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BMJ Open Is Committed to Open Peer Review. As Part of This Commitment We Make the Peer Review History of Every Article We Publish Publicly Available BMJ Open: first published as 10.1136/bmjopen-2018-023761 on 25 July 2018. Downloaded from BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email [email protected] http://bmjopen.bmj.com/ on September 27, 2021 by guest. Protected copyright. BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-023761 on 25 July 2018. Downloaded from 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 ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2018-023761 Article Type: Research Date Submitted by the Author: 23-Apr-2018 Complete List of Authors: Mir, Hassan; McMaster University, Medicine; Siemieniuk, Reed; Mcmaster University, Clinical Epidemiology and Biostatistics; University of Toronto, Department of Medicine Ge, Long; The First Clinical Medical College of Lanzhou University, Foroutan, Farid; University Health Network, Medicine/Cardiology Fralick, Michael; University of Toronto, Eliot Phillison Clinician Scientist Training Program, Department of Medicine Syed, Talha; McMaster University Department of Medicine, Medicine Lopes, Luciane; Universidade de Sorocaba Kuijpers, Ton; Nederlands Huisartsen Genootschap, Guideline development and research Mas, Jean-Louis; Sainte-Anne Hospital, Neurology http://bmjopen.bmj.com/ Vandvik, Per; Norwegian Knowledge Centre for the Health Services, Agoritsas, Thomas; University Hospitals of Geneva, Division of General Internal Medicine & Division of Clinical Epidemiology; McMaster University Faculty of Health Sciences, Department of Health Research Methods, Evidence, and Impact Guyatt, Gordon; Mcmaster University, Clinical Epidemiology and Biostatistics Cryptogenic stroke, Patent foramen ovale, Anticoagulation < on September 27, 2021 by guest. Protected copyright. Keywords: HAEMATOLOGY, Antiplatelet, PFO Closure For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 101 BMJ Open Patent foramen ovale closure, antiplatelet therapy or anticoagulation in patients with patent BMJ Open: first published as 10.1136/bmjopen-2018-023761 on 25 July 2018. Downloaded from 1 2 3 foramen ovale and cryptogenic stroke: a systematic review and network meta-analysis 4 5 incorporating complementary external evidence 6 7 Hassan Mir1, internal medicine and cardiology physician, Reed A.C. Siemieniuk1,2, PhD student and 8 3 4,5 6 9 internal medicine physician, Long Ge , PhD student, Farid Foroutan , PHD student, Michael Fralick , 10 1 11 research fellow and internal medicine physician, Talha Syed , internal medicine and cardiology 12 physician, Luciane Cruz Lopes7, clinical pharmacologist, Ton Kuijpers8, clinical epidemiologist, Jean- 13 14 Louis Mas9, professor, Per O. Vandvik10,11, associate professor, Thomas Agoritsas1,12, assistant 15 1 16 professor, Gordon H. GuyattFor, distinguished peer professorreview only 17 18 1. Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St West, Hamilton, Ontario, Canada L8S 4L8 19 2. Department of Medicine, University of Toronto, Toronto, Ontario, Canada 20 3. Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China 21 4. Department of Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main St West, Hamilton, Ontario, Canada L8S 4L8 22 5. Heart Failure/Transplant Program, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada 23 6. Eliot Phillipson Clinician Scientist Training Program, Department of Medicine, University of Toronto, Toronto, Canada, M5G 2C4 24 7. University of Sorocaba, UNISO, Sorocaba, Sao Paulo, Brazil 25 8. Department of guideline development and research, Dutch College of General Practitioners, Utrecht, The Netherlands 26 9. Sainte-Anne Hospital, Department of Neurology, 1 rue Cabanis, 75015 Paris. 27 10. Norwegian Institute of Public Health, Oslo, Norway 28 11. Department of Medicine, Innlandet Hospital Trust - division Gjøvik, Norway 29 12. Division General Internal Medicine & Division of Clinical Epidemiology, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, CH-1211, Geneva, Switzerland 30 31 32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39 40 on September 27, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 101 Abstract BMJ Open: first published as 10.1136/bmjopen-2018-023761 on 25 July 2018. Downloaded from 1 2 3 Objective: To examine the relative impact of three management options in patients less than 60 4 5 years old with cryptogenic stroke and a patent foramen ovale (PFO): PFO closure plus antiplatelet 6 7 therapy, antiplatelet therapy alone, and anticoagulation alone. 