroke. https://doi.org/10.1161/strokeaha.117.020030 Google Scholar