{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:03:48Z","timestamp":1791849828595,"version":"4.3.4"},"reference-count":37,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T00:00:00Z","timestamp":1660694400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100015269","name":"Hungarian Government","doi-asserted-by":"crossref","award":["GINOP-2.3.3-15-2016-00031"],"award-info":[{"award-number":["GINOP-2.3.3-15-2016-00031"]}],"id":[{"id":"10.13039\/501100015269","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Objective<\/jats:title>\n<jats:p>As stroke represents one of the leading causes of mortality and disability worldwide, we aimed to determine the preventive effect of different antiplatelet therapies after an ischemic stroke or transient ischemic attack.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Network meta-analysis evaluating antiplatelet regimes after an ischemic stroke or transient ischemic attack. Searches were conducted in MEDLINE, EMBASE, and Cochrane Library databases until Nov. 23, 2021, for randomized controlled trials. Direct comparisons within trials were combined with indirect evidence from other trials by using a frequentist model. An additive network meta-analysis model was used to evaluate the influence of individual components. The primary efficacy endpoint was a recurrent stroke, the main safety outcomes were the risk of major bleeding and mortality at the longest available follow-up.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>58 randomized controlled trials (175,730 patients) were analyzed. The analysis involved 20 antithrombotic strategies including different antiplatelet agents, combinations with aspirin, and anticoagulant therapies. Cilostazol proved to be the most efficacious in reducing stroke recurrence and the risk of bleeding (RR = 0.66, 95%CI = 0.55\u20130.80 and RR = 0.39, 95%CI = 0.08\u20132.01) compared to aspirin, respectively. Intensification with combinations of aspirin with ticagrelor or clopidogrel resulted in a lower risk of stroke recurrence (RR = 0.79, 95%CI = 0.67\u20130.93 and RR = 0.79, 95%CI = 0.72\u20130.87) but carried a higher bleeding risk (RR = 3.01, 95%CI = 1.65\u20135.49 and RR = 1.78 95%CI = 1.49\u20132.13).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>The prognosis of patients with an ischemic stroke or transient ischemic attack is improved with antiplatelets. Cilostazol showed the best risk-benefit characteristics without trade-off with the risk of major bleeding. Improved stroke recurrence with intensified antiplatelet regimens is counterbalanced with higher bleeding risk, and consequently, mortality remains unaffected. Treatment decisions in stroke survivals should integrate the assessment of bleeding risk for better identification of patients with the highest benefit of treatment intensification.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec005\">\n<jats:title>Systematic review registration<\/jats:title>\n<jats:p>Prospero registration number: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.crd.york.ac.uk\/prospero\/display_record.php?ID=CRD42020197143\" xlink:type=\"simple\">CRD42020197143<\/jats:ext-link>, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.crd.york.ac.uk\/prospero\/display_record.php?RecordID=197143\" xlink:type=\"simple\">https:\/\/www.crd.york.ac.uk\/prospero\/display_record.php?RecordID=197143<\/jats:ext-link>.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0273103","type":"journal-article","created":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T17:35:57Z","timestamp":1660757757000},"page":"e0273103","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["Antithrombotic therapy for secondary prevention in patients with stroke or transient ischemic attack: A multiple treatment network meta-analysis of randomized controlled trials"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1406-4016","authenticated-orcid":true,"given":"D\u00e1niel","family":"Tornyos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e1s","family":"Kom\u00f3csi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"B\u00e1lint","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e9ter","family":"Kup\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oumaima El Alaoui","family":"El Abdallaoui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e1szl\u00f3","family":"Szap\u00e1ry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e1szl\u00f3 Botond","family":"Szap\u00e1ry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,8,17]]},"reference":[{"key":"pone.0273103.ref001","doi-asserted-by":"crossref","first-page":"E344","DOI":"10.1161\/STR.0000000000000211","article-title":"Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke a guideline for healthcare professionals from the American Heart Association\/American Stroke A","volume":"50","author":"WJ Powers","year":"2019","journal-title":"Stroke"},{"issue":"7","key":"pone.0273103.ref002","doi-asserted-by":"crossref","first-page":"2160","DOI":"10.1161\/STR.0000000000000024","article-title":"Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: A guideline for healthcare professionals from the American Heart Association\/American Stroke Association","volume":"45","author":"WN Kernan","year":"2014","journal-title":"Stroke"},{"issue":"3","key":"pone.0273103.ref003","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1056\/NEJMoa1916870","article-title":"Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA","volume":"383","author":"SC Johnston","year":"2020","journal-title":"New England Journal of Medicine"},{"issue":"9","key":"pone.0273103.ref004","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1177\/1747493018786616","article-title":"Canadian Stroke Best Practice Recommendations for Acute Stroke Management: Prehospital, Emergency Department, and Acute Inpatient Stroke Care, 6th Edition, Update 2018.","volume":"13","author":"JM Boulanger","year":"2018","journal-title":"International Journal of Stroke."