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However, the findings from the systematic review were not clear when observational studies were also included.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We searched <jats:styled-content style=\"fixed-case\">MEDLINE<\/jats:styled-content>, Embase, and Cochrane databases. The primary endpoints were recurrent stroke or transient ischemic attack (<jats:styled-content style=\"fixed-case\">TIA<\/jats:styled-content>). The secondary outcomes were all\u2010cause death, atrial fibrillation (<jats:styled-content style=\"fixed-case\">AF<\/jats:styled-content>), and hemorrhagic events.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Five randomized trials and fourteen observational studies (6301 participants) were eligible. <jats:styled-content style=\"fixed-case\">PFO<\/jats:styled-content> closure was superior to medical therapy for stroke prevention risk ratios ([<jats:styled-content style=\"fixed-case\">RR<\/jats:styled-content>], 0.38; 95% <jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content>, 0.24\u20100.60), but showed increased risk of <jats:styled-content style=\"fixed-case\">AF<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">RR<\/jats:styled-content>, 4.96; 95% <jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content>, 2.31\u201010.7). There was no significant difference in <jats:styled-content style=\"fixed-case\">TIA<\/jats:styled-content> recurrence, death, and hemorrhagic events. Subgroup analyses showed that patients with factors such as substantial residual shunt, the presence of atrial septal aneurysm (<jats:styled-content style=\"fixed-case\">ASA<\/jats:styled-content>), male, and age &lt;45\u00a0years had a lower risk of recurrent stroke when <jats:styled-content style=\"fixed-case\">PFO<\/jats:styled-content>s were closed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In patients with cryptogenic stroke, <jats:styled-content style=\"fixed-case\">PFO<\/jats:styled-content> closure does appeared to be superior to medical therapy in stroke prevention, with an increased incidence of <jats:styled-content style=\"fixed-case\">AF<\/jats:styled-content>. Male, age &lt;45\u00a0years, substantial residual shunt, and the history of <jats:styled-content style=\"fixed-case\">ASA<\/jats:styled-content> are the factors that will predict the benefit when <jats:styled-content style=\"fixed-case\">PFO<\/jats:styled-content> is closed.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.12980","type":"journal-article","created":{"date-parts":[[2018,5,27]],"date-time":"2018-05-27T18:21:01Z","timestamp":1527445261000},"page":"853-862","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Patent foramen ovale closure for patients with cryptogenic stroke: A systematic review and comprehensive meta\u2010analysis of 5 randomized controlled trials and 14 observational studies"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0248-8161","authenticated-orcid":false,"given":"Xi","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Neurology Huashan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi\u2010Dong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology Huashan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6630-112X","authenticated-orcid":false,"given":"Yi","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Neurology Huashan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Neurology Huashan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,5,27]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1212\/CPJ.0000000000000086"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2015.12.023"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3182a08d59"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.4244\/EIJV9I11A225"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/STR.0000000000000158"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1610057"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1009639"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1705915"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1301440"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1707404"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1211716"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.117.020030"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.7326\/M17-2679"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-018-8750-x"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijsu.2010.02.007"},{"key":"e_1_2_8_17_1","unstructured":"HigginsJPT GreenS eds.Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. 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