Long-term Stroke Recurrence in Atrial Fibrillation: Differential Predictors of Ischaemic and Haemorrhagic Risk

Long-term Stroke Recurrence in Atrial Fibrillation: Differential Predictors of Ischaemic and Haemorrhagic Risk | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Long-term Stroke Recurrence in Atrial Fibrillation: Differential Predictors of Ischaemic and Haemorrhagic Risk Daniel Guisado-Alonso, Elisa Cuadrado-Godia, Jordi Jiménez-Conde, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7453175/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Predictors of long-term ischaemic and haemorrhagic stroke recurrence (LTSR) after acute ischaemic stroke (AIS) with AF remain uncertain. This study aimed to identify independent predictors of LTSR in patients with AF-related AIS. Methods We conducted a prospective observational study of consecutive AIS patients with AF enrolled in a hospital-based registry (January 2005–June 2022). The primary endpoint was LTSR, defined as any new ischaemic or haemorrhagic cerebrovascular event occurring during follow-up, which began 90 days after the AIS event. Independent predictors of overall, ischaemic, and haemorrhagic LTSR were identified using Fine–Gray competing risk models. Results A total of 1,212 patients (median age 79 years, 42.3% male) were included. During a median follow-up of 43.0 months, 220 patients (18.1%) experienced LTSR (incidence 0.039 events/person-year), predominantly ischaemic. In multivariable Fine–Gray models, known AF before the index stroke (sHR 2.1), large artery atherosclerosis (LAA) (sHR 2.6), small artery occlusion (SAO) (sHR 1.7), and higher CHA₂DS₂-VASc scores were independently associated with increased LTSR risk, while anticoagulation—particularly with Direct Oral Anticoagulants (DOACs) (sHR 0.46)—was protective. AF detected after stroke (AFDAS) (sHR 0.47) was associated with lower risk of ischaemic LTSR, and LAA defined a high-risk subgroup. Notably, SAO was the only independent predictor of haemorrhagic LTSR (sHR 3.2). DOAC showed a non-significant trend toward protection for haemorrhagic events. Conclusion In AF-related AIS, AFDAS was associated with lower risk of LTSR, while anticoagulation—particularly with DOACs—was strongly protective. The presence of competing stroke etiologies identified differential high-risk subgroups for ischaemic and haemorrhagic recurrence, highlighting the need for individualized prevention strategies. Health sciences/Cardiology Health sciences/Diseases Health sciences/Medical research Health sciences/Neurology Health sciences/Risk factors Figures Figure 1 Figure 2 INTRODUCTION Atrial fibrillation (AF) is a prevalent cause of acute ischaemic stroke (AIS) that requires anticoagulant therapy for secondary prevention, and is associated with an increased risk of recurrence compared to other stroke etiologies [ 1 , 2 ]. In recent years, extensive research has focused on AF in AIS due to the emergence of novel anticoagulant therapies[ 3 – 5 ] and advances in AF detection. However, most studies evaluating ischaemic and haemorrhagic recurrence have focused on the early post-stroke period or have been restricted to selected populations, such as patients with cryptogenic stroke, individuals undergoing extended cardiac monitoring, or participants enrolled in clinical trials[ 6 ]. AIMS This study aims to identify independent predictors of long-term ischaemic and haemorrhagic stroke recurrence (LTSR) in a large hospital-based cohort of patients with AIS and AF. METHODS Study Population This prospective observational study used data from an ongoing registry of 8,186 consecutive AIS patients treated at Hospital del Mar Barcelona, a Comprehensive Stroke Center between January 2005 and June 2022. We included patients with AF who survived at least 90 days after stroke onset, either with known AF prior to AIS or with AF detected within 90 days thereafter. Patients with incomplete etiological work-up or other infrequent competing causes were excluded ( Figure 1: flow chart ). The diagnosis of AF was based on criteria previously used[7]: either electrocardiographic evidence of arrhythmia lasting >1 minute or confirmation via cardiac monitoring. Upon admission to the stroke unit, patients underwent a comprehensive and standardized etiological evaluation, including continuous heart rhythm monitoring with automatic detection for up to 72 hours (minimum 24 hours). Discharge planning, including decisions regarding extended monitoring, additional investigations or initiation of anticoagulation, was at the discretion of the treating neurologist, based on clinical findings, neurological course and contemporaneous guidelines[8]. All cardiac monitoring data during the stroke unit stay were reviewed by a neurologist and, when necessary, by a cardiologist. Follow-up Holter recordings were interpreted by cardiologists specialized in arrhythmias. AF status was classified into three categories: known (history of atrial fibrillation prior to the index stroke), at stroke onset (first documented atrial fibrillation on admission), and AFDAS (atrial fibrillation detected after admission for the index stroke or during follow-up within 90 days). Data Collection A structured questionnaire captured demographics (age, sex), vascular risk factors (hypertension, diabetes mellitus, dyslipidemia, peripheral vascular disease, coronary artery disease, heart failure and valvular disease, defined as moderate or severe stenosis or regurgitation on echocardiography[8], lifestyle factors (active smoking, alcohol overuse) and clinical variables. Initial severity was assessed by NIHSS. Anticoagulation type at 90 days (Direct Oral Anticoagulants [DOAC] [9] , vitamin K antagonist [VKA] or none) was recorded. Stroke etiology was assigned according to the Causative Classification of Stroke System (CCS)[10]. Patients were categorized as having cardioembolic stroke if AF was the sole identified etiologic cause. In cases where AF coexisted with at least one additional competing etiologic factor, such as small artery occlusion (SAO), large artery atherosclerosis (LAA), or both, patients were classified as having concomitant stroke etiology (CSE)[10]. This approach allows cases that might otherwise be classified as “Unclassified” in the CCS to be recognized as having multiple potential etiological factors contributing to the stroke. Study Endpoint and Follow-Up The primary endpoint was LTSR, defined as any new ischaemic or haemorrhagic cerebrovascular event during follow-up. All events were adjudicated by neurologists based on clinical and imaging data. Follow-up duration was calculated for each patient as the time from index stroke to LTSR, death, loss to follow-up, or end of the study period (June 30, 2024), whichever occurred first. Follow-up consisted of a neurological assessment at 90 days post-stroke and subsequently at intervals of 3 to 12 months. All patient events, death certificates, electronic health records and hospital admissions were reviewed. Primary care physicians were consulted to verify patient status before classifying losses to follow-up. When necessary, supplementary information was obtained from patient or proxy interviews, hospital records, and