},{"issue":"1","key":"pone.0273103.ref005","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1056\/NEJMoa1603060","article-title":"Ticagrelor versus aspirin in acute stroke or transient ischemic attack","volume":"375","author":"SC Johnston","year":"2016","journal-title":"New England Journal of Medicine"},{"key":"pone.0273103.ref006","article-title":"Ticagrelor plus aspirin versus clopidogrel plus aspirin for platelet reactivity in patients with minor stroke or transient ischaemic attack: Open label, blinded endpoint, randomised controlled phase II trial.","volume":"365","author":"Y Wang","year":"2019","journal-title":"The BMJ"},{"issue":"1","key":"pone.0273103.ref007","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1161\/CIRCULATIONAHA.114.014791","article-title":"Clopidogrel with aspirin in acute minor stroke or transient ischemic attack (CHANCE) trial one-year outcomes.","volume":"132","author":"Y Wang","year":"2015","journal-title":"Circulation"},{"issue":"2","key":"pone.0273103.ref008","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S1474-4422(09)70361-8","article-title":"Early treatment with aspirin plus extended-release dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of symptom onset (EARLY trial): a randomised, open-label, blinded-endpoint trial.","volume":"9","author":"R Dengler","year":"2010","journal-title":"The Lancet Neurology"},{"issue":"1\u20132","key":"pone.0273103.ref009","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.jns.2011.09.038","article-title":"Cilostazol combined with aspirin prevents early neurological deterioration in patients with acute ischemic stroke: A pilot study","volume":"313","author":"T Nakamura","year":"2012","journal-title":"Journal of the Neurological Sciences"},{"issue":"3","key":"pone.0273103.ref010","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1056\/NEJMoa1800410","article-title":"Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA.","volume":"379","author":"SC Johnston","year":"2018","journal-title":"New England Journal of Medicine"},{"issue":"9431","key":"pone.0273103.ref011","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0140-6736(04)16721-4","article-title":"Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): Randomised, double-blind, placebo-controlled trial.","volume":"364","author":"PHC Diener","year":"2004","journal-title":"Lancet"},{"issue":"12","key":"pone.0273103.ref012","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1056\/NEJMoa0805002","article-title":"Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke","volume":"359","author":"RL Sacco","year":"2008","journal-title":"New England Journal of Medicine"},{"issue":"8","key":"pone.0273103.ref013","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1056\/NEJM198908243210804","article-title":"A Randomized Trial Comparing Ticlopidine Hydrochloride with Aspirin for the Prevention of Stroke in High-Risk Patients.","volume":"321","author":"WK Hass","year":"1989","journal-title":"New England Journal of Medicine"},{"issue":"23","key":"pone.0273103.ref014","doi-asserted-by":"crossref","first-page":"2736","DOI":"10.1161\/CIRCULATIONAHA.110.009449","article-title":"Standardized bleeding definitions for cardiovascular clinical trials: A consensus report from the bleeding academic research consortium","volume":"123","author":"R Mehran","year":"2011","journal-title":"Circulation"},{"issue":"1","key":"pone.0273103.ref015","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1111\/j.1538-7836.2009.03678.x","article-title":"Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients","volume":"8","author":"S Schulman","year":"2010","journal-title":"Journal of Thrombosis and Haemostasis"},{"key":"pone.0273103.ref016","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1111\/j.1538-7836.2005.01204.x","article-title":"Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.","volume":"3","author":"S Schulman","year":"2005","journal-title":"Journal of Thrombosis and Haemostasis"},{"key":"pone.0273103.ref017","volume-title":"GRADEpro Guideline Development Tool","author":"GRADEpro GDT","year":"2022"},{"key":"pone.0273103.ref018","unstructured":"The Nordic Cochrane Centre. Review Manager. Cochrane Collaboration. 2014."},{"key":"pone.0273103.ref019","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/978-3-319-21416-0_8","article-title":"Meta-Analysis with R: Ch 8\u2014Network Meta-Analysis.","author":"G Schwarzer","year":"2015","journal-title":"Meta-Analysis with R."},{"issue":"1","key":"pone.0273103.ref020","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s12874-015-0060-8","article-title":"Ranking treatments in frequentist network meta-analysis works without resampling methods.","volume":"15","author":"G R\u00fccker","year":"2015","journal-title":"BMC Medical Research Methodology."},{"issue":"1","key":"pone.0273103.ref021","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/2046-4053-4-1","article-title":"Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.","volume":"4","author":"D Moher","year":"2015","journal-title":"Systematic Reviews."