{"paper_id":"6d110b18-ca72-4a95-a3ac-6857f6f0c5b9","body_text":"Heart Failure, Recurrent Vascular Events and Death in Patients with Ischemic Stroke - Results of the MonDAFIS study | 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 Research Article Heart Failure, Recurrent Vascular Events and Death in Patients with Ischemic Stroke - Results of the MonDAFIS study Serdar Tütüncü, Manuel Olma, Claudia Kunze, Joanna Dietzel, Johannes Schurig, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3303557/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background Heart failure (HF) is associated with poor outcome after stroke, but data from large prospective trials are sparse. Methods We assessed the impact of HF on clinical endpoints in patients hospitalized with acute ischemic stroke or transient ischemic attack (TIA) enrolled in the prospective, multicenter Systematic Monitoring for Detection of Atrial Fibrillation in Patients with Acute Ischemic Stroke (MonDAFIS) trial. HF was defined as left ventricular ejection fraction (LVEF) < 55% or a history of HF on admission. The composite of recurrent stroke, major bleeding, myocardial infarction, and all-cause death, and its components during the subsequent 24 months were assessed. We used estimated hazard ratios in confounder-adjusted models. Results Overall, 410/2,562 (16.0%) stroke patients fulfilled the HF criteria (i.e. 381 [14.9%] with LVEF > 55% and 29 [1.9%] based on medical history). Patients with HF had more often diabetes, coronary and peripheral arterial disease and presented with more severe strokes on admission. HF at baseline correlated with myocardial infarction (HR 2.21; 95%CI 1.02–4.79), and all-cause death (HR 1.67; 95%CI 1.12–2.50), but not with major bleed (HR 1.93; 95%CI 0.73–5.06) or recurrent stroke/TIA (HR 1.08; 95%CI 0.75–1.57). The data were adjusted for age, stroke severity, cardiovascular risk factors, and randomization. Conclusions Patients with ischemic stroke or TIA and comorbid HF have a higher risk of myocardial infarction and death compared with non-HF patients whereas the risk of recurrent stroke or major hemorrhage was similar. Trial registration number Clinicaltrials.gov NCT02204267 Ischemic Stroke Heart Failure Vascular Outcome Mortality Figures Figure 1 Figure 2 Introduction The prevalence of both stroke and heart failure (HF) is high in the elderly, and there is a long list of common cardiovascular risk factors, including hypertension, diabetes, sleep apnea, kidney dysfunction, or atrial fibrillation (AF). HF is regarded as an independent risk factor for ischemic stroke, and about 9% of all ischemic strokes are assumed to be related to HF. [ 1 ] Furthermore, there is an association between HF with unfavorable clinical outcome and mortality after stroke. [ 2 – 6 ] In contrast, it is less clear whether HF is also associated with recurrent vascular events following an ischemic stroke. Data on recurrent ischemic stroke in stroke patients with HF are conflicting: a systemic review and meta-analysis of seven prospective trials with differing follow-up times demonstrated a significant association of HF with recurrent ischemic stroke in 9,173 ischemic stroke patients. [ 7 ] However, a retrospective insurance data-based analysis showed no significant association of recurrent stroke and HF in 370,527 ischemic stroke patients.[ 8 ] While there are several publications focusing on myocardial infarction following ischemic stroke [ 9 , 10 ], data on the association of myocardial infarction with HF in ischemic stroke patients are scarce. [ 11 ] In addition, studies examining the occurrence of major bleeding in association with heart failure in ischemic stroke patients are missing. In this post-hoc analysis of the prospective multicenter MonDAFIS study, we analyzed the impact of HF at baseline on the composite of recurrent stroke, major bleeding, myocardial infarction, and all-cause death within 24 months after hospitalization for acute ischemic stroke or transient ischemic attack (TIA). [ 12 , 13 ] Furthermore, we investigated the association of each vascular endpoint separately with HF and rates of oral anticoagulation after 24 months in patients with or without HF at baseline. Methods Study cohort MonDAFIS was an investigator-initiated randomized trial sponsored by the Charité - Universitätsmedizin Berlin, Berlin, Germany, and supported by an unrestricted research grant from Bayer Vital GmbH, Leverkusen, Germany to the Charité. The study rationale and design 12 as well as the primary and secondary endpoints [ 13 ] were published previously. The MonDAFIS study received primary approval from the Ethics Committee of the Charité - Universitätsmedizin Berlin, Germany. All 39 participating study centers provided approval from their respective ethics committees. All study patients gave written informed consent. The MonDAFIS trial complies with the Declaration of Helsinki. A critical event committee adjudicated all serious adverse events (including recurrent stroke, myocardial infarction, major bleeding, and all-cause death) blinded to trial randomization. Study Population Men or women ≥ 18 years of age were eligible for study enrollment if they had an ischemic stroke according to WHO criteria [ 14 ], a TIA with new-onset neurological deficit present and documented by a neurologist on hospital admission, or a TIA with corresponding acute ischemic lesion(s) on brain imaging. Patients were excluded due to withdrawal of informed consent and data deletion or lack of any data. Detailed information regarding further in- and exclusion criteria as well as the trial intervention was published previously. [ 13 ] In the vast majority of MonDAFIS patients, left ventricular ejection fraction (LVEF) was determined by echocardiography at baseline as part of routine diagnostic procedures. The LVEF was captured in the eCRF as a categorized variable (LVEF ≥ 55% (“normal”), LVEF 31–54% (“slightly reduced”), LVEF ≤ 30% (“reduced”)). The rationale for this definition was based on the ESC guidelines for measuring LVEF that was valid at the time of study conception. In addition, heart failure (HF) was considered as pre-existing at baseline if it was reported by the patient or evident from existing medical reports (history of HF). In the present analysis, patients with a documented LVEF < 55% and/or a history of HF at baseline were considered HF patients. Patients without echocardiography during the index-stroke/TIA related hospital stay were excluded from the present analysis. Outcomes In line with the pre-defined secondary endpoint of the MonDAFIS study, we assessed the composite of recurrent stroke, myocardial infarction, major bleed, and all-cause death within two years after the index stroke in defined subgroups. Furthermore, the individual components of the composite endpoint were analyzed separately. The rate of oral anticoagulation within 24 months after the index event was assessed in patients with and without HF at baseline. Statistical Methods This is an explorative analysis of the MonDAFIS study data set using predefined outcomes. Baseline characteristics are reported as frequencies and percentages for categorical variables or median and limits of the interquartile range (IQR; [25th and 75th percentile]) for metric variables. For the outcomes of interest, we conducted event-free survival analyses comparing cumulative hazards between patient groups. Event-free survival-time, as well as survival, was measured in person-days until one of the events of the combined endpoint or death occurred, the study ended, or the participant was lost to follow-up. These dropouts are censored at the time of last contact. We used Kaplan-Meier curves and the log-rank test to compare crude cumulative hazard distributions. Cox Proportional Hazard models (crude and adjusted for cardiovascular risk factors as arterial hypertension, diabetes mellitus, hyperlipoproteinemia, coronary heart disease, detection of atrial fibrillation and group randomization given as model 1 and model 2 with further adjustment for intravenous thrombolysis and endovascular thrombectomy in addition) were used to estimate hazard ratios (HR) for each vascular endpoint, the composite endpoint for all-cause death risk within two years after ischemic stroke or TIA. Cox Proportional Hazard assumption was checked. For the endpoint ‘oral anticoagulation 24 months after index event’ a multiple binary logistic regression analysis (adjusted for AF and detection of left atrial and/or ventricular thrombus) was conducted and adjusted odds ratios, as well as respective confidence intervals (CI), (CI) are reported. Data preparation was done using the software IBM SPSS Statistics 24. Results Of 3,431 patients included in MonDAFIS, LVEF was available in 2,562 (75%) patients (mean age 67 [57–76] years, 39.5% female, median NIHSS score on admission 2 points [ 1 – 4 ]). Figure 1 shows the derivation of the study population. Patients without documented LVEF were older, more often had a TIA as index event and a stroke or TIA before the index event (Table 1 Online Supplement). Overall, 381/2,562 (14.9%) patients had a LVEF < 55% and 75/2,562 patients had a documented past medical history of HF (of which 29 had a LVEF ≥ 55%). Therefore, a total of 410/2,562 (16.0%) patients fulfilled at least one