the regional healthcare database (“Historia Clínica Compartida de Catalunya”). Patients who died or were lost to follow-up within 90 days of stroke onset were excluded from the LTSR analysis. Statistical Continuous variables are reported as means with standard deviations or medians with interquartile ranges, as appropriate, and categorical variables as frequencies and percentages. Baseline characteristics were compared across groups using non-parametric methods for continuous variables and chi-square tests for categorical variables. Univariable associations between predictors and LTSR were examined using appropriate statistical tests. Kaplan–Meier survival curves and competing-risk cumulative incidence (CIF) plots were estimated for LTSR and stratified by AF status, anticoagulant type, LAA, and SAO to illustrate recurrence and competing risk over time. The incidence rate of recurrence was calculated as recurrent events per person-year at risk. Variables for inclusion in the multivariable Fine–Gray competing risk models were selected a priori based on clinical relevance and statistical significance in univariable analyses (p<0.05). The final model included AF status (known, at stroke onset, or AFDAS), SAO, LAA, CHA₂DS₂-VASc score, anticoagulant type (none, VKA, or DOAC), and initial severity. To avoid collinearity or lack of independent association, the individual components of the CHA₂DS₂-VASc score, as well as related vascular risk factors (age, sex, hypertension, diabetes mellitus, dyslipidemia, coronary artery disease, peripheral vascular disease, heart failure, valvular disease), active smoking, and alcohol overuse, were not included in the multivariable models. The proportional subdistribution hazards assumption was assessed using diagnostic plots and time-dependent interaction terms and was satisfied in all models. Cumulative incidence functions were also visually inspected to verify the proportionality of hazards over time. All analyses were performed in R (version 4.4.1) by a blinded investigator (J-J-B), following STROBE guidelines. Statistical significance was set at p<0.05. Ethics Statement The study was conducted in accordance with the Declaration of Helsinki. Ethical approval for this study was obtained from the Hospital del Mar Clinical Research Ethics Committee - Drug Research Ethics Committee (CEIm) (Approval No. CEIM 2008/3038/I). Written informed consent was obtained from all participants. Data Availability Statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Data sharing is subject to a formal data transfer agreement, in compliance with anonymization and data protection regulations. RESULTS Study Population A total of 1,949 consecutive AIS cases with AF were registered. After excluding 33 cases with incomplete etiological evaluation and 3 with other major competing causes, 1,913 remained. Ninety patients lost to follow-up after discharge and 611 who died within 90 days of stroke onset were further excluded, resulting in a final cohort of 1,212 patients ( Figure 1: Flowchart ). Baseline Characteristics Median age was 79.0 years (IQR 73–84) and 42.3% were male. Hypertension was present in 82.3%, diabetes mellitus in 33.7%, and dyslipidemia in 47.3%. Median CHA₂DS₂-VASc score was 6 (IQR 5–7) and median NIHSS on admission was 5 (IQR 2–10); NIHSS was lower in patients without long-term stroke recurrence (p=0.004) ( Table 1 ). CSE were identified in 18.7% overall and were more frequent in patients with recurrence (34.3% vs 15.6%; p<0.001): SAO in 10.1%, LAA in 7.8%, and both in 0.8%. Atrial fibrillation was known before stroke in 67.4%, diagnosed at onset in 15.0%, and classified as AFDAS in 17.6%. AFDAS was less frequent in patients without recurrence (9.8% vs 19.1%; p=0.001), whereas known AF was more common (78.4% vs 65.2%; p<0.001). Anticoagulation was initiated in 82.8% overall, but less frequently in patients without recurrence (72.1% vs 84.9%; p<0.001). Competing‐risk cumulative incidence curves stratified by AF status, anticoagulant type, LAA and SAO are shown in Figure 2 . LTSR Mean follow-up was 55.3 months (median 43.0; IQR 19.9–81.7; range 0.04–18.9). LTSR occurred in 220 patients (18.1%; incidence rate 0.039 events/person-year), comprising 121 nonfatal ischaemic strokes, 68 fatal ischaemic strokes, 5 nonfatal haemorrhagic strokes, 10 fatal haemorrhagic strokes, and 16 TIAs (7.3%). During follow-up, 517 patients (42.7%) died, 166 (13.7%) were lost to follow-up, and 309 (25.5%) completed the study without recurrence or death (see Supplementary Figure 1 for the overall cumulative incidence curve). Multivariable Fine–Gray models In the multivariable Fine–Gray model for overall LTSR ( Table 2 ), known AF was independently associated with an increased risk of recurrence compared to AFDAS, while AF at stroke onset showed a non-significant trend. Both SAO (sHR 1.69, 95% CI 1.19–2.41; p=0.003) and LAA (sHR 2.58, 95% CI 1.78–3.74; p<0.001), as well as higher CHA₂DS₂-VASc score (per point increase: sHR 1.12, 95% CI 1.02–1.24; p=0.022), were independently associated with greater risk. Anticoagulation with DOAC (sHR 0.46, 95% CI 0.32–0.65; p<0.001) or VKA (sHR 0.60, 95% CI 0.43–0.84; p=0.003) was associated with a lower risk of LTSR. Initial severity (per point increase) showed a non-significant trend (sHR 0.98, 95% CI 0.96–1.00; p=0.057). Results for ischaemic and haemorrhagic LTSR are presented in Supplementary Tables S1 and S2 , respectively. In the ischaemic LTSR model, AFDAS was independently associated with a lower risk (sHR 0.47, 95% CI 0.28–0.77; p=0.003), while AF at stroke onset again showed a non-significant trend (sHR 0.68, 95% CI 0.43–1.07; p=0.096). SAO showed a non-significant trend (sHR 1.45, 95% CI 0.98–2.15; p=0.064), whereas LAA was independently associated with increased risk (sHR 1.98, 95% CI 1.30–3.00; p=0.001). CHA₂DS₂-VASc was not significantly associated (sHR per point 1.02, 95% CI 0.93–1.14; p=0.644). Anticoagulant therapy with DOAC (sHR 0.54, 95% CI 0.37–0.79; p=0.002) or VKA (sHR 0.67, 95% CI 0.46–0.98; p=0.038) remained significantly protective. Higher initial severity was inversely associated with ischaemic LTSR (sHR 0.97, 95% CI 0.94–0.99; p=0.007). In the haemorrhagic LTSR model, neither AF status nor CHA₂DS₂-VASc was significantly associated with risk. SAO was independently associated with a higher risk of haemorrhagic LTSR (sHR 3.24, 95% CI 1.05–9.94; p=0.040), while LAA was not significant (sHR 1.60, 95% CI 0.37–6.97; p=0.533). Anticoagulation with DOAC showed a non-significant trend toward protection (sHR 0.12, 95% CI 0.01–1.01; p=0.051), and VKA was not associated. Initial severity was not significantly associated (sHR 0.95, 95% CI 0.87–1.03; p=0.221). DISCUSSION In this hospital-based cohort of AIS patients with AF, the LTSR remained substantial despite widespread anticoagulation (18.1% over 3.6 years; 3.9 events/100 personyears), with a predominance of ischaemic events. These findings are consistent with previous population-based studies and multicenter registries, which have reported comparable long-term recurrence rates in patients with AF receiving oral anticoagulant therapy[11–14]. Known AF was independently associated with an increased risk