},{"issue":"3","key":"pone.0273103.ref022","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v036.i03","article-title":"Conducting meta-analyses in {R} with the {metafor} package","volume":"36","author":"W. Viechtbauer","year":"2010","journal-title":"Journal of Statistical Software"},{"issue":"4","key":"pone.0273103.ref023","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1002\/jrsm.1058","article-title":"Network meta-analysis, electrical networks and graph theory.","volume":"3","author":"G. R\u00fccker","year":"2012","journal-title":"Research Synthesis Methods."},{"issue":"21","key":"pone.0273103.ref024","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.1016\/0006-2952(84)90103-5","article-title":"Purification of cyclic adenosine monophosphate phosphodiesterase from human platelets using new-inhibitor sepharose chromatography","volume":"33","author":"U Hayato","year":"1984","journal-title":"Biochemical Pharmacology"},{"key":"pone.0273103.ref025","doi-asserted-by":"crossref","first-page":"56B","DOI":"10.1016\/S0828-282X(06)70987-4","article-title":"The vascular effects of cilostazol","volume":"22","author":"WS Weintraub","year":"2006","journal-title":"Canadian Journal of Cardiology"},{"issue":"2","key":"pone.0273103.ref026","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1124\/jpet.104.079780","article-title":"Cilostazol reduces atherosclerosis by inhibition of superoxide and tumor necrosis factor-\u03b1 formation in low-density lipoprotein receptor-null mice fed high cholesterol","volume":"313","author":"JH Lee","year":"2005","journal-title":"Journal of Pharmacology and Experimental Therapeutics"},{"issue":"2","key":"pone.0273103.ref027","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1161\/hh0202.104108","article-title":"Cyclic Nucleotide Phosphodiesterase 1C Promotes Human Arterial Smooth Muscle Cell Proliferation","volume":"90","author":"SD Rybalkin","year":"2002","journal-title":"Circulation Research"},{"issue":"4","key":"pone.0273103.ref028","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.atherosclerosissup.2005.09.002","article-title":"Cilostazol: Potential mechanism of action for antithrombotic effects accompanied by a low rate of bleeding","volume":"6","author":"S. Goto","year":"2005","journal-title":"Atherosclerosis Supplements"},{"issue":"8","key":"pone.0273103.ref029","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1161\/01.CIR.0000117403.64398.53","article-title":"Remnant Lipoprotein Particles Induce Apoptosis in Endothelial Cells by NAD(P)H Oxidase-Mediated Production of Superoxide and Cytokines via Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Activation: Prevention by Cilostazol.","volume":"109","author":"HK Shin","year":"2004","journal-title":"Circulation"},{"issue":"3","key":"pone.0273103.ref030","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1124\/jpet.300.3.787","article-title":"Neuroprotective effect of cilostazol against focal cerebral ischemia via antiapoptotic action in rats","volume":"300","author":"JM Choi","year":"2002","journal-title":"Journal of Pharmacology and Experimental Therapeutics"},{"issue":"1","key":"pone.0273103.ref031","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0021-9150(01)00431-2","article-title":"Cilostazol represses vascular cell adhesion molecule-1 gene transcription via inhibiting NF-\u03baB binding to its recognition sequence","volume":"158","author":"M Otsuki","year":"2001","journal-title":"Atherosclerosis"},{"key":"pone.0273103.ref032","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.jns.2019.02.037","article-title":"Comparative efficacy and safety of multiple antiplatelet therapies for secondary prevention of ischemic stroke or transient ischemic attack: A network meta-analysis","volume":"399","author":"Xiang R wu","year":"2019","journal-title":"Journal of the Neurological Sciences"},{"issue":"4","key":"pone.0273103.ref033","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1161\/STROKEAHA.118.023978","article-title":"Optimal Duration of Aspirin Plus Clopidogrel After Ischemic Stroke or Transient Ischemic Attack: A Systematic Review and Meta-Analysis","volume":"50","author":"H Rahman","year":"2019","journal-title":"Stroke"},{"issue":"3","key":"pone.0273103.ref034","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1093\/eurheartj\/ehx419","article-title":"2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS","volume":"39","author":"M Valgimigli","year":"2018","journal-title":"European Heart Journal"},{"key":"pone.0273103.ref035","article-title":"Cangrelor and Stenting in Acute Ischemic Stroke: Monocentric Case Series.","author":"M Elhorany","year":"2020","journal-title":"Clinical Neuroradiology"},{"issue":"12","key":"pone.0273103.ref036","doi-asserted-by":"crossref","first-page":"3503","DOI":"10.1161\/STROKEAHA.119.026655","article-title":"Cilostazol mono and combination treatments in ischemic stroke an updated systematic review and meta-analysis","volume":"50","author":"SM Kim","year":"2019","journal-title":"Stroke"},{"issue":"1","key":"pone.0273103.ref037","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1159\/000327036","article-title":"Cilostazol in Acute Ischemic Stroke Treatment (CAIST Trial): A Randomized Double-Blind Non-Inferiority Trial.","volume":"32","author":"YS Lee","year":"2011","journal-title":"Cerebrovascular Diseases"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0273103","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T17:36:28Z","timestamp":1660757788000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0273103"}},"subtitle":[],"editor":[{"given":"Masaki","family":"Mogi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,8,17]]},"references-count":37,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,8,17]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0273103","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,17]]}}}