of the pre-defined HF criteria (Fig. 1 ). Baseline characteristics and results of multiple binary logistic regression of patients with vs without HF are shown in Table 1 . Table 1 Baseline characteristics of MonDAFIS study patients with or without heart failure at baseline. Univariate analysis Multivariate analysis Heart failure n = 410 No heart failure n = 2,151 p-value OR (95% CI)* p-value Age, years , median [IQR] 69 [60–77] 66 [56–76] < 0.001 1.01 (0.99–1.02) 0.078 Age categories, years , n (%) 0.001 - - <65 149 (36.3) 991 (46.1) - - 65–74 121 (29.5) 566 (26.3) - - 75–84 116 (28.3) 521 (24.2) - - >84 24 (5.9) 73 (3.4) - - Female sex , n (%) 119 (29.0) 866 (40.3) < 0.001 0.79 (0.61–1.03) 0.081 Body weight , kg, mean (SD) [IQR] 81 [70–95] 80 [70–90] 0.009 1.01 (1.00-1.02) 0.052 Index stroke , n (%) 0.020 TIA 99 (24.1) 640 (29.8) 1 Stroke 311 (75.9) 1,507 (70.2) 1.11 (0.86–1.44) 0.422 NIHSS score on admission , median [IQR] 3 [ 1 – 5 ] 2 [ 1 – 4 ] 0.013 1.05 (1.02–1.09) 0.002 In-hospital treatment , n (%) Intravenous thrombolysis 91 (22.2) 500 (23.2) 0.644 - - Endovascular treatment 15 (3.7) 56 (2.6) 0.233 - - Hemicraniectomy 1 (0.2) 1 (0.0) 0.190 - - Carotid surgery or stenting 9 (2.2) 33 (1.5) 0.334 - - Cardiovascular risk factors , n (%) Diabetes mellitus 150 (36.6) 508 (23.6) < 0.001 1.33 (1.04–1.70) 0.026 Hypertension 346 (84.4) 1,615 (75.2) < 0.001 1.14 (0.83–1.57) 0.408 Hypercholesterolemia 237 (57.8) 1,125 (52.4) 0.043 1.06 (0.84–1.33) 0.634 Coronary heart disease 116 (28.3) 191 (8.9) < 0.001 3.12 (2.36–4.13) < 0.001 Peripheral arterial disease 34 (8.3) 60 (2.8) < 0.001 2.04 (1.28–3.25) 0.003 Prior ischemic stroke or TIA 68 (16.6) 326 (15.2) 0.469 - - Smoker 211 (51.7) 1,017 (47.6) 0.129 - - Randomization to the intervention group , n (%) 200 (48.8) 1,072 (49.8) 0.695 - - **OR and 95% CI for continues variables were expressed per point (BMI, NIHSS) or per each year of age. Patients with HF more often had diabetes mellitus [OR 1.33; 95%CI 1.04–1.70; P = 0.026], coronary artery disease [OR 3.12; 95%CI 2.36–4.13; P < 0.001], and peripheral arterial disease [OR 2.03; 95%CI 1.27–3.24; P = 0.003] than non-HF patients. Moreover, patients with HF had a higher stroke severity on admission than patients without HF [assessed by the NIHSS score; OR per point 1.05; 95%CI 1.02–1.09; P = 0.002). Association of heart failure with clinical outcomes Within two years after index stroke or TIA, the predefined composite endpoint occurred in 480/2,561 (14.0%) of patients, including recurrent stroke in 301 (8.8%) patients, myocardial infarction in 43 (1.3%) patients, major bleeding in 32 (0.9%) patients and all-cause death in 175 (5.1%) patients. Recurrent ischemic stroke or TIA occurred in 283/2,561 (8.3%) patients, while 18/2,561 (0.7%) patients had a hemorrhagic stroke within two years. After adjusting for cardiovascular risk factors, stroke severity and randomization (model 1), HF was associated with myocardial infarction [HR 2.21; 95% CI 1.02–4.79; P = 0.046], and all-cause death [HR 1.67; 95%CI 1.12–2.49, P = 0.013] within 2 years after the index event. On the contrary, neither the composite endpoint [HR 1.28; 95%CI 0.99–1.66] nor recurrent ischemic stroke or TIA [HR 1.07; 95%CI: 0.74–1.55] nor major bleeding [HR 1.93; 95%CI 0.73–5.06] (Fig. 2 and Table 2 ) was significantly increased in stroke patients with HF. Additional adjustment for intravenous thrombolysis and endovascular thrombectomy (model 2) yielded similar results (Table 2 ). Also, excluding patients with a documented medical history of HF but normal LVEF (≥ 55%) at baseline yielded similar results (Table 2 Online Supplement). Table 2 Adjusted survival analyses, Cox regression, hazard ratios for the composite endpoint (recurrent stroke, myocardial infarction, major bleeding, all-cause death) and its components as well as recurrent ischemic stroke/TIA within 24 months after the index stroke/TIA for patients with heart failure (n = 410) compared to those without heart failure at baseline. Crude Adjusted, Model 1 a Adjusted, Model 2 a HR (95%CI) P HR (95%CI) P HR (95%CI) P Composite endpoint b 1.54 (1.20-1.98) 0.001 1.28 (0.99-1.66) 0.065 1.29 (0.99-1.67) 0.060 All-cause death 2.15 (1.46-3.16) <0.001 1.67 (1.12-2.49) 0.013 1.65 (1.10-2.47) 0.015 Recurrent stroke c 1.21 (0.86-1.69) 0.274 1.08 (0.76-1.54) 0.668 1.09 (0.77-1.56) 0.620 Recurrent ischemic stroke or TIA 1.16 (0.81-1.65) 0.425 1.07 (0.74-1.55) 0.737 1.08 (0.75-1.57) 0.680 Recurrent ischemic stroke 1.24 (0.83-1.85) 0.299 1.08 (0.71-1.66) 0.719 1.09 (0.71-1.67) 0.683 Recurrent TIA 0.91 (0.43-1.93) 0.806 0.98 (0.46-2.11) 0.955 0.99 (0.46-2.14) 0.986 Myocardial infarction 3.96 (1.94-8.08) <0.001 2.21 (1.02-4.79) 0.046 2. 18 (1.01-4.76) 0.050 Major bleed 1.93 (0.76-4.89) 0.168 1.93 (0.73-5.06) 0.184 1.89 (0.72-4.99) 0.196 a) Adjusted Model 1: for age, stroke severity (NIHSS score on admission), diabetes mellitus, arterial hypertension, hyperlipoproteinemia, coronary heart disease, detection of atrial fibrillation in-hospital, randomization; Adjusted Model 2: all variables of Adjusted Model 1 and additionally intravenous thrombolysis and endovascular thrombectomy b) Recurrent stroke, MI, major bleed, all cause death c) Ischemic Stroke, Transient Ischemic Attack, Intracerebral Hemorrhage, Subarachnoid Hemorrhage Secondary stroke prevention in patients with heart failure Information on oral anticoagulation at 24 months was available in 2,072/2,561 (80.9%) patients and, similarly, on antiplatelet treatment in 2,075/2,561 (81.0%) patients. Overall, 312/2,072 (15.1%) patients were on anticoagulation and 1,645/2,075 (79.4%) patients on antiplatelets at 24 months. In patients with HF at baseline, information on oral anticoagulation at 24 months was available in 304/410 (74.2%) patients. There was a statistically significant difference in the rate oral anticoagulation in HF patients vs. non-HF patients (63/304 [20.7%] vs. 249/1768 [14.1%], respectively, p = 0.004). AF was diagnosed in 46/63 (73.0%) of those with oral anticoagulants and HF. The rate of oral anticoagulation was 15.7% in HF patients vs 11.8% in non-HF patients at 6 months after the index stroke/TIA (p = 0.046) and 16.6% vs 12.9% after 12 months (p = 0.072) (Table 3 online supplement). After multivariate adjustment (including newly detected AF within 24 months and left ventricular or left atrial thrombus at baseline), there was no significant association between HF status at baseline and oral anticoagulation after 24 months [OR 0.89; 95%CI 0.51–1.56; P = 0.689]. Discussion The prospective multicenter MonDAFIS study shows that ischemic stroke or TIA patients with comorbid HF had a significantly higher rate of myocardial infarction and all-cause mortality within 24 months than non-HF patients. One strength of our post hoc analysis is the large number of clinical endpoints assessed by an independent endpoint committee and standardized follow-up for 24 months. Our data confirm that stroke/TIA patients with comorbid HF are not only more likely to have cardiovascular risk factors (such as diabetes, coronary heart disease, peripheral arterial disease) but also to have more severe strokes than stroke patients without HF. [ 2 ] Our finding of a statistically higher rate of myocardial infarction over 24 months after stroke/TIA in the presence of HF is consistent with the results of a large multicenter registry in the UK based on NHS primary care data of 9,840 patients. [ 11 ] The detected higher mortality rate in ischemic stroke patients with comorbid HF is also in line with previous studies. [ 6 , 8 ] Of note, the rate of recurrent stroke as well as recurrent ischemic stroke or TIA was not associated with HF in our study, which was also found in a retrospective analysis of a large registry but is not consistent with a meta-analysis of prospective studies.[ 7 , 8 ] The follow up period of 2 years was may be too short to observe any potential association between HF and ischemic stroke – the authors of the WARCEF trial reported a higher rate of ischemic strokes during a follow up period that was approximately 1.5 years longer. One study reported a significant association of recurrent intracerebral hemorrhage in patients with HF compared to non-HF patients. [ 8 ] In MonDAFIS, the HF status at baseline was not associated with the rate of major bleeding after stroke, even though 21% of HF patients received oral anticoagulation at 24 months. In fact, OAC status was not statistically different between HF vs. non-HF patients after adjusting for AF and presence of cardiac thrombi. There are some limitations that should be mentioned. First, the MonDAFIS study was not designed to investigate the impact of HF on recurrent vascular events or death. Second, as echocardiography was conducted according to routine clinical practice respective data were available for only 75% of the total study population. Third, we had no systematic information on biomarkers, like natriuretic peptides. Fourth, we had no further information on HF status after hospital discharge after the index-stroke/TIA. Fifth, our results cannot be applied to all stroke patients, as patients had to provide informed consent to participate in the MonDAFIS study. Finally, we have no detailed information on cause of death, as autopsy was performed in a minority of study patients