of LTSR compared to AFDAS. Both SAO and LAA, as well as higher CHA₂DS₂-VASc scores, were independently associated with increased risk, whereas anticoagulant therapy—particularly DOACs but also VKAs—was associated with a substantial reduction in LTSR risk. In analyses restricted to ischaemic LTSR, LAA continued to be independently associated with a higher risk, while AFDAS and anticoagulant therapy remained protective. Notably, SAO was the only independent predictor of haemorrhagic LTSR, while DOACs showed a non-significant trend toward a protective effect. While previous studies of AFDAS have mainly focused on recurrence risk in the initial years after stroke, evidence regarding long-term outcomes remains limited, with most data restricted to short- and mid-term follow-up[ 15 – 20 ]. The prognostic significance of AFDAS has also been controversial: some reports found similar risks of recurrent stroke and death between AFDAS and known AF[ 21 ], whereas a recent meta-analysis demonstrated that AFDAS is associated with lower risk of ischaemic stroke recurrence and mortality, and a comparable risk of intracerebral haemorrhage[ 22 ]. Our results contribute new evidence confirming that this lower risk profile in AFDAS persists in the long term. The lower risk of LTSR in AFDAS is likely multifactorial. Several classifications based on the timing and method of AF detection after stroke have been proposed[ 15 – 20 ], due to a potential therapeutic implication. Recent research has highlighted the importance of AF burden, defined by the frequency and duration of AF episodes, as a key prognostic factor[ 17 , 19 , 20 ]. This concept is closely related to atrial cardiomyopathy, or "sick atrium," which refers to structural, architectural, contractile, or electrophysiological changes in the atrial myocardium that increase the risk of arrhythmogenesis and thromboembolism[ 23 , 24 ]. AFDAS is typically associated with less extensive atrial remodeling, including reduced fibrosis, dilation, and impaired contractility[ 25 ], leading to a lower risk of thrombus formation and subsequent embolic events[ 24 ]. In contrast, patients with known AF often have a higher AF burden and are more likely to exhibit structural cardiac abnormalities and a greater accumulation of vascular risk factors[ 16 , 26 , 27 ], all contributing to an increased risk of LTSR. Anticoagulation therapy conferred a protective effect in our cohort, reducing LTSR risk by approximately 54% in patients treated with DOACs (sHR 0.46, 95% CI 0.32–0.65, p < 0.001) and by 40% in those receiving VKAs (sHR 0.60, 95% CI 0.43–0.84, p = 0.003), compared to no anticoagulation. These results are in line with evidence from randomized controlled trials, which have demonstrated at least non-inferior efficacy and improved safety of DOACs compared to VKAs[ 9 ]. In analyses restricted to ischaemic LTSR, the protective effect of anticoagulation was confirmed, while in the haemorrhagic LTSR model, DOACs showed a non-significant trend toward a protective effect. Taken together, our findings support current clinical guidelines[ 8 , 28 ], which emphasize the superiority of anticoagulation—particularly DOACs—for secondary stroke prevention in patients with AF[[ 6 ]. Moreover, in clinical practice, it is well recognized that patients with AF frequently present with CSE due to shared cardiovascular risk factors[ 11 – 13 , 29 , 30 ]. In our cohort, the frequency of CSE was 18.7%, which is consistent with previous reports ranging from 7.7–24%[ 11 – 14 ]. Most prior studies on the prognostic impact of CSE in stroke patients with AF have focused primarily on atherosclerosis, particularly carotid atherosclerosis[ 13 , 14 ], although the coexistence of SAO in individuals with AF is also well documented[ 11 , 31 ]. Our study expands on previous research by incorporating a larger cohort, extended follow-up, and comprehensive etiological assessment using the CCS causative classification. This approach demonstrates that patients with CSE constitute a subgroup at significantly higher risk of LTSR, consistent with previous studies reporting increased rates of ischaemic stroke recurrence and mortality in this population[ 12 , 13 , 30 ]. Importantly, LTSR risk differed by CSE subtype, with LAA being the strongest predictor of ischaemic recurrence[ 32 , 33 ], while concomitant SAO was associated with an increased risk of haemorrhagic events. These findings suggest that patients with LAA are at particularly high risk for ischaemic recurrence and may require more intensive secondary prevention. The potential benefit and safety of strategies beyond anticoagulation—such as intensive lipid-lowering therapy targeting LDL cholesterol below 55 mg/dL[ 34 ] or dual antithrombotic therapy—remain to be established in these subgroups. In contrast, patients with concomitant SAO may derive greater benefit from optimal vascular risk factor control, particularly strict blood pressure management[ 35 ], which remains essential to reducing haemorrhagic LTSR risk. Among other factors analyzed, the CHA₂DS₂-VASc score—a standard risk stratification tool—was independently associated with LTSR risk in our cohort[ 36 – 38 ]. Although CHA₂DS₂-VASc remains well validated for clinical risk assessment, we believe that its predictive value in this context likely reflects the cumulative impact of age and comorbidities, rather than strong associations of each individual component in univariate analysis. Initial severity was not independently associated with LTSR in the global multivariable models. However, in the analysis restricted to ischaemic LTSR, higher initial severity was independently associated with a lower risk of recurrence. While some previous studies have reported an association between initial stroke severity and recurrence risk[ 27 ], we did not observe this relationship in the long term. We believe this may be explained by the high competing risk of mortality associated with greater initial severity in this elderly cohort, which likely limited the detection of recurrent events despite statistical adjustment. Limitations This study was conducted at a single center, which may limit the generalizability of the findings to other populations and healthcare settings. Patients with early mortality or incomplete follow-up were excluded, which may introduce selection bias and restrict the applicability of results to the entire AIS population with AF. The observational design did not allow for systematic assessment of echocardiographic parameters or treatment adherence, potentially limiting the evaluation of structural cardiac risk factors and the quality of anticoagulation. These limitations should be considered when interpreting our findings and underscore the need for future multicenter studies with more comprehensive clinical characterization. CONCLUSION This large, hospital-based cohort study with extended follow-up identifies independent predictors of LTSR in patients with AF-related stroke. Our findings confirm the protective effect of anticoagulant therapy—particularly DOACs—and the lower risk profile of AFDAS, even in the long term. Concomitant etiologies are common; LAA defines a subgroup at highest risk for ischaemic