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Meta-Analysis
. 2025 Jul 1;82(7):696-705.
doi: 10.1001/jamaneurol.2025.1337.

Residual Risk of Recurrent Stroke Despite Anticoagulation in Patients With Atrial Fibrillation: A Systematic Review and Meta-Analysis

John J McCabe  1   2   3 , Yuen Cheung  1   2   3 , Marianne Foley  1   2   3 , Stephen O Brennan  1   2   3 , Jane Buckley  1   2   3 , Pol Camps Renom  4 , Tim Cassidy  1   3   5 , Ronan Collins  1   6 , Eamon Dolan  1   7 , Gerrit M Grosse  8 , Joseph Harbison  1   9 , Kirstyn James  1   10 , Kayvan Khadjooi  11 , Isuru Induruwa  11 , Mira Katan  8 , Senan Maher  1 , Margaret O'Connor  1   12 , Martin O'Donnell  1   13 , Francisco Purroy  14 , Padraig Synott  1   2   3 , Peter J Kelly  1   2   15
Affiliations
Meta-Analysis

Residual Risk of Recurrent Stroke Despite Anticoagulation in Patients With Atrial Fibrillation: A Systematic Review and Meta-Analysis

John J McCabe et al. JAMA Neurol. .

Abstract

Importance: Atrial fibrillation (AF) is a leading cause of stroke, and oral anticoagulants (OAC) reduce this risk. However, there are limited data on the residual risk of recurrent stroke in patients with AF.

Objective: To determine the recurrent stroke risk in patients with AF by performing a systematic review and meta-analysis.

Data sources: Eligible studies were identified by searching Ovid MEDLINE and Embase from inception (Ovid: January 1946; Embase: January 1970) until January 2025.

Study selection: Eligible studies enrolled patients with prior ischemic stroke and AF, reported information on incidence of recurrent stroke, and had follow-up data for 1 or more years. Three reviewers independently screened abstracts and performed full-text reviews.

Data extraction and synthesis: Data extraction was performed by 2 reviewers and independently verified by a third. Incidence rates were pooled using random-effects meta-analysis. Analysis was repeated in patients whose qualifying event occurred despite OAC. Study quality was assessed using the Quality In Prognosis Studies tool.

Main outcomes and measures: The primary outcome was recurrent ischemic stroke. The secondary outcomes were any recurrent stroke (ischemic stroke or intra-cerebral hemorrhage [ICH]) and ICH during follow-up.

Results: A total of 23 studies were identified, which included 78 733 patients and 140 307 years of follow-up. The median proportion of OAC use across studies was 92%. The pooled incidence of recurrent ischemic stroke was 3.75% per year (95% CI, 3.17%-4.33%). The risk was higher in noninterventional observational cohorts (4.20% per year; 95% CI, 3.41%-4.99%) compared with randomized clinical trials (2.26% per year; 95% CI, 1.96%-2.57%) (P value for interaction <.001). The risk of any recurrent stroke was 4.88% per year (95% CI, 3.87%-5.90%), and the risk of ICH was 0.58% per year (95% CI, 0.43%-0.73%). In patients with stroke despite OAC, the risk was 7.20% per year (95% CI, 5.05%-9.34%) for ischemic stroke, 8.96% per year (95% CI, 8.25%-9.67%) for any stroke, and 1.40% per year (95% CI, 0.40%-2.40%) for ICH.

Conclusions and relevance: In this systematic review and meta-analysis, even with modern prevention therapy, the residual recurrence risk after AF-related stroke is high, with an estimated 1 in 6 patients experiencing a recurrent ischemic stroke at 5 years. These data demonstrate an urgent need to improve our understanding of the biological processes responsible for recurrence, improve risk stratification, and develop new secondary prevention strategies after AF-related stroke.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr McCabe reported grants from the Irish Institute of Clinical Neuroscience during the conduct of the study. Dr Collins reported speaker honoraria from Daiichi Sankyo outside the submitted work. Dr Grosse reported personal fees from Bayer AG and Boehringer Ingelheim and grants from the Lower Saxony Ministry of Science and Culture and the German Federal Ministry of Education and Research outside the submitted work. Dr Induruwa reported employment by Boehringer Ingelheim during the conduct of the study, but the company had had no input in or influence on this work. Dr Katan reported grants from the Swiss Heart Foundation, the Swiss National Science Foundation, and the USZ Foundation during the conduct of the study; scientific in-kind contributions from BRAHMS Thermo Fisher Scientific and Roche Diagnostics; and advisory board fees from Bristol Myers Squibb/Janssen Consulting outside the submitted work. No other disclosures were reported.

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