only. Conclusion Patients with acute ischemic stroke or TIA with comorbid HF have a higher prevalence of cardiovascular risk factors, suffered more severe (index) strokes and have a higher risk for myocardial infarctions or all-cause death within 24 months after the index stroke. Special attention should be paid to the prevention of myocardial infarction in this patient population and cardiac follow-up should be recommended in stroke patients with HF. Declarations Acknowledgment None. Source of funding The MonDAFIS study was an investigator-initiated, prospective, randomized, multicenter study sponsored by the Charité - Universitätsmedizin Berlin, Germany and supported by an unrestricted research grant from Bayer Vital GmbH, Leverkusen, Germany to the Charité – Universitätsmedizin Berlin, Germany. Statement and Declarations PK is listed as inventor on two patents held by the University of Birmingham, Birmingham, UK (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). PK receives research support for basic, translational, and clinical research projects from the EU, British Heart Foundation, Leducq Foundation, the UK Medical Research Council, and German Centre for Cardiovascular Research, from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies in the past. GT has received speakers' honoraria or consulting fees from Amarin, Daichi Sanyo, Acandis, Bayer Healthcare, Boehringer Ingelheim, Covidien, Bristol-Myers Squibb, Portola, Stryker, and Pfizer. DGN has received speakers' honoraria and consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Novartis, and Pfizer. JR has received speakers' honoraria and consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and AstraZeneca. UL reports honoraria and reimbursements for lectures, participation in studies, scientific cooperations (with Saarland University, Saarland, Germany), consulting, travel, support (of colleagues), or support of scientific meetings by Amgen, Bayer, Boehringer Ingelheim, Daiichi Sankyo, MSD, Sanofi, and Servier, outside the submitted work. RV reports grants, personal fees, and being a shareholder from Bayer; grants from Boehringer; grants and personal fees from Bristol-Myers Squibb and Pfizer; grants from Daiichi Sankyo, Medtronic, and Biogen; personal fees from Javelin, Abbott, and AstraZeneca; and holding shares in Novartis, outside the submitted work. RV is an investigator of Imperial National Institutes of Health Research Biomedical Research Centre and partially funded by the EU's Horizon 2020 research and innovation programme (grant agreement 754517 [PRESTIGE-AF]). PUH reports grants from Charité, Universitätsmedizin Berlin during study conduct (within MonDAFIS for biometry; member of the scientific board); research grants from the German Ministry of Research and Education, German Research Foundation, the Bavarian State (ministry for science and the arts; within STAAB COVID-19), the EU, Berlin Chamber of Physicians, German Parkinson Society, University Hospital Würzburg, Robert Koch Institute, German Heart Foundation, Federal Joint Committee within the Innovationfond, University Hospital Heidelberg (within RASUNOA-prime; supported by an unrestricted research grant to the University Hospital Heidelberg from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, and Daiichi Sankyo), and University Göttingen (within FIND-AF(randomised); supported by an unrestricted research grant to the University Göttingen from Boehringer Ingelheim), outside the submitted work. KGH reports speakers' honoraria, consulting fees or lecture honoraria from Abbott, Alexion, AMARIN, AstraZeneca, Bayer Healthcare, Sanofi, Boehringer Ingelheim, Daiichi Sankyo, Pfizer, Bristol-Myers Squibb, Biotronik, Medtronic, Portola, Premier Research, SUN Pharma, WL Gore and Associates, and Edwards Lifesciences, as well as study support by Bayer and Getemed. ME reports grants from Bayer and fees paid to the Charité from AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Covidien, Daiichi Sankyo, GlaxoSmithKline, Novartis, Pfizer, and Sanofi. All other authors declare no competing interests outside the submitted work. References Doehner W, Ural D, Haeusler KG et al (2018) Heart and brain interaction in patients with heart failure: overview and proposal for a taxonomy. A position paper from the Study Group on Heart and Brain Interaction of the Heart Failure Association. 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Am Heart J 172:19–25 Haeusler KG, Kirchhof P, Kunze C et al (2021) Systematic monitoring for detection of atrial fibrillation in patients with acute ischaemic stroke (MonDAFIS): a randomised, open-label, multicentre study. Lancet Neurol 20(6):426–436 Hatano S (1976) Experience from a multicentre stroke register: a preliminary report. Bull World Health Organ 54(5):541–553 Supplementary Files MHFONLINESUPPLEMENT.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 04 Oct, 2023 Reviewers invited by journal 01 Oct, 2023 Editor assigned by journal 29 Aug, 2023 First submitted to journal 28 Aug, 2023 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. 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Berlin\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Joanna\",\"middleName\":\"\",\"lastName\":\"Dietzel\",\"suffix\":\"\"},{\"id\":237223734,\"identity\":\"4e532227-45a9-4ddf-9ee7-ab0c6a601230\",\"order_by\":4,\"name\":\"Johannes Schurig\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Center for Stroke Research Berlin: Centrum fur Schlaganfallforschung Berlin\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Johannes\",\"middleName\":\"\",\"lastName\":\"Schurig\",\"suffix\":\"\"},{\"id\":237223735,\"identity\":\"9bed98f0-ca4d-4965-9f77-2be5541d9608\",\"order_by\":5,\"name\":\"Michael Rosenkranz\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Albertinen-Hospital: Albertinen Krankenhaus\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Michael\",\"middleName\":\"\",\"lastName\":\"Rosenkranz\",\"suffix\":\"\"},{\"id\":237223736,\"identity\":\"3a83e355-dd4a-4fa8-84f9-7697ab757c3a\",\"order_by\":6,\"name\":\"Robert Stingele\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"DRK Kliniken Berlin: Deutsches Rotes Kreuz Schwesternschaft Berlin Krankenhaus gGmbH\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Robert\",\"middleName\":\"\",\"lastName\":\"Stingele\",\"suffix\":\"\"},{\"id\":237223737,\"identity\":\"e1129d74-729b-4756-99b5-4bc2844e2365\",\"order_by\":7,\"name\":\"Matthias Maschke\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Krankenhaus der Barmherzigen Brüder Trier: Krankenhaus der Barmherzigen Bruder Trier\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Matthias\",\"middleName\":\"\",\"lastName\":\"Maschke\",\"suffix\":\"\"},{\"id\":237223738,\"identity\":\"fcd2a4ce-7277-439d-92bb-82272802b67d\",\"order_by\":8,\"name\":\"Peter Heuschmann\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University of Würzburg: Julius-Maximilians-Universitat Wurzburg\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Peter\",\"middleName\":\"\",\"lastName\":\"Heuschmann\",\"suffix\":\"\"},{\"id\":237223739,\"identity\":\"6ab2650a-5a3c-42e6-9d59-e14efa55b792\",\"order_by\":9,\"name\":\"Paulus Kirchhof\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"UKE: Universitatsklinikum Hamburg-Eppendorf\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Paulus\",\"middleName\":\"\",\"lastName\":\"Kirchhof\",\"suffix\":\"\"},{\"id\":237223740,\"identity\":\"ad575858-1b93-4f3f-8af3-509462ef2f61\",\"order_by\":10,\"name\":\"Ulrich Laufs\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Leipzig University: Universitat Leipzig\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ulrich\",\"middleName\":\"\",\"lastName\":\"Laufs\",\"suffix\":\"\"},{\"id\":237223741,\"identity\":\"49f0eecf-003c-4d3c-a888-1b9d84bc241b\",\"order_by\":11,\"name\":\"Darius Nabavi\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Vivantes Hospitals Neukolln: Vivantes Klinikum Neukolln\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Darius\",\"middleName\":\"\",\"lastName\":\"Nabavi\",\"suffix\":\"\"},{\"id\":237223742,\"identity\":\"4c5f1936-92cb-4dcb-ad5d-e9bee8b30f73\",\"order_by\":12,\"name\":\"Joachim Röther\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Asklepios Western Hospital Hamburg: Asklepios Westklinikum Hamburg\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Joachim\",\"middleName\":\"\",\"lastName\":\"Röther\",\"suffix\":\"\"},{\"id\":237223743,\"identity\":\"0ed2c92a-b296-45ad-b97e-89b882d2e551\",\"order_by\":13,\"name\":\"Götz Thomalla\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"UKE: Universitatsklinikum Hamburg-Eppendorf\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Götz\",\"middleName\":\"\",\"lastName\":\"Thomalla\",\"suffix\":\"\"},{\"id\":237223744,\"identity\":\"7b9ed32e-4015-46ac-af31-48947655e287\",\"order_by\":14,\"name\":\"Roland Veltkamp\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Universitätsklinikum Essen: Universitatsklinikum Essen\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Roland\",\"middleName\":\"\",\"lastName\":\"Veltkamp\",\"suffix\":\"\"},{\"id\":237223745,\"identity\":\"b44b7bfa-a5cb-4e3c-82c9-eca1058f6cb0\",\"order_by\":15,\"name\":\"Matthias Endres\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Charite Universitatsmedizin Berlin Campus Charite Mitte: Charite Universitatsmedizin Berlin\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Matthias\",\"middleName\":\"\",\"lastName\":\"Endres\",\"suffix\":\"\"},{\"id\":237223746,\"identity\":\"c0c8c40e-c908-420a-8157-8b03798ae183\",\"order_by\":16,\"name\":\"Karl Gerog Häusler\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"University Hospital Wurzburg: Universitatsklinikum Wurzburg\",\"correspondingAuthor\":false,\"submittingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Karl\",\"middleName\":\"Gerog\",\"lastName\":\"Häusler\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2023-08-28 13:41:21\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-3303557/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-3303557/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":44212037,\"identity\":\"64d315e2-0d33-45a9-a92f-24a0f7ba9137\",\"added_by\":\"auto\",\"created_at\":\"2023-10-06 20:57:43\",\"extension\":\"jpeg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":476809,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eDerivation of the study population.