LTSR, and, notably, concomitant SAO independently increases the risk of long-term haemorrhagic recurrence. These results underscore the importance of comprehensive etiological assessment and support the need for individualized secondary prevention strategies in AF-related stroke. Declarations Acknowledgements: This work was supported, in part, by Ministerio de ciencia, innovación y universidades de España (Instituto de Salud Carlos III, RICORS-ICTUS, RD24/0009/0011), the Sara Borrell Fellowship (J.J.B., CD022/0001), and the European Union’s Horizon Europe research and innovation programme under Grant No. 101136244 (TARGET). The authors declare no potential conflicts of interest related to this study. We gratefully acknowledge the contributions of all the staff at Hospital del Mar, as well as the patients and supporting facilities, whose efforts have been instrumental in establishing and maintaining the BasicMar registry. Competing Interests: None Funding : This work was supported, in part, by Spanish Ministry of Science, Innovation and Universities (Instituto de Salud Carlos III, RICORS-ICTUS, RD24/0009/0011). Sara Borell (J.J.B., CD022/0001) and European Unions´s Horizon Europe research and innovation programme under Grant nº 101136244 (TARGET) Author Contributions: D.G.-A. and E.C.-G. contributed equally as first authors and were involved in study conception and design, data analysis and interpretation, and drafting of the manuscript. J.J.-B., E.G.-S., and A.O. contributed equally as senior authors, overseeing study design, methodology, data interpretation, and critical revision of the manuscript. J.J.-C., A.R.-C., I.F.-P., A.M.-G., A.S.-P., M.V.-P., J.P.-S., S.V.-N., and L.P.-M. contributed to data acquisition, analysis, and critical review. All authors reviewed and approved the final version of the manuscript. Data Availability The data that support the findings of this study are available from the corresponding author upon reasonable request. Data sharing is subject to a formal data transfer agreement, in compliance with anonymization and data protection regulations. 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Utility of the CHA2DS2-VASc score for predicting ischaemic stroke in patients with or without atrial fibrillation: a systematic review and meta-analysis. Eur. J. Prev. Cardiol. 29 , 625–631. 10.1093/eurjpc/zwab018 (2022). Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table12.docx Supplementarymaterial.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7453175","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":524927700,"identity":"4d0a3e7a-37dc-4096-b770-1fcfa54476d4","order_by":0,"name":"Daniel Guisado-Alonso","email":"","orcid":"","institution":"Hospital del Mar Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Guisado-Alonso","suffix":""},{"id":524927701,"identity":"36299d1c-f0e8-4228-82ae-9f31f2bf5759","order_by":1,"name":"Elisa Cuadrado-Godia","email":"","orcid":"","institution":"Hospital del Mar","correspondingAuthor":false,"prefix":"","firstName":"Elisa","middleName":"","lastName":"Cuadrado-Godia","suffix":""},{"id":524927702,"identity":"dcd2424b-1f04-4941-8bb0-08f1b66d2912","order_by":2,"name":"Jordi Jiménez-Conde","email":"","orcid":"","institution":"Hospital del Mar Research Institute","correspondingAuthor":false,"prefix":"","firstName":"Jordi","middleName":"","lastName":"Jiménez-Conde","suffix":""},{"id":524927703,"identity":"ac690026-e22e-47f9-9ad5-7d99ec30237b","order_by":3,"name":"Ana Rodriguez-Campello","email":"","orcid":"","institution":"Pompeu Fabra University","correspondingAuthor":false,"prefix":"","firstName":"Ana","middleName":"","lastName":"Rodriguez-Campello","suffix":""},{"id":524927704,"identity":"c34ae941-686e-4341-a493-3d83973fc364","order_by":4,"name":"Isabel Fernández-Pérez","email":"","orcid":"","institution":"Hospital del 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07:09:04","extension":"html","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":133811,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7453175/v1/ed107ae5bb26832a303d6c58.html"},{"id":93009895,"identity":"658a70a9-ff43-46bc-9f46-f9f79dbc2096","added_by":"auto","created_at":"2025-10-08 07:09:01","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":44504,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart of study population and exclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 8 186 consecutive patients with acute ischaemic stroke (AIS) treated between January 2005 and June 2022 were screened. Of these, 1 949 had atrial fibrillation (AF) known prior to or detected within 90 days of stroke onset. Thirty-three patients with incomplete etiological evaluation and three with other major competing causes were excluded. During the first 3 months, 611 patients died and 90 were lost to follow-up. The remaining 1 212 patients comprised the final cohort for long-term stroke recurrence (LTSR) analysis.\u003c/p\u003e","description":"","filename":"Fig.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7453175/v1/dca3d2e04a0912f7481d0d9b.jpg"},{"id":93009871,"identity":"2edd0666-0e31-4f01-8ca9-fac42da51a40","added_by":"auto","created_at":"2025-10-08 07:09:00","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":106409,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCompeting-risk cumulative incidence curves for long-term stroke recurrence\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePanel A: Cumulative incidence stratified by atrial fibrillation (AF) status (AF detected after stroke [AFDAS], AF at stroke onset, known AF). Panel B: Cumulative incidence stratified by type of oral anticoagulant (direct oral anticoagulant [DOAC], vitamin K antagonist [VKA], or no anticoagulation).\u003cbr\u003e\nPanel C: Cumulative incidence according to presence of large-artery atherosclerosis. Panel D: Cumulative incidence according to presence of small vessel disease. Cumulative incidence was estimated by the Fine–Gray method, with death treated as a competing event.\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7453175/v1/211a6d09dff83e2f0f2986c5.jpg"},{"id":94986823,"identity":"0bf82981-5956-4e05-ae90-3afe9acee4bf","added_by":"auto","created_at":"2025-11-03 07:00:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":912718,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7453175/v1/485d905a-70b8-4192-af40-14ed9f1597b7.pdf"},{"id":93009869,"identity":"43aad205-a8c9-4ee3-9706-9d7a8c4644a5","added_by":"auto","created_at":"2025-10-08 07:08:59","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":413576,"visible":true,"origin":"","legend":"","description":"","filename":"Table12.docx","url":"https://assets-eu.researchsquare.com/files/rs-7453175/v1/dfe6a4e05220f7ceaca329c2.docx"},{"id":93009872,"identity":"05e959d1-1d66-4237-848b-d686ca30eca3","added_by":"auto","created_at":"2025-10-08 07:09:00","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":83092,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-7453175/v1/48b0e54320043c98e5d49a13.