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
- pfo closure
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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.
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