\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e* LVEF=Left Ventricular Ejection Fraction, **Data of one MonDAFIS patient was excluded from analysis due to conflicting information regarding first diagnosis of heart failure during in-hospital stay.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage1.jpeg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3303557/v1/b254e72d00d2d5db95aaa1e6.jpeg\"},{\"id\":44212035,\"identity\":\"acbf3ad7-2507-43b5-9a3e-a4862a346bb6\",\"added_by\":\"auto\",\"created_at\":\"2023-10-06 20:57:43\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":55205,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eTime to event analysis. Occurrence of \\u003cu\\u003emyocardial infarction (A\\u003c/u\\u003e) or \\u003cu\\u003eall-cause death (B)\\u003c/u\\u003e within 24 months according to heart failure status at baseline.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3303557/v1/4b5e753ca548bfea18918b38.png\"},{\"id\":44213266,\"identity\":\"bdabac2c-292d-44af-b62f-abb252ac15ad\",\"added_by\":\"auto\",\"created_at\":\"2023-10-06 21:05:43\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":576448,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3303557/v1/c7fbd282-baf2-4e6f-8359-722ace94ecee.pdf\"},{\"id\":44212036,\"identity\":\"19a7f6b1-a91d-4f2f-a10a-a4891c477231\",\"added_by\":\"auto\",\"created_at\":\"2023-10-06 20:57:43\",\"extension\":\"docx\",\"order_by\":4,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":26033,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"MHFONLINESUPPLEMENT.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-3303557/v1/5060068cdb4d2e1f4996b93f.docx\"}],\"financialInterests\":\"\",\"formattedTitle\":\"Heart Failure, Recurrent Vascular Events and Death in Patients with Ischemic Stroke - Results of the MonDAFIS study\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eThe prevalence of both stroke and heart failure (HF) is high in the elderly, and there is a long list of common cardiovascular risk factors, including hypertension, diabetes, sleep apnea, kidney dysfunction, or atrial fibrillation (AF). HF is regarded as an independent risk factor for ischemic stroke, and about 9% of all ischemic strokes are assumed to be related to HF. [\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e] Furthermore, there is an association between HF with unfavorable clinical outcome and mortality after stroke. [\\u003cspan additionalcitationids=\\\"CR3 CR4 CR5\\\" citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e] In contrast, it is less clear whether HF is also associated with recurrent vascular events following an ischemic stroke. Data on recurrent ischemic stroke in stroke patients with HF are conflicting: a systemic review and meta-analysis of seven prospective trials with differing follow-up times demonstrated a significant association of HF with recurrent ischemic stroke in 9,173 ischemic stroke patients. [\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e] However, a retrospective insurance data-based analysis showed no significant association of recurrent stroke and HF in 370,527 ischemic stroke patients.[\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e] While there are several publications focusing on myocardial infarction following ischemic stroke [\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e], data on the association of myocardial infarction with HF in ischemic stroke patients are scarce. [\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e] In addition, studies examining the occurrence of major bleeding in association with heart failure in ischemic stroke patients are missing.\\u003c/p\\u003e \\u003cp\\u003eIn this post-hoc analysis of the prospective multicenter MonDAFIS study, we analyzed the impact of HF at baseline on the composite of recurrent stroke, major bleeding, myocardial infarction, and all-cause death within 24 months after hospitalization for acute ischemic stroke or transient ischemic attack (TIA). [\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e] Furthermore, we investigated the association of each vascular endpoint separately with HF and rates of oral anticoagulation after 24 months in patients with or without HF at baseline.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStudy cohort\\u003c/h2\\u003e \\u003cp\\u003eMonDAFIS was an investigator-initiated randomized trial sponsored by the Charit\\u0026eacute; - Universit\\u0026auml;tsmedizin Berlin, Berlin, Germany, and supported by an unrestricted research grant from Bayer Vital GmbH, Leverkusen, Germany to the Charit\\u0026eacute;. The study rationale and design\\u003csup\\u003e12\\u003c/sup\\u003e as well as the primary and secondary endpoints [\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e] were published previously. The MonDAFIS study received primary approval from the Ethics Committee of the Charit\\u0026eacute; - Universit\\u0026auml;tsmedizin Berlin, Germany. All 39 participating study centers provided approval from their respective ethics committees. All study patients gave written informed consent. The MonDAFIS trial complies with the Declaration of Helsinki. A critical event committee adjudicated all serious adverse events (including recurrent stroke, myocardial infarction, major bleeding, and all-cause death) blinded to trial randomization.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStudy Population\\u003c/h2\\u003e \\u003cp\\u003eMen or women\\u0026thinsp;\\u0026ge;\\u0026thinsp;18 years of age were eligible for study enrollment if they had an ischemic stroke according to WHO criteria [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e], a TIA with new-onset neurological deficit present and documented by a neurologist on hospital admission, or a TIA with corresponding acute ischemic lesion(s) on brain imaging. Patients were excluded due to withdrawal of informed consent and data deletion or lack of any data. Detailed information regarding further in- and exclusion criteria as well as the trial intervention was published previously. [\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e]\\u003c/p\\u003e \\u003cp\\u003eIn the vast majority of MonDAFIS patients, left ventricular ejection fraction (LVEF) was determined by echocardiography at baseline as part of routine diagnostic procedures. The LVEF was captured in the eCRF as a categorized variable (LVEF\\u0026thinsp;\\u0026ge;\\u0026thinsp;55% (\\u0026ldquo;normal\\u0026rdquo;), LVEF 31\\u0026ndash;54% (\\u0026ldquo;slightly reduced\\u0026rdquo;), LVEF\\u0026thinsp;\\u0026le;\\u0026thinsp;30% (\\u0026ldquo;reduced\\u0026rdquo;)). The rationale for this definition was based on the ESC guidelines for measuring LVEF that was valid at the time of study conception. In addition, heart failure (HF) was considered as pre-existing at baseline if it was reported by the patient or evident from existing medical reports (history of HF). In the present analysis, patients with a documented LVEF\\u0026thinsp;\\u0026lt;\\u0026thinsp;55% and/or a history of HF at baseline were considered HF patients. Patients without echocardiography during the index-stroke/TIA related hospital stay were excluded from the present analysis.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eOutcomes\\u003c/h2\\u003e \\u003cp\\u003eIn line with the pre-defined secondary endpoint of the MonDAFIS study, we assessed the composite of recurrent stroke, myocardial infarction, major bleed, and all-cause death within two years after the index stroke in defined subgroups. Furthermore, the individual components of the composite endpoint were analyzed separately. The rate of oral anticoagulation within 24 months after the index event was assessed in patients with and without HF at baseline.