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Long-term Stroke Recurrence in Atrial Fibrillation: Differential Predictors of Ischaemic and Haemorrhagic Risk","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAtrial fibrillation (AF) is a prevalent cause of acute ischaemic stroke (AIS) that requires anticoagulant therapy for secondary prevention, and is associated with an increased risk of recurrence compared to other stroke etiologies [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In recent years, extensive research has focused on AF in AIS due to the emergence of novel anticoagulant therapies[\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] and advances in AF detection. However, most studies evaluating ischaemic and haemorrhagic recurrence have focused on the early post-stroke period or have been restricted to selected populations, such as patients with cryptogenic stroke, individuals undergoing extended cardiac monitoring, or participants enrolled in clinical trials[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eAIMS\u003c/h3\u003e\n\u003cp\u003eThis study aims to identify independent predictors of long-term ischaemic and haemorrhagic stroke recurrence (LTSR) in a large hospital-based cohort of patients with AIS and AF.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003cdiv id=\"Sec4\" class=\"Section3\"\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003eStudy Population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis prospective observational study used data from an ongoing registry of 8,186 consecutive AIS patients treated at Hospital del Mar Barcelona, a Comprehensive Stroke Center between January 2005 and June 2022. We included patients with AF who survived at least 90 days after stroke onset, either with known AF prior to AIS or with AF detected within 90 days thereafter. Patients with incomplete etiological work-up or other infrequent competing causes were excluded (\u003cstrong\u003eFigure 1: flow chart\u003c/strong\u003e). The diagnosis of AF was based on criteria previously used[7]: either electrocardiographic evidence of arrhythmia lasting \u0026gt;1 minute or confirmation via cardiac monitoring. Upon admission to the stroke unit, patients underwent a comprehensive and standardized etiological evaluation, including continuous heart rhythm monitoring with automatic detection for up to 72 hours (minimum 24 hours). Discharge planning, including decisions regarding extended monitoring, additional investigations or initiation of anticoagulation, was at the discretion of the treating neurologist, based on clinical findings, neurological course and contemporaneous guidelines[8]. All cardiac monitoring data during the stroke unit stay were reviewed by a neurologist and, when necessary, by a cardiologist. Follow-up Holter recordings were interpreted by cardiologists specialized in arrhythmias. AF status was classified into three categories: known (history of atrial fibrillation prior to the index stroke), at stroke onset (first documented atrial fibrillation on admission), and\u0026nbsp;AFDAS (atrial fibrillation detected after admission for the index stroke or during follow-up within 90 days).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Collection\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA structured questionnaire captured demographics (age, sex), vascular risk factors (hypertension, diabetes mellitus, dyslipidemia, peripheral vascular disease, coronary artery disease, heart failure and valvular disease, defined as moderate or severe stenosis or regurgitation on echocardiography[8], lifestyle factors (active smoking, alcohol overuse) and clinical variables. Initial severity was assessed by NIHSS. Anticoagulation type at 90 days (Direct Oral Anticoagulants [DOAC] [9] , vitamin K antagonist [VKA] or none) was recorded. Stroke etiology was assigned according to the Causative Classification of Stroke System (CCS)[10]. Patients were categorized as having cardioembolic stroke if AF was the sole identified etiologic cause. In cases where AF coexisted with at least one additional competing etiologic factor, such as small artery occlusion (SAO), large artery atherosclerosis (LAA), or both, patients were classified as having concomitant stroke etiology (CSE)[10]. This approach allows cases that might otherwise be classified as “Unclassified” in the CCS to be recognized as having multiple potential etiological factors contributing to the stroke.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Endpoint and Follow-Up\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint was LTSR, defined as any new ischaemic or haemorrhagic cerebrovascular event during follow-up. All events were adjudicated by neurologists based on clinical and imaging data. Follow-up duration was calculated for each patient as the time from index stroke to LTSR, death, loss to follow-up, or end of the study period (June 30, 2024), whichever occurred first. \u0026nbsp;Follow-up consisted of a neurological assessment at 90 days post-stroke and subsequently at intervals of 3 to 12 months. All patient events, death certificates, electronic health records and hospital admissions were reviewed. Primary care physicians were consulted to verify patient status before classifying losses to follow-up. When necessary, supplementary information was obtained from patient or proxy interviews, hospital records, and the regional healthcare database (“Historia Clínica Compartida de Catalunya”). Patients who died or were lost to follow-up within 90 days of stroke onset were excluded from the LTSR analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContinuous variables are reported as means with standard deviations or medians with interquartile ranges, as appropriate, and categorical variables as frequencies and percentages. Baseline characteristics were compared across groups using non-parametric methods for continuous variables and chi-square tests for categorical variables. Univariable associations between predictors and LTSR were examined using appropriate statistical tests. Kaplan–Meier survival curves and competing-risk \u0026nbsp;cumulative incidence (CIF) plots were estimated for LTSR and stratified by AF status, anticoagulant type, LAA, and SAO to illustrate recurrence and competing risk over time. The incidence rate of recurrence was calculated as recurrent events per person-year at risk. Variables for inclusion in the multivariable Fine–Gray competing risk models were selected a priori based on clinical relevance and statistical significance in univariable analyses (p\u0026lt;0.05). The final model included AF status (known, at stroke onset, or AFDAS), SAO, LAA, CHA₂DS₂-VASc score, anticoagulant type (none, VKA, or DOAC), and initial severity. To avoid collinearity or lack of independent association, the individual components of the CHA₂DS₂-VASc score, as well as related vascular risk factors (age, sex, hypertension, diabetes mellitus, dyslipidemia, coronary artery disease, peripheral vascular disease, heart failure, valvular disease), active smoking, and alcohol overuse, were not included in the multivariable models. The proportional subdistribution hazards assumption was assessed using diagnostic plots and time-dependent interaction terms and was satisfied in all models. Cumulative incidence functions were also visually inspected to verify the proportionality of hazards over time. All analyses were performed in R (version 4.4.1) by a blinded investigator (J-J-B), following STROBE guidelines. Statistical significance was set at p\u0026lt;0.05.