8 9 Design: Systematic review and network meta-analysis (NMA) supported by complementary external 10 11 12 evidence 13 14 Data sources: Medline, EMBASE, and Cochrane CENTRAL. 15 16 Study selection: RandomisedFor controlled peer trials review (RCTs) addressing only PFO closure and/or medical 17 18 19 therapies in patients with PFO and cryptogenic stroke. 20 21 Review methods: We conducted an NMA complemented with external evidence and rated certainty 22 23 of evidence using the GRADE system. 24 25 26 Results: Ten RCTs in eight studies proved eligible (n=4416). Seven RCTs (n = 3913) addressed 27 28 PFO closure versus medical therapy. Of these, 3 (n=1257) addressed PFO closure versus antiplatelet 29 30 therapy, 3 (n=2303) addressed PFO closure versus mixed antiplatelet and anticoagulation therapies, 31 32 and 1 (n= 353) addressed PFO closure versus anticoagulation. The remaining three RCTs (n= 503) http://bmjopen.bmj.com/ 33 34 35 addressed anticoagulant versus antiplatelet therapy. PFO closure versus antiplatelet therapy 36 37 probably results in substantial reduction in ischaemic stroke recurrence (risk difference per 1000 38 39 patients over 5 years [RD]: -87, 95% credible interval [CrI] -100 to -33; moderate certainty). 40 on September 27, 2021 by guest. Protected copyright. 41 42 Compared with anticoagulation, PFO closure may confer little or no difference in ischaemic stroke 43 44 recurrence (low certainty) but probably has a lower risk of major bleeding (RD -20, 95% Crl -27 to -2, 45 46 moderate certainty). Relative to either medical therapy, PFO closure probably increases the risk of 47 48 49 persistent atrial fibrillation (RD 18, CI +5 to +56, moderate certainty) and device-related adverse 50 51 events (RD +36, 95% CI +23 to +50, high certainty). Anticoagulation, compared to antiplatelet 52 53 therapy, may reduce the risk of ischaemic stroke recurrence (RD -71, 95% CrI -100 to +17, low 54 55 certainty), but probably increases the risk of major bleeding (RD +12, CrI -5 to +65, moderate 56 57 58 certainty). 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 101 BMJ Open Conclusions: In patients less than 60 years old, PFO closure probably confers an important BMJ Open: first published as 10.1136/bmjopen-2018-023761 on 25 July 2018. Downloaded from 1 2 3 reduction in ischaemic stroke recurrence compared to antiplatelet therapy alone but may make no 4 5 difference compared to anticoagulation. PFO closure incurs a risk of persistent atrial fibrillation and 6 7 device-related adverse events. Compared to alternatives, anticoagulation probably increases major 8 9 bleeding. 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39 40 on September 27, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 101 INTRODUCTION: BMJ Open: first published as 10.1136/bmjopen-2018-023761 on 25 July 2018. Downloaded from 1 2 3 Stroke is one of the leading causes of death worldwide and, for those who survive, often results in 4 5 substantial disability. Central to the management of patients with stroke is preventing additional 6 7 ischaemic events; the optimal management depends on the underlying aetiology. 8 9 In up to 40% of patients with an acute ischaemic stroke, investigations fail to identify a clear cause – 10 11 12 the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria classify these strokes as “of 13 14 undetermined aetiology” or “cryptogenic” (1). Patients who have had a cryptogenic stroke are less 15 16 likely to have classical riskFor factors peer for stroke (e.g.,review hypertension, only hyperlipidaemia, diabetes mellitus) 17 18 19 and are more likely to have a patent foramen ovale (PFO) compared to patients with a stroke from a 20 21 known aetiology (2, 3). 22 23 A PFO can allow a systemic venous thrombus to travel directly into the systemic arterial circulation 24 25 26 instead of the pulmonary venous circulation – a phenomenon known as a paradoxical embolism (4, 27 28 5). The importance of this phenomenon as a cause of stroke is, however, controversial.
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