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003eStatistical Methods\\u003c/h2\\u003e \\u003cp\\u003eThis is an explorative analysis of the MonDAFIS study data set using predefined outcomes. Baseline characteristics are reported as frequencies and percentages for categorical variables or median and limits of the interquartile range (IQR; [25th and 75th percentile]) for metric variables. For the outcomes of interest, we conducted event-free survival analyses comparing cumulative hazards between patient groups. Event-free survival-time, as well as survival, was measured in person-days until one of the events of the combined endpoint or death occurred, the study ended, or the participant was lost to follow-up. These dropouts are censored at the time of last contact. We used Kaplan-Meier curves and the log-rank test to compare crude cumulative hazard distributions. Cox Proportional Hazard models (crude and adjusted for cardiovascular risk factors as arterial hypertension, diabetes mellitus, hyperlipoproteinemia, coronary heart disease, detection of atrial fibrillation and group randomization given as model 1 and model 2 with further adjustment for intravenous thrombolysis and endovascular thrombectomy in addition) were used to estimate hazard ratios (HR) for each vascular endpoint, the composite endpoint for all-cause death risk within two years after ischemic stroke or TIA. Cox Proportional Hazard assumption was checked. For the endpoint \\u0026lsquo;oral anticoagulation 24 months after index event\\u0026rsquo; a multiple binary logistic regression analysis (adjusted for AF and detection of left atrial and/or ventricular thrombus) was conducted and adjusted odds ratios, as well as respective confidence intervals (CI), (CI) are reported. Data preparation was done using the software IBM SPSS Statistics 24.\\u003c/p\\u003e \\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003eOf 3,431 patients included in MonDAFIS, LVEF was available in 2,562 (75%) patients (mean age 67 [57\\u0026ndash;76] years, 39.5% female, median NIHSS score on admission 2 points [\\u003cspan class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e\\u0026ndash;\\u003cspan class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]). Figure\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e shows the derivation of the study population. Patients without documented LVEF were older, more often had a TIA as index event and a stroke or TIA before the index event (Table\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e Online Supplement).\\u003c/p\\u003e\\n\\u003cp\\u003eOverall, 381/2,562 (14.9%) patients had a LVEF\\u0026thinsp;\\u0026lt;\\u0026thinsp;55% and 75/2,562 patients had a documented past medical history of HF (of which 29 had a LVEF\\u0026thinsp;\\u0026ge;\\u0026thinsp;55%). Therefore, a total of 410/2,562 (16.0%) patients fulfilled at least one of the pre-defined HF criteria (Fig.\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). Baseline characteristics and results of multiple binary logistic regression of patients with vs without HF are shown in Table\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cdiv class=\\\"gridtable\\\"\\u003e\\n\\u003ctable id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e\\u003ccaption\\u003e\\n\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e\\n\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\n\\u003cp\\u003eBaseline characteristics of MonDAFIS study patients with or without heart failure at baseline.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003c/caption\\u003e\\n\\u003cthead\\u003e\\n\\u003ctr\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\n\\u003cth colspan=\\\"2\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eUnivariate analysis\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\n\\u003cth colspan=\\\"2\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eMultivariate analysis\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eHeart failure\\u003c/p\\u003e\\n\\u003cp\\u003en\\u0026thinsp;=\\u0026thinsp;410\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eNo heart failure\\u003c/p\\u003e\\n\\u003cp\\u003en\\u0026thinsp;=\\u0026thinsp;2,151\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cem\\u003ep-value\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eOR (95% CI)*\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ep-value\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/thead\\u003e\\n\\u003ctbody\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAge, years\\u003c/strong\\u003e, median [IQR]\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e69 [60\\u0026ndash;77]\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e66 [56\\u0026ndash;76]\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1.01 (0.99\\u0026ndash;1.02)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.078\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAge categories, years\\u003c/strong\\u003e, n (%)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0.001\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u0026lt;65\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e149 (36.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e991 (46.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e65\\u0026ndash;74\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e121 (29.5)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e566 (26.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e75\\u0026ndash;84\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e116 (28.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e521 (24.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u0026gt;84\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e24 (5.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e73 (3.4)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFemale sex\\u003c/strong\\u003e, n (%)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e119 (29.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e866 (40.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.79 (0.61\\u0026ndash;1.03)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.081\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eBody weight\\u003c/strong\\u003e, kg, mean (SD) [IQR]\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e81 [70\\u0026ndash;95]\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e80 [70\\u0026ndash;90]\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0.009\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1.01 (1.00-1.02)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.052\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eIndex stroke\\u003c/strong\\u003e, n (%)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0.020\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eTIA\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e99 (24.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e640 (29.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eStroke\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e311 (75.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1,507 (70.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1.11 (0.86\\u0026ndash;1.44)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.422\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eNIHSS score on admission\\u003c/strong\\u003e, median [IQR]\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e3 [\\u003cspan class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e\\u0026ndash;\\u003cspan class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e]\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e2 [\\u003cspan class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e\\u0026ndash;\\u003cspan class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0.013\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1.05 (1.02\\u0026ndash;1.09)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.002\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eIn-hospital treatment\\u003c/strong\\u003e, n (%)\\u003c/p\\u003e\\n\\u003cp\\u003eIntravenous thrombolysis\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e91 (22.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e500 (23.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.644\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eEndovascular treatment\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e15 (3.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e56 (2.6)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0.233\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eHemicraniectomy\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1 (0.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1 (0.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0.190\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eCarotid surgery or stenting\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e9 (2.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e33 (1.5)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0.334\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCardiovascular risk factors\\u003c/strong\\u003e, n (%)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eDiabetes mellitus\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e150 (36.6)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e508 (23.6)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1.33 (1.04\\u0026ndash;1.70)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.026\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eHypertension\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e346 (84.4)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1,615 (75.