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki. Ethical approval for this study was obtained from the \u003cem\u003eHospital del Mar Clinical Research Ethics Committee - Drug Research Ethics Committee (CEIm)\u0026nbsp;\u003c/em\u003e(Approval No. CEIM 2008/3038/I). Written informed consent was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request. Data sharing is subject to a formal data transfer agreement, in compliance with anonymization and data protection regulations.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eStudy Population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 1,949 consecutive AIS cases with AF were registered. After excluding 33 cases with incomplete etiological evaluation and 3 with other major competing causes, 1,913 remained. Ninety patients lost to follow-up after discharge and 611 who died within 90 days of stroke onset were further excluded, resulting in a final cohort of 1,212 patients (\u003cstrong\u003eFigure\u0026nbsp;1: Flowchart\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMedian age was 79.0 years (IQR 73–84) and 42.3% were male. Hypertension was present in 82.3%, diabetes mellitus in 33.7%, and dyslipidemia in 47.3%. Median CHA₂DS₂-VASc score was 6 (IQR 5–7) and median NIHSS on admission was 5 (IQR 2–10); NIHSS was lower in patients without long-term stroke recurrence (p=0.004) (\u003cstrong\u003eTable 1\u003c/strong\u003e). CSE were identified in 18.7% overall and were more frequent in patients with recurrence (34.3% vs 15.6%; p\u0026lt;0.001): SAO in 10.1%, LAA in 7.8%, and both in 0.8%. Atrial fibrillation was known before stroke in 67.4%, diagnosed at onset in 15.0%, and classified as AFDAS in 17.6%. AFDAS was less frequent in patients without recurrence (9.8% vs 19.1%; p=0.001), whereas known AF was more common (78.4% vs 65.2%; p\u0026lt;0.001). Anticoagulation was initiated in 82.8% overall, but less frequently in patients without recurrence (72.1% vs 84.9%; p\u0026lt;0.001). Competing‐risk cumulative incidence curves stratified by AF status, anticoagulant type, LAA and SAO are shown in \u003cstrong\u003eFigure 2\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLTSR\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMean follow-up was 55.3 months (median 43.0; IQR 19.9–81.7; range 0.04–18.9). LTSR occurred in 220 patients (18.1%; incidence rate 0.039 events/person-year), comprising 121 nonfatal ischaemic strokes, 68 fatal ischaemic strokes, 5 nonfatal haemorrhagic strokes, 10 fatal haemorrhagic strokes, and 16 TIAs (7.3%). During follow-up, 517 patients (42.7%) died, 166 (13.7%) were lost to follow-up, and 309 (25.5%) completed the study without recurrence or death (see \u003cstrong\u003eSupplementary Figure 1\u003c/strong\u003e for the overall cumulative incidence curve).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMultivariable Fine–Gray models\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the multivariable Fine–Gray model for overall LTSR (\u003cstrong\u003eTable 2\u003c/strong\u003e), known AF was independently associated with an increased risk of recurrence compared to AFDAS, while AF at stroke onset showed a non-significant trend. Both SAO (sHR 1.69, 95% CI 1.19–2.41; p=0.003) and LAA (sHR 2.58, 95% CI 1.78–3.74; p\u0026lt;0.001), as well as higher CHA₂DS₂-VASc score (per point increase: sHR 1.12, 95% CI 1.02–1.24; p=0.022), were independently associated with greater risk. Anticoagulation with DOAC (sHR 0.46, 95% CI 0.32–0.65; p\u0026lt;0.001) or VKA (sHR 0.60, 95% CI 0.43–0.84; p=0.003) was associated with a lower risk of LTSR. Initial severity (per point increase) showed a non-significant trend (sHR 0.98, 95% CI 0.96–1.00; p=0.057). Results for ischaemic and haemorrhagic LTSR are presented in \u003cstrong\u003eSupplementary Tables S1 and S2\u003c/strong\u003e, respectively. In the ischaemic LTSR model, AFDAS was independently associated with a lower risk (sHR 0.47, 95% CI 0.28–0.77; p=0.003), while AF at stroke onset again showed a non-significant trend (sHR 0.68, 95% CI 0.43–1.07; p=0.096). SAO showed a non-significant trend (sHR 1.45, 95% CI 0.98–2.15; p=0.064), whereas LAA was independently associated with increased risk (sHR 1.98, 95% CI 1.30–3.00; p=0.001). CHA₂DS₂-VASc was not significantly associated (sHR per point 1.02, 95% CI 0.93–1.14; p=0.644). Anticoagulant therapy with DOAC (sHR 0.54, 95% CI 0.37–0.79; p=0.002) or VKA (sHR 0.67, 95% CI 0.46–0.98; p=0.038) remained significantly protective. Higher initial severity was inversely associated with ischaemic LTSR (sHR 0.97, 95% CI 0.94–0.99; p=0.007). In the haemorrhagic LTSR model, neither AF status nor CHA₂DS₂-VASc was significantly associated with risk. SAO was independently associated with a higher risk of haemorrhagic LTSR (sHR 3.24, 95% CI 1.05–9.94; p=0.040), while LAA was not significant (sHR 1.60, 95% CI 0.37–6.97; p=0.533). Anticoagulation with DOAC showed a non-significant trend toward protection (sHR 0.12, 95% CI 0.01–1.01; p=0.051), and VKA was not associated. Initial severity was not significantly associated (sHR 0.95, 95% CI 0.87–1.03; p=0.221).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this hospital-based cohort of AIS patients with AF, the LTSR remained substantial despite widespread anticoagulation (18.1% over 3.6 years; 3.9 events/100 personyears), with a predominance of ischaemic events. These findings are consistent with previous population-based studies and multicenter registries, which have reported comparable long-term recurrence rates in patients with AF receiving oral anticoagulant therapy[11\u0026ndash;14]. Known AF was independently associated with an increased risk of LTSR compared to AFDAS. Both SAO and LAA, as well as higher CHA₂DS₂-VASc scores, were independently associated with increased risk, whereas anticoagulant therapy\u0026mdash;particularly DOACs but also VKAs\u0026mdash;was associated with a substantial reduction in LTSR risk. In analyses restricted to ischaemic LTSR, LAA continued to be independently associated with a higher risk, while AFDAS and anticoagulant therapy remained protective. Notably, SAO was the only independent predictor of haemorrhagic LTSR, while DOACs showed a non-significant trend toward a protective effect.