Article Text

Download PDFPDF

Patent foramen ovale closure, antiplatelet therapy or anticoagulation in patients with patent foramen ovale and cryptogenic stroke: a systematic review and network meta-analysis incorporating complementary external evidence
  1. Hassan Mir1,2,
  2. Reed Alexander C Siemieniuk1,2,
  3. Long Cruz Ge3,
  4. Farid Foroutan4,5,
  5. Michael Fralick6,
  6. Talha Syed1,
  7. Luciane Cruz Lopes7,
  8. Ton Kuijpers8,
  9. Jean-Louis Mas9,
  10. Per O Vandvik10,11,
  11. Thomas Agoritsas1,12,13,
  12. Gordon H Guyatt1
  1. 1 Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
  2. 2 Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  3. 3 Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
  4. 4 Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
  5. 5 Heart Failure/Transplant Program, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
  6. 6 Eliot Phillipson Clinician Scientist Training Program, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  7. 7 Pharmaceutical Sciences Graduate Course, University of Sorocaba, UNISO, Sao Paulo, Brazil
  8. 8 Department of Guideline Development and Research, Dutch College of General Practitioners, Utrecht, The Netherlands
  9. 9 Department of Neurology, Sainte-Anne Hospital, Paris, France
  10. 10 Norwegian Institute of Public Health, Oslo, Norway
  11. 11 Department of Medicine, Innlandet Hospital Trust—Division Gjøvik, Oslo, Norway
  12. 12 Division of General Internal Medicine, University Hospitals of Geneva, Geneva, Switzerland
  13. 13 Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland
  1. Correspondence to Dr Hassan Mir; hassan.mir1{at}


Objective To examine the relative impact of three management options in patients aged <60 years with cryptogenic stroke and a patent foramen ovale (PFO): PFO closure plus antiplatelet therapy, antiplatelet therapy alone and anticoagulation alone.

Design Systematic review and network meta-analysis (NMA) supported by complementary external evidence.

Data sources Medline, EMBASE and Cochrane CENTRAL.

Study selection Randomised controlled trials (RCTs) addressing PFO closure and/or medical therapies in patients with PFO and cryptogenic stroke.

Review methods We conducted an NMA complemented with external evidence and rated certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.

Results Ten RCTs in eight studies proved eligible (n=4416). Seven RCTs (n=3913) addressed PFO closure versus medical therapy. Of these, three (n=1257) addressed PFO closure versus antiplatelet therapy, three (n=2303) addressed PFO closure versus mixed antiplatelet and anticoagulation therapies and one (n=353) addressed PFO closure versus anticoagulation. The remaining three RCTs (n=503) addressed anticoagulant versus antiplatelet therapy. PFO closure versus antiplatelet therapy probably results in substantial reduction in ischaemic stroke recurrence (risk difference per 1000 patients over 5 years (RD): −87, 95% credible interval (CrI) −100 to −33; moderate certainty). Compared with anticoagulation, PFO closure may confer little or no difference in ischaemic stroke recurrence (low certainty) but probably has a lower risk of major bleeding (RD −20, 95% CrI −27 to −2, moderate certainty). Relative to either medical therapy, PFO closure probably increases the risk of persistent atrial fibrillation (RD 18, 95% CI +5 to +56, moderate certainty) and device-related adverse events (RD +36, 95% CI +23 to +50, high certainty). Anticoagulation, compared with antiplatelet therapy, may reduce the risk of ischaemic stroke recurrence (RD −71, 95% CrI −100 to +17, low certainty), but probably increases the risk of major bleeding (RD +12, 95% CrI −5 to +65, moderate certainty).

Conclusions In patients aged <60 years, PFO closure probably confers an important reduction in ischaemic stroke recurrence compared with antiplatelet therapy alone but may make no difference compared with anticoagulation. PFO closure incurs a risk of persistent atrial fibrillation and device-related adverse events. Compared with alternatives, anticoagulation probably increases major bleeding.

PROSPERO registration number CRD42017081567.

  • cryptogenic stroke
  • patent foramen ovale
  • anticoagulation
  • antiplatelet
  • pfo closure

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:

View Full Text

Statistics from


  • Contributors GHG and RACS conceived the study idea. HM performed the literature search and data analysis. HM, RACS, TA, GHG, POV interpreted the data analysis. HM, RACS and GHG wrote the first draft of the manuscript. TS, LL and MF acquired data and judged risk of bias in the studies. FF extracted patient level survival data from Kaplan-Meier curves. LG provided statistical advice. RACS, GHG, TA, POV, TK, J-LM and MF critically reviewed the manuscript. HM had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. HM is guarantor.

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

  • Disclaimer The lead author (HM) affirms that the manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted and that any discrepancies from the study as planned have been explained.

  • Competing interests All authors have completed the BMJ Rapid Recommendations disclosure form, which asks about any possible financial, intellectual and professional conflicts of interest (available on request). To summarise, J-LM has received consulting honoraria from Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, GECKO and Servier. HM, RACS, TK, PV, TA and GHG are also panel members of the linked Rapid Recommendation guideline panel.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Extra data can be accessed via the Dryad data repository at with the doi: 10.5061/dryad.ng017rc

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Linked Articles