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1.14 (0.83\\u0026ndash;1.57)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.408\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eHypercholesterolemia\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e237 (57.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1,125 (52.4)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0.043\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1.06 (0.84\\u0026ndash;1.33)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.634\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eCoronary heart disease\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e116 (28.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e191 (8.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e3.12 (2.36\\u0026ndash;4.13)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ePeripheral arterial disease\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e34 (8.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e60 (2.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e2.04 (1.28\\u0026ndash;3.25)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.003\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ePrior ischemic stroke or TIA\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e68 (16.6)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e326 (15.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0.469\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eSmoker\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e211 (51.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1,017 (47.6)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0.129\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eRandomization to the intervention group\\u003c/strong\\u003e, n (%)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e200 (48.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1,072 (49.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0.695\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e-\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/tbody\\u003e\\n\\u003ctfoot\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd colspan=\\\"6\\\"\\u003e**OR and 95% CI for continues variables were expressed per point (BMI, NIHSS) or per each year of age.\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/tfoot\\u003e\\n\\u003c/table\\u003e\\n\\u003c/div\\u003e\\n\\u003cp\\u003ePatients with HF more often had diabetes mellitus [OR 1.33; 95%CI 1.04\\u0026ndash;1.70; \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.026], coronary artery disease [OR 3.12; 95%CI 2.36\\u0026ndash;4.13; \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001], and peripheral arterial disease [OR 2.03; 95%CI 1.27\\u0026ndash;3.24; \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.003] than non-HF patients. Moreover, patients with HF had a higher stroke severity on admission than patients without HF [assessed by the NIHSS score; OR per point 1.05; 95%CI 1.02\\u0026ndash;1.09; \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.002).\\u003c/p\\u003e\\n\\u003cdiv id=\\\"Sec8\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003eAssociation of heart failure with clinical outcomes\\u003c/h2\\u003e\\n\\u003cp\\u003eWithin two years after index stroke or TIA, the predefined composite endpoint occurred in 480/2,561 (14.0%) of patients, including recurrent stroke in 301 (8.8%) patients, myocardial infarction in 43 (1.3%) patients, major bleeding in 32 (0.9%) patients and all-cause death in 175 (5.1%) patients. Recurrent ischemic stroke or TIA occurred in 283/2,561 (8.3%) patients, while 18/2,561 (0.7%) patients had a hemorrhagic stroke within two years.\\u003c/p\\u003e\\n\\u003cp\\u003eAfter adjusting for cardiovascular risk factors, stroke severity and randomization (model 1), HF was associated with myocardial infarction [HR 2.21; 95% CI 1.02\\u0026ndash;4.79; \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.046], and all-cause death [HR 1.67; 95%CI 1.12\\u0026ndash;2.49, \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.013] within 2 years after the index event. On the contrary, neither the composite endpoint [HR 1.28; 95%CI 0.99\\u0026ndash;1.66] nor recurrent ischemic stroke or TIA [HR 1.07; 95%CI: 0.74\\u0026ndash;1.55] nor major bleeding [HR 1.93; 95%CI 0.73\\u0026ndash;5.06] (Fig.\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e and Table\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e) was significantly increased in stroke patients with HF. Additional adjustment for intravenous thrombolysis and endovascular thrombectomy (model 2) yielded similar results (Table\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). Also, excluding patients with a documented medical history of HF but normal LVEF (\\u0026ge;\\u0026thinsp;55%) at baseline yielded similar results (Table\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e Online Supplement).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cdiv class=\\\"gridtable\\\"\\u003e\\n\\u003ctable id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e\\u003ccaption\\u003e\\n\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e\\n\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\n\\u003cp\\u003eAdjusted survival analyses, Cox regression, hazard ratios for the composite endpoint (recurrent stroke, myocardial infarction, major bleeding, all-cause death) and its components as well as recurrent ischemic stroke/TIA within 24 months after the index stroke/TIA for patients with heart failure (n\\u0026thinsp;=\\u0026thinsp;410) compared to those without heart failure at baseline.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003c/caption\\u003e\\n\\u003ctbody\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"236\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"123\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCrude\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"142\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAdjusted, Model 1\\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"57\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd colspan=\\\"2\\\" width=\\\"208\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAdjusted, Model 2\\u003csup\\u003ea\\u003c/sup\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"236\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"123\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eHR (95%CI)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eP\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"142\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eHR (95%CI)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"57\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eP\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"132\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eHR (95%CI)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e\\u003cem\\u003eP\\u003c/em\\u003e\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"236\\\"\\u003e\\n\\u003cp\\u003eComposite endpoint\\u003csup\\u003eb\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"123\\\"\\u003e\\n\\u003cp\\u003e1.54 (1.20-1.98)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e0.001\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"142\\\"\\u003e\\n\\u003cp\\u003e1.28 (0.99-1.66)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"57\\\"\\u003e\\n\\u003cp\\u003e0.065\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"132\\\"\\u003e\\n\\u003cp\\u003e1.29 (0.99-1.67)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e0.060\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"236\\\"\\u003e\\n\\u003cp\\u003eAll-cause death\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"123\\\"\\u003e\\n\\u003cp\\u003e2.15 (1.46-3.16)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e\\u0026lt;0.001\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"142\\\"\\u003e\\n\\u003cp\\u003e1.67 (1.12-2.49)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"57\\\"\\u003e\\n\\u003cp\\u003e0.013\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"132\\\"\\u003e\\n\\u003cp\\u003e1.65 (1.10-2.47)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e0.015\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"236\\\"\\u003e\\n\\u003cp\\u003eRecurrent stroke\\u003csup\\u003ec\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"123\\\"\\u003e\\n\\u003cp\\u003e1.21 (0.86-1.69)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e0.274\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"142\\\"\\u003e\\n\\u003cp\\u003e1.08 (0.76-1.54)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"57\\\"\\u003e\\n\\u003cp\\u003e0.668\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"132\\\"\\u003e\\n\\u003cp\\u003e1.09 (0.77-1.56)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e0.620\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"236\\\"\\u003e\\n\\u003cp\\u003eRecurrent ischemic stroke or TIA\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"123\\\"\\u003e\\n\\u003cp\\u003e1.16 (0.81-1.65)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e0.425\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"142\\\"\\u003e\\n\\u003cp\\u003e1.07 (0.74-1.55)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"57\\\"\\u003e\\n\\u003cp\\u003e0.737\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"132\\\"\\u003e\\n\\u003cp\\u003e1.08 (0.75-1.57)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e0.680\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"236\\\"\\u003e\\n\\u003cp\\u003eRecurrent ischemic stroke\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"123\\\"\\u003e\\n\\u003cp\\u003e1.24 (0.83-1.85)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e0.299\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"142\\\"\\u003e\\n\\u003cp\\u003e1.08 (0.71-1.66)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"57\\\"\\u003e\\n\\u003cp\\u003e0.719\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"132\\\"\\u003e\\n\\u003cp\\u003e1.09 (0.71-1.67)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e0.683\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"236\\\"\\u003e\\n\\u003cp\\u003eRecurrent TIA\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"123\\\"\\u003e\\n\\u003cp\\u003e0.91 (0.43-1.93)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e0.806\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"142\\\"\\u003e\\n\\u003cp\\u003e0.98 (0.46-2.11)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"57\\\"\\u003e\\n\\u003cp\\u003e0.955\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"132\\\"\\u003e\\n\\u003cp\\u003e0.99 (0.46-2.14)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e0.986\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"236\\\"\\u003e\\n\\u003cp\\u003eMyocardial infarction\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"123\\\"\\u003e\\n\\u003cp\\u003e3.96 (1.94-8.08)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e\\u0026lt;0.001\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"142\\\"\\u003e\\n\\u003cp\\u003e2.21 (1.02-4.79)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"57\\\"\\u003e\\n\\u003cp\\u003e0.046\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"132\\\"\\u003e\\n\\u003cp\\u003e2. 18 (1.01-4.76)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e0.050\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd width=\\\"236\\\"\\u003e\\n\\u003cp\\u003eMajor bleed\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"123\\\"\\u003e\\n\\u003cp\\u003e1.93 (0.76-4.89)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e0.168\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"142\\\"\\u003e\\n\\u003cp\\u003e1.93 (0.73-5.06)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"57\\\"\\u003e\\n\\u003cp\\u003e0.184\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"132\\\"\\u003e\\n\\u003cp\\u003e1.89 (0.72-4.99)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd width=\\\"76\\\"\\u003e\\n\\u003cp\\u003e0.196\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003ea) Adjusted Model 1: for age, stroke severity (NIHSS score on admission), diabetes mellitus, arterial hypertension, hyperlipoproteinemia, coronary heart disease, detection of atrial fibrillation in-hospital, randomization; Adjusted Model 2: all variables of Adjusted Model 1 and additionally intravenous thrombolysis and endovascular thrombectomy b) Recurrent stroke, MI, major bleed, all cause death c) Ischemic Stroke, Transient Ischemic Attack, Intracerebral Hemorrhage, Subarachnoid Hemorrhage\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec9\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003eSecondary stroke prevention in patients with heart failure\\u003c/h2\\u003e\\n\\u003cp\\u003eInformation on oral anticoagulation at 24 months was available in 2,072/2,561 (80.9%) patients and, similarly, on antiplatelet treatment in 2,075/2,561 (81.0%) patients. Overall, 312/2,072 (15.1%) patients were on anticoagulation and 1,645/2,075 (79.4%) patients on antiplatelets at 24 months. In patients with HF at baseline, information on oral anticoagulation at 24 months was available in 304/410 (74.2%) patients. There was a statistically significant difference in the rate oral anticoagulation in HF patients vs. non-HF patients (63/304 [20.7%] vs. 249/1768 [14.1%], respectively, p\\u0026thinsp;=\\u0026thinsp;0.004). AF was diagnosed in 46/63 (73.0%) of those with oral anticoagulants and HF. The rate of oral anticoagulation was 15.7% in HF patients vs 11.8% in non-HF patients at 6 months after the index stroke/TIA (p\\u0026thinsp;=\\u0026thinsp;0.046) and 16.6% vs 12.9% after 12 months (p\\u0026thinsp;=\\u0026thinsp;0.072) (Table\\u0026nbsp;3 online supplement).\\u003c/p\\u003e\\n\\u003cp\\u003eAfter multivariate adjustment (including newly detected AF within 24 months and left ventricular or left atrial thrombus at baseline), there was no significant association between HF status at baseline and oral anticoagulation after 24 months [OR 0.89; 95%CI 0.51\\u0026ndash;1.56; \\u003cem\\u003eP\\u003c/em\\u003e\\u0026thinsp;=\\u0026thinsp;0.689].\\u003c/p\\u003e\\n\\u003c/div\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eThe prospective multicenter MonDAFIS study shows that ischemic stroke or TIA patients with comorbid HF had a significantly higher rate of myocardial infarction and all-cause mortality within 24 months than non-HF patients. One strength of our post hoc analysis is the large number of clinical endpoints assessed by an independent endpoint committee and standardized follow-up for 24 months. Our data confirm that stroke/TIA patients with comorbid HF are not only more likely to have cardiovascular risk factors (such as diabetes, coronary heart disease, peripheral arterial disease) but also to have more severe strokes than stroke patients without HF. [\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e] Our finding of a statistically higher rate of myocardial infarction over 24 months after stroke/TIA in the presence of HF is consistent with the results of a large multicenter registry in the UK based on NHS primary care data of 9,840 patients. [\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e] The detected higher mortality rate in ischemic stroke patients with comorbid HF is also in line with previous studies. [\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e] Of note, the rate of recurrent stroke as well as recurrent ischemic stroke or TIA was not associated with HF in our study, which was also found in a retrospective analysis of a large registry but is not consistent with a meta-analysis of prospective studies.[\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e] The follow up period of 2 years was may be too short to observe any potential association between HF and ischemic stroke \\u0026ndash; the authors of the WARCEF trial reported a higher rate of ischemic strokes during a follow up period that was approximately 1.5 years longer. One study reported a significant association of recurrent intracerebral hemorrhage in patients with HF compared to non-HF patients. [\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e] In MonDAFIS, the HF status at baseline was not associated with the rate of major bleeding after stroke, even though 21% of HF patients received oral anticoagulation at 24 months. In fact, OAC status was not statistically different between HF vs. non-HF patients after adjusting for AF and presence of cardiac thrombi.\\u003c/p\\u003e \\u003cp\\u003eThere are some limitations that should be mentioned. First, the MonDAFIS study was not designed to investigate the impact of HF on recurrent vascular events or death. Second, as echocardiography was conducted according to routine clinical practice respective data were available for only 75% of the total study population. Third, we had no systematic information on biomarkers, like natriuretic peptides. Fourth, we had no further information on HF status after hospital discharge after the index-stroke/TIA. Fifth, our results cannot be applied to all stroke patients, as patients had to provide informed consent to participate in the MonDAFIS study. Finally, we have no detailed information on cause of death, as autopsy was performed in a minority of study patients only.\\u003c/p\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cp\\u003ePatients with acute ischemic stroke or TIA with comorbid HF have a higher prevalence of cardiovascular risk factors, suffered more severe (index) strokes and have a higher risk for myocardial infarctions or all-cause death within 24 months after the index stroke. Special attention should be paid to the prevention of myocardial infarction in this patient population and cardiac follow-up should be recommended in stroke patients with HF.\\u003c/p\\u003e \"},{\"header\":\"Declarations\",\"content\":\"\\u003ch2\\u003eAcknowledgment\\u003c/h2\\u003e \\u003cp\\u003eNone.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eSource of funding \\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe MonDAFIS study was an investigator-initiated, prospective, randomized, multicenter study sponsored by the Charit\\u0026eacute; - Universit\\u0026auml;tsmedizin Berlin, Germany and supported by an unrestricted research grant from Bayer Vital GmbH, Leverkusen, Germany to the Charit\\u0026eacute; \\u0026ndash; Universit\\u0026auml;tsmedizin Berlin, Germany.