\u003c/p\u003e\u003cp\u003eWhile previous studies of AFDAS have mainly focused on recurrence risk in the initial years after stroke, evidence regarding long-term outcomes remains limited, with most data restricted to short- and mid-term follow-up[\u003cspan additionalcitationids=\"CR16 CR17 CR18 CR19\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The prognostic significance of AFDAS has also been controversial: some reports found similar risks of recurrent stroke and death between AFDAS and known AF[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], whereas a recent meta-analysis demonstrated that AFDAS is associated with lower risk of ischaemic stroke recurrence and mortality, and a comparable risk of intracerebral haemorrhage[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Our results contribute new evidence confirming that this lower risk profile in AFDAS persists in the long term. The lower risk of LTSR in AFDAS is likely multifactorial. Several classifications based on the timing and method of AF detection after stroke have been proposed[\u003cspan additionalcitationids=\"CR16 CR17 CR18 CR19\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], due to a potential therapeutic implication. Recent research has highlighted the importance of AF burden, defined by the frequency and duration of AF episodes, as a key prognostic factor[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. This concept is closely related to atrial cardiomyopathy, or \"sick atrium,\" which refers to structural, architectural, contractile, or electrophysiological changes in the atrial myocardium that increase the risk of arrhythmogenesis and thromboembolism[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. AFDAS is typically associated with less extensive atrial remodeling, including reduced fibrosis, dilation, and impaired contractility[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], leading to a lower risk of thrombus formation and subsequent embolic events[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In contrast, patients with known AF often have a higher AF burden and are more likely to exhibit structural cardiac abnormalities and a greater accumulation of vascular risk factors[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], all contributing to an increased risk of LTSR.\u003c/p\u003e\u003cp\u003eAnticoagulation therapy conferred a protective effect in our cohort, reducing LTSR risk by approximately 54% in patients treated with DOACs (sHR 0.46, 95% CI 0.32\u0026ndash;0.65, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and by 40% in those receiving VKAs (sHR 0.60, 95% CI 0.43\u0026ndash;0.84, p\u0026thinsp;=\u0026thinsp;0.003), compared to no anticoagulation. These results are in line with evidence from randomized controlled trials, which have demonstrated at least non-inferior efficacy and improved safety of DOACs compared to VKAs[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In analyses restricted to ischaemic LTSR, the protective effect of anticoagulation was confirmed, while in the haemorrhagic LTSR model, DOACs showed a non-significant trend toward a protective effect. Taken together, our findings support current clinical guidelines[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], which emphasize the superiority of anticoagulation\u0026mdash;particularly DOACs\u0026mdash;for secondary stroke prevention in patients with AF[[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMoreover, in clinical practice, it is well recognized that patients with AF frequently present with CSE due to shared cardiovascular risk factors[\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In our cohort, the frequency of CSE was 18.7%, which is consistent with previous reports ranging from 7.7\u0026ndash;24%[\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Most prior studies on the prognostic impact of CSE in stroke patients with AF have focused primarily on atherosclerosis, particularly carotid atherosclerosis[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], although the coexistence of SAO in individuals with AF is also well documented[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Our study expands on previous research by incorporating a larger cohort, extended follow-up, and comprehensive etiological assessment using the CCS causative classification. This approach demonstrates that patients with CSE constitute a subgroup at significantly higher risk of LTSR, consistent with previous studies reporting increased rates of ischaemic stroke recurrence and mortality in this population[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Importantly, LTSR risk differed by CSE subtype, with LAA being the strongest predictor of ischaemic recurrence[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], while concomitant SAO was associated with an increased risk of haemorrhagic events. These findings suggest that patients with LAA are at particularly high risk for ischaemic recurrence and may require more intensive secondary prevention. The potential benefit and safety of strategies beyond anticoagulation\u0026mdash;such as intensive lipid-lowering therapy targeting LDL cholesterol below 55 mg/dL[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] or dual antithrombotic therapy\u0026mdash;remain to be established in these subgroups. In contrast, patients with concomitant SAO may derive greater benefit from optimal vascular risk factor control, particularly strict blood pressure management[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], which remains essential to reducing haemorrhagic LTSR risk.\u003c/p\u003e\u003cp\u003eAmong other factors analyzed, the CHA₂DS₂-VASc score\u0026mdash;a standard risk stratification tool\u0026mdash;was independently associated with LTSR risk in our cohort[\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Although CHA₂DS₂-VASc remains well validated for clinical risk assessment, we believe that its predictive value in this context likely reflects the cumulative impact of age and comorbidities, rather than strong associations of each individual component in univariate analysis. Initial severity was not independently associated with LTSR in the global multivariable models. However, in the analysis restricted to ischaemic LTSR, higher initial severity was independently associated with a lower risk of recurrence. While some previous studies have reported an association between initial stroke severity and recurrence risk[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], we did not observe this relationship in the long term. We believe this may be explained by the high competing risk of mortality associated with greater initial severity in this elderly cohort, which likely limited the detection of recurrent events despite statistical adjustment.\u003c/p\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eLimitations\u003c/h2\u003e\u003cp\u003eThis study was conducted at a single center, which may limit the generalizability of the findings to other populations and healthcare settings. Patients with early mortality or incomplete follow-up were excluded, which may introduce selection bias and restrict the applicability of results to the entire AIS population with AF. The observational design did not allow for systematic assessment of echocardiographic parameters or treatment adherence, potentially limiting the evaluation of structural cardiac risk factors and the quality of anticoagulation. These limitations should be considered when interpreting our findings and underscore the need for future multicenter studies with more comprehensive clinical characterization.