{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T01:46:41Z","timestamp":1789264001029,"version":"build-2803163510"},"reference-count":35,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T00:00:00Z","timestamp":1731024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Four randomized controlled trials (RCTs) did not show a benefit of direct oral anticoagulant (DOAC) treatment compared with antiplatelet therapy for the prevention of recurrent strokes in patients with embolic stroke of undetermined source (ESUS). However, the balance between efficacy and safety in subgroups needs to be better defined. We aimed to assess the relative benefits of DOACs in key subgroups of adult patients with ESUS. Methods: We searched major databases (PubMed, Embase, CENTRAL, and Web of Science) for RCTs published from inception to 16 June 2024. The primary outcome was recurrent stroke, and the main safety outcomes were major bleeding and clinically relevant non-major bleeding (CRNB). We assessed the risk of bias using the Cochrane Risk of Bias tool 2. Results: We identified four RCTs, involving a total of 13,970 patients with ESUS. Compared to antiplatelet therapy, treatment with DOAC did not reduce the risk of recurrent stroke (RR 0.95, 95% CI 0.83\u20131.08, p = 0.45) or ischemic stroke (RR 0.92, 95% CI 0.80\u20131.05, p = 0.22) or increase major bleeding (RR 1.57, 95% CI 0.87\u20132.83; p = 0.14). DOAC treatment was associated with a significantly higher risk of CRNMB compared to aspirin (RR 1.52, 95% CI: 1.22\u20131.90; p = 0.0002). The subgroup analysis demonstrated that use of DOACs was associated with a significant protective effect in patients aged 75 or older (RR 0.76, 95% CI 0.60\u20130.97, p = 0.03) and when the time from index stroke to randomization was \u22658 days (RR 0.80, 95% CI 0.66\u20130.97, p = 0.02) in preventing recurrency of any type of stroke. Conclusions: Our meta-analysis showed lack of overall benefit of anticoagulation with DOAC compared to antiplatelet therapy for recurrent stroke prevention in adult patients with ESUS. However, the subgroup analyses suggest the possibility of interactions between age and timing of randomization since stroke and treatment with an DOAC in terms of recurrent stroke prevention. Further research toward tailoring the antithrombotic strategy according to patient characteristics is needed.<\/jats:p>","DOI":"10.3390\/jcm13226730","type":"journal-article","created":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T03:53:14Z","timestamp":1731383594000},"page":"6730","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Direct Oral Anticoagulants Versus Aspirin for Stroke Prevention After Embolic Stroke of Undetermined Source: An Updated Meta-Analysis of Randomized Controlled Trials"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3011-7405","authenticated-orcid":false,"given":"Edoardo","family":"Pirera","sequence":"first","affiliation":[{"name":"Internal Medicine and Stroke Care Ward, Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (Promise) G. D\u2019Alessandro, University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4349-3322","authenticated-orcid":false,"given":"Lucio","family":"D\u2019Anna","sequence":"additional","affiliation":[{"name":"Department of Stroke and Neuroscience, Charing Cross Hospital, Imperial College London NHS Healthcare Trust, London W2 1NY, UK"},{"name":"Department of Brain Sciences, Imperial College London, London SW7 2AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4529-3703","authenticated-orcid":false,"given":"Domenico","family":"Di Raimondo","sequence":"additional","affiliation":[{"name":"Internal Medicine and Stroke Care Ward, Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (Promise) G. D\u2019Alessandro, University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6440-7318","authenticated-orcid":false,"given":"Antonino","family":"Tuttolomondo","sequence":"additional","affiliation":[{"name":"Internal Medicine and Stroke Care Ward, Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (Promise) G. D\u2019Alessandro, University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/S1474-4422(13)70310-7","article-title":"Embolic strokes of undetermined source: The case for a new clinical construct","volume":"13","author":"Hart","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1161\/01.STR.24.1.35","article-title":"Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment","volume":"24","author":"Adams","year":"1993","journal-title":"Stroke"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1161\/STROKEAHA.116.016414","article-title":"Embolic Stroke of Undetermined Source","volume":"48","author":"Hart","year":"2017","journal-title":"Stroke"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/S1474-4422(15)70027-X","article-title":"Diagnosis of atrial fibrillation after stroke and transient ischaemic attack: A systematic review and meta-analysis","volume":"14","author":"Sposato","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/S1474-4422(17)30002-9","article-title":"Holter-electrocardiogram-monitoring in patients with acute ischaemic stroke (Find-AF RANDOMISED): An open-label randomised controlled trial","volume":"16","author":"Wachter","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1056\/NEJMoa1311376","article-title":"Atrial Fibrillation in Patients with Cryptogenic Stroke","volume":"370","author":"Gladstone","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1161\/STROKEAHA.114.007240","article-title":"Embolic Strokes of Undetermined Source in the Athens Stroke Registry","volume":"46","author":"Ntaios","year":"2015","journal-title":"Stroke"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2478","DOI":"10.1056\/NEJMoa1313600","article-title":"Cryptogenic Stroke and Underlying Atrial Fibrillation","volume":"370","author":"Sanna","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1056\/NEJMoa1802686","article-title":"Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source","volume":"378","author":"Hart","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1056\/NEJMoa1813959","article-title":"Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source","volume":"380","author":"Diener","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Geisler, T., Keller, T., Martus, P., Poli, K., Serna-Higuita, L.M., Schreieck, J., Gawaz, M., T\u00fcnnerhoff, J., Bombach, P., and N\u00e4gele, T. (2023). Apixaban versus Aspirin for Embolic Stroke