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.
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.
['Mir|Hassan|H|0000-0002-7486-8123', 'Siemieniuk|Reed Alexander C|RAC|', 'Ge|Long|L|', 'Foroutan|Farid|F|', 'Fralick|Michael|M|', 'Syed|Talha|T|', 'Lopes|Luciane Cruz|LC|', 'Kuijpers|Ton|T|', 'Mas|Jean-Louis|JL|', 'Vandvik|Per O|PO|', 'Agoritsas|Thomas|T|0000-0002-6182-9969', 'Guyatt|Gordon H|GH|']
D000925:Anticoagulants D001281:Atrial Fibrillation D002545:Brain Ischemia D006348:Cardiac Surgical Procedures D003131:Combined Modality Therapy D054092:Foramen Ovale, Patent D006801:Humans D000071076:Network Meta-Analysis D010975:Platelet Aggregation Inhibitors D011183:Postoperative Complications D012008:Recurrence D055502:Secondary Prevention D020521:Stroke
patent foramen ovale antiplatelet anticoagulation cryptogenic stroke pfo closure