\u003c/p\u003e\u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThis large, hospital-based cohort study with extended follow-up identifies independent predictors of LTSR in patients with AF-related stroke. Our findings confirm the protective effect of anticoagulant therapy\u0026mdash;particularly DOACs\u0026mdash;and the lower risk profile of AFDAS, even in the long term. Concomitant etiologies are common; LAA defines a subgroup at highest risk for ischaemic LTSR, and, notably, concomitant SAO independently increases the risk of long-term haemorrhagic recurrence. These results underscore the importance of comprehensive etiological assessment and support the need for individualized secondary prevention strategies in AF-related stroke.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eThis work was supported, in part, by Ministerio de ciencia, innovación y universidades de España (Instituto de Salud Carlos III, RICORS-ICTUS, RD24/0009/0011), the Sara Borrell Fellowship (J.J.B., CD022/0001), and the European Union’s Horizon Europe research and innovation programme under Grant No. 101136244 (TARGET). The authors declare no potential conflicts of interest related to this study. We gratefully acknowledge the contributions of all the staff at Hospital del Mar, as well as the patients and supporting facilities, whose efforts have been instrumental in establishing and maintaining the BasicMar registry.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This work was supported, in part, by Spanish Ministry of Science, Innovation and Universities (Instituto de Salud Carlos III, RICORS-ICTUS, RD24/0009/0011). Sara Borell (J.J.B., CD022/0001) and European Unions´s Horizon Europe research and innovation programme under Grant nº 101136244 (TARGET)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003eD.G.-A. and E.C.-G. contributed equally as first authors and were involved in study conception and design, data analysis and interpretation, and drafting of the manuscript. J.J.-B., E.G.-S., and A.O. contributed equally as senior authors, overseeing study design, methodology, data interpretation, and critical revision of the manuscript. J.J.-C., A.R.-C., I.F.-P., A.M.-G., A.S.-P., M.V.-P., J.P.-S., S.V.-N., and L.P.-M. contributed to data acquisition, analysis, and critical review. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request. Data sharing is subject to a formal data transfer agreement, in compliance with anonymization and data protection regulations.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWolf, P. A., Abbott, R. D. \u0026amp; Kannel, W. B. 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Stroke\u003c/em\u003e. \u003cb\u003e6\u003c/b\u003e, 164\u0026ndash;175. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1747-4949.2010.00573.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1747-4949.2010.00573.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2011).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen, L. Y. et al. CHA \u003csub\u003e2\u003c/sub\u003e DS \u003csub\u003e2\u003c/sub\u003e -VASc Score and Stroke Prediction in Atrial Fibrillation in Whites, Blacks, and Hispanics. \u003cem\u003eStroke\u003c/em\u003e \u003cb\u003e50\u003c/b\u003e, 28\u0026ndash;33. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/STROKEAHA.118.021453\u003c/span\u003e\u003cspan address=\"10.1161/STROKEAHA.118.021453\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbouzid, M. R. et al. Assessing Stroke and Mortality Risk in Heart Failure: The CHA2DS2-VASc Score\u0026rsquo;s Prognostic Value in Patients With and Without Atrial Fibrillation: A Meta-Analysis. \u003cem\u003eCardiol Rev Published Online First: 15 August\u003c/em\u003e. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/CRD.0000000000000749\u003c/span\u003e\u003cspan address=\"10.1097/CRD.0000000000000749\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2024).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSiddiqi, T. J. et al. Utility of the CHA2DS2-VASc score for predicting ischaemic stroke in patients with or without atrial fibrillation: a systematic review and meta-analysis. \u003cem\u003eEur. J. Prev. Cardiol.\u003c/em\u003e \u003cb\u003e29\u003c/b\u003e, 625\u0026ndash;631. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/eurjpc/zwab018\u003c/span\u003e\u003cspan address=\"10.1093/eurjpc/zwab018\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7453175/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7453175/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePredictors of long-term ischaemic and haemorrhagic stroke recurrence (LTSR) after acute ischaemic stroke (AIS) with AF remain uncertain. This study aimed to identify independent predictors of LTSR in patients with AF-related AIS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003cbr\u003e\nWe conducted a prospective observational study of consecutive AIS patients with AF enrolled in a hospital-based registry (January 2005–June 2022). The primary endpoint was LTSR, defined as any new ischaemic or haemorrhagic cerebrovascular event occurring during follow-up, which began 90 days after the AIS event. Independent predictors of overall, ischaemic, and haemorrhagic LTSR were identified using Fine–Gray competing risk models.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003cbr\u003e\nA total of 1,212 patients (median age 79 years, 42.3% male) were included. During a median follow-up of 43.0 months, 220 patients (18.1%) experienced LTSR (incidence 0.039 events/person-year), predominantly ischaemic. In multivariable Fine–Gray models, known AF before the index stroke (sHR 2.1), large artery atherosclerosis (LAA) (sHR 2.6), small artery occlusion (SAO) (sHR 1.7), and higher CHA₂DS₂-VASc scores were independently associated with increased LTSR risk, while anticoagulation—particularly with Direct Oral Anticoagulants (DOACs) (sHR 0.46)—was protective. AF detected after stroke (AFDAS) (sHR 0.47) was associated with lower risk of ischaemic LTSR, and LAA defined a high-risk subgroup. Notably, SAO was the only independent predictor of haemorrhagic LTSR (sHR 3.2). DOAC showed a non-significant trend toward protection for haemorrhagic events.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003cbr\u003e\nIn AF-related AIS, AFDAS was associated with lower risk of LTSR, while anticoagulation—particularly with DOACs—was strongly protective. The presence of competing stroke etiologies identified differential high-risk subgroups for ischaemic and haemorrhagic recurrence, highlighting the need for individualized prevention strategies.\u003c/p\u003e","manuscriptTitle":"Long-term Stroke Recurrence in Atrial Fibrillation: Differential Predictors of Ischaemic and Haemorrhagic Risk","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-08 07:08:37","doi":"10.21203/rs.3.rs-7453175/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"252504a6-d333-4390-93e9-c67e84eb3805","owner":[],"postedDate":"October 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":55789756,"name":"Health sciences/Cardiology"},{"id":55789757,"name":"Health sciences/Diseases"},{"id":55789758,"name":"Health sciences/Medical research"},{"id":55789759,"name":"Health sciences/Neurology"},{"id":55789760,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2025-10-31T18:08:37+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-08 07:08:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7453175","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7453175","identity":"rs-7453175","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}