of Undetermined Source. NEJM Evid., 3.","DOI":"10.1056\/EVIDoa2300235"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1001\/jama.2023.27188","article-title":"Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients with Atrial Cardiopathy","volume":"331","author":"Kamel","year":"2024","journal-title":"JAMA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1177\/23969873221076971","article-title":"Oral anticoagulation versus antiplatelet therapy for secondary stroke prevention in patients with embolic stroke of undetermined source: A systematic review and meta-analysis","volume":"7","author":"Hariharan","year":"2022","journal-title":"Eur. Stroke J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1007\/s11239-024-03017-7","article-title":"Direct oral anticoagulants in embolic stroke of undetermined source: An updated meta-analysis","volume":"57","author":"Marinheiro","year":"2024","journal-title":"J. Thromb. Thrombolysis"},{"key":"ref_15","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":"Schulman","year":"2005","journal-title":"J. Thromb. Haemost."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1378\/chest.09-1584","article-title":"Refining Clinical Risk Stratification for Predicting Stroke and Thromboembolism in Atrial Fibrillation Using a Novel Risk Factor-Based Approach","volume":"137","author":"Lip","year":"2010","journal-title":"Chest"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: A revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Julian, P., Higgins, T., and Thomas, J. (2019). Cochrane Handbook for Systematic Reviews of Interventions, Wiley-Blackwell.","DOI":"10.1002\/9781119536604"},{"key":"ref_19","first-page":"1","article-title":"The jackknife-a review","volume":"61","author":"Miller","year":"1974","journal-title":"Biometrika"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"North American Symptomatic Carotid Endarterectomy Trial Collaborators, Barnett, H.J.M., Taylor, D.W., Haynes, R.B., Sackett, D.L., Peerless, S.J., Ferguson, G.G., Fox, A.J., Rankin, R.N., and Hachinski, V.C. (1991). Beneficial Effect of Carotid Endarterectomy in Symptomatic Patients with High-Grade Carotid Stenosis. N. Engl. J. Med., 325, 445\u2013453.","DOI":"10.1056\/NEJM199108153250701"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1161\/01.STR.30.9.1751","article-title":"The North American Symptomatic Carotid Endarterectomy Trial","volume":"30","author":"Ferguson","year":"1999","journal-title":"Stroke"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1177\/2396987316663049","article-title":"Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: Design of the NAVIGATE ESUS randomized trial","volume":"1","author":"Hart","year":"2016","journal-title":"Eur. Stroke J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1111\/ene.12843","article-title":"Insertable cardiac monitors after cryptogenic stroke\u2014A risk factor based approach to enhance the detection rate for paroxysmal atrial fibrillation","volume":"23","author":"Poli","year":"2016","journal-title":"Eur. J. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e209949","DOI":"10.1212\/WNL.0000000000209949","article-title":"Anticoagulation vs Antiplatelets Across Subgroups of Embolic Stroke of Undetermined Source: A Meta-Analysis of Randomized Controlled Trials","volume":"103","author":"Ghannam","year":"2024","journal-title":"Neurology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/S0140-6736(16)30468-8","article-title":"Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: Time-course analysis of randomised trials","volume":"388","author":"Rothwell","year":"2016","journal-title":"Lancet"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1093\/oxfordjournals.aje.a010035","article-title":"Random-Effects Meta-Analyses Are Not Always Conservative","volume":"150","author":"Poole","year":"1999","journal-title":"Am. J. Epidemiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.jacc.2019.11.024","article-title":"Embolic Stroke of Undetermined Source: JACC Review Topic of the Week","volume":"75","author":"Ntaios","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3184","DOI":"10.1161\/STROKEAHA.119.025813","article-title":"Aortic Arch Atherosclerosis in Patients with Embolic Stroke of Undetermined Source","volume":"50","author":"Ntaios","year":"2019","journal-title":"Stroke"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1212\/WNL.0000000000002978","article-title":"Nonstenotic carotid plaque on CT angiography in patients with cryptogenic stroke","volume":"87","author":"Coutinho","year":"2016","journal-title":"Neurology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.jcmg.2012.01.012","article-title":"Prevalence of Nonstenosing, Complicated Atherosclerotic Plaques in Cryptogenic Stroke","volume":"5","author":"Freilinger","year":"2012","journal-title":"JACC Cardiovasc. Imaging"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1161\/STROKEAHA.119.025168","article-title":"Efficacy and Safety of Rivaroxaban Versus Aspirin in Embolic Stroke of Undetermined Source and Carotid Atherosclerosis","volume":"50","author":"Ntaios","year":"2019","journal-title":"Stroke"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.jns.2017.09.027","article-title":"Embolic stroke of undetermined source: The role of the nonstenotic carotid plaque","volume":"382","author":"Bulwa","year":"2017","journal-title":"J. Neurol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ntaios, G., Perlepe, K., Sirimarco, G., Strambo, D., Eskandari, A., Karagkiozi, E., Vemmou, A., Koroboki, E., Manios, E., and Makaritsis, K. (2019). Carotid plaques and detection of atrial fibrillation in embolic stroke of undetermined source. Neurology, 92.","DOI":"10.1212\/WNL.0000000000007611"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1111\/ene.13275","article-title":"Non-obstructive carotid atherosclerosis and patent foramen ovale in young adults with cryptogenic stroke","volume":"24","author":"Jaffre","year":"2017","journal-title":"Eur. J. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/22\/6730\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:28:55Z","timestamp":1760113735000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/22\/6730"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,8]]},"references-count":35,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["jcm13226730"],"URL":"https:\/\/doi.org\/10.3390\/jcm13226730","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,8]]}}}