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eStatement and Declarations\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003ePK is listed as inventor on two patents held by the University of Birmingham, Birmingham, UK (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). PK receives research support for basic, translational, and clinical research projects from the EU, British Heart Foundation, Leducq Foundation, the UK Medical Research Council, and German Centre for Cardiovascular Research, from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies in the past. GT has received speakers\\u0026apos; honoraria or consulting fees from Amarin, Daichi Sanyo, Acandis, Bayer Healthcare, Boehringer Ingelheim, Covidien, Bristol-Myers Squibb, Portola, Stryker, and Pfizer. DGN has received speakers\\u0026apos; honoraria and consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Novartis, and Pfizer. JR has received speakers\\u0026apos; honoraria and consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and AstraZeneca. UL reports honoraria and reimbursements for lectures, participation in studies, scientific cooperations (with Saarland University, Saarland, Germany), consulting, travel, support (of colleagues), or support of scientific meetings by Amgen, Bayer, Boehringer Ingelheim, Daiichi Sankyo, MSD, Sanofi, and Servier, outside the submitted work. RV reports grants, personal fees, and being a shareholder from Bayer; grants from Boehringer; grants and personal fees from Bristol-Myers Squibb and Pfizer; grants from Daiichi Sankyo, Medtronic, and Biogen; personal fees from Javelin, Abbott, and AstraZeneca; and holding shares in Novartis, outside the submitted work. RV is an investigator of Imperial National Institutes of Health Research Biomedical Research Centre and partially funded by the EU\\u0026apos;s Horizon 2020 research and innovation programme (grant agreement 754517 [PRESTIGE-AF]). PUH reports grants from Charit\\u0026eacute;, Universit\\u0026auml;tsmedizin Berlin during study conduct (within MonDAFIS for biometry; member of the scientific board); research grants from the German Ministry of Research and Education, German Research Foundation, the Bavarian State (ministry for science and the arts; within STAAB COVID-19), the EU, Berlin Chamber of Physicians, German Parkinson Society, University Hospital W\\u0026uuml;rzburg, Robert Koch Institute, German Heart Foundation, Federal Joint Committee within the Innovationfond, University Hospital Heidelberg (within RASUNOA-prime; supported by an unrestricted research grant to the University Hospital Heidelberg from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, and Daiichi Sankyo), and University G\\u0026ouml;ttingen (within FIND-AF(randomised); supported by an unrestricted research grant to the University G\\u0026ouml;ttingen from Boehringer Ingelheim), outside the submitted work. KGH reports speakers\\u0026apos; honoraria, consulting fees or lecture honoraria from Abbott, Alexion, AMARIN, AstraZeneca, Bayer Healthcare, Sanofi, Boehringer Ingelheim, Daiichi Sankyo, Pfizer, Bristol-Myers Squibb, Biotronik, Medtronic, Portola, Premier Research, SUN Pharma, WL Gore and Associates, and Edwards Lifesciences, as well as study support by Bayer and Getemed. ME reports grants from Bayer and fees paid to the Charit\\u0026eacute; from AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Covidien, Daiichi Sankyo, GlaxoSmithKline, Novartis, Pfizer, and Sanofi. All other authors declare no competing interests outside the submitted work. \\u0026nbsp;\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eDoehner W, Ural D, Haeusler KG et al (2018) Heart and brain interaction in patients with heart failure: overview and proposal for a taxonomy. A position paper from the Study Group on Heart and Brain Interaction of the Heart Failure Association. Eur J Heart Fail 20(2):199\\u0026ndash;215\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBarkhudaryan A, Doehner W, Scherbakov N (2021) Ischemic Stroke and Heart Failure: Facts and Numbers. An Update. J Clin Med ;10(5)\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHaeusler KG, Laufs U, Endres M (2011) Chronic heart failure and ischemic stroke. Stroke 42(10):2977\\u0026ndash;2982\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eTai YH, Chang CC, Yeh CC et al (2020) Long-Term Risk of Stroke and Poststroke Outcomes in Patients with Heart Failure: Two Nationwide Studies. Clin Epidemiol 12:1235\\u0026ndash;1244\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSennfalt S, Pihlsgard M, Petersson J, Norrving B, Ullberg T (2020) Long-term outcome after ischemic stroke in relation to comorbidity - An observational study from the Swedish Stroke Register (Riksstroke). Eur Stroke J 5(1):36\\u0026ndash;46\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eScherbakov N, Haeusler KG, Doehner W (2015) Ischemic stroke and heart failure: facts and numbers. ESC Heart Fail 2(1):1\\u0026ndash;4\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKatsanos AH, Parissis J, Frogoudaki A et al (2016) Heart failure and the risk of ischemic stroke recurrence: A systematic review and meta-analysis. J Neurol Sci 362:182\\u0026ndash;187\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePana TA, Wood AD, Perdomo-Lampignano JA et al (2019) Impact of heart failure on stroke mortality and recurrence. Heart Asia 11(1):e011139\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAlqahtani F, Aljohani S, Tarabishy A, Busu T, Adcock A, Alkhouli M (2017) Incidence and Outcomes of Myocardial Infarction in Patients Admitted With Acute Ischemic Stroke. Stroke 48(11):2931\\u0026ndash;2938\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eScheitz JF, Nolte CH, Doehner W, Hachinski V, Endres M (2018) Stroke-heart syndrome: clinical presentation and underlying mechanisms. Lancet Neurol 17(12):1109\\u0026ndash;1120\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePana TA, Wood AD, Mamas MA et al (2019) Myocardial infarction after acute ischaemic stroke: Incidence, mortality and risk factors. Acta Neurol Scand 140(3):219\\u0026ndash;228\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHaeusler KG, Kirchhof P, Heuschmann PU et al (2016) Impact of standardized MONitoring for Detection of Atrial Fibrillation in Ischemic Stroke (MonDAFIS): Rationale and design of a prospective randomized multicenter study. Am Heart J 172:19\\u0026ndash;25\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHaeusler KG, Kirchhof P, Kunze C et al (2021) Systematic monitoring for detection of atrial fibrillation in patients with acute ischaemic stroke (MonDAFIS): a randomised, open-label, multicentre study. Lancet Neurol 20(6):426\\u0026ndash;436\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHatano S (1976) Experience from a multicentre stroke register: a preliminary report. Bull World Health Organ 54(5):541\\u0026ndash;553\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"internal-and-emergency-medicine\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"iaem\",\"sideBox\":\"Learn more about [Internal and Emergency Medicine](http://link.springer.com/journal/11739)\",\"snPcode\":\"11739\",\"submissionUrl\":\"https://www.editorialmanager.com/iaem/default.aspx\",\"title\":\"Internal and Emergency Medicine\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false},\"keywords\":\"Ischemic Stroke, Heart Failure, Vascular Outcome, Mortality\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-3303557/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-3303557/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e \\u003cp\\u003eHeart failure (HF) is associated with poor outcome after stroke, but data from large prospective trials are sparse.\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e \\u003cp\\u003eWe assessed the impact of HF on clinical endpoints in patients hospitalized with acute ischemic stroke or transient ischemic attack (TIA) enrolled in the prospective, multicenter \\u003cem\\u003eSystematic Monitoring for Detection of Atrial Fibrillation in Patients with Acute Ischemic Stroke\\u003c/em\\u003e (MonDAFIS) trial. HF was defined as left ventricular ejection fraction (LVEF)\\u0026thinsp;\\u0026lt;\\u0026thinsp;55% or a history of HF on admission. The composite of recurrent stroke, major bleeding, myocardial infarction, and all-cause death, and its components during the subsequent 24 months were assessed. We used estimated hazard ratios in confounder-adjusted models.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e \\u003cp\\u003eOverall, 410/2,562 (16.0%) stroke patients fulfilled the HF criteria (i.e. 381 [14.9%] with LVEF\\u0026thinsp;\\u0026gt;\\u0026thinsp;55% and 29 [1.9%] based on medical history). Patients with HF had more often diabetes, coronary and peripheral arterial disease and presented with more severe strokes on admission. HF at baseline correlated with myocardial infarction (HR 2.21; 95%CI 1.02\\u0026ndash;4.79), and all-cause death (HR 1.67; 95%CI 1.12\\u0026ndash;2.50), but not with major bleed (HR 1.93; 95%CI 0.73\\u0026ndash;5.06) or recurrent stroke/TIA (HR 1.08; 95%CI 0.75\\u0026ndash;1.57). The data were adjusted for age, stroke severity, cardiovascular risk factors, and randomization.\\u003c/p\\u003e\\u003ch2\\u003eConclusions\\u003c/h2\\u003e \\u003cp\\u003ePatients with ischemic stroke or TIA and comorbid HF have a higher risk of myocardial infarction and death compared with non-HF patients whereas the risk of recurrent stroke or major hemorrhage was similar.\\u003c/p\\u003e\\u003ch2\\u003eTrial registration number\\u003c/h2\\u003e \\u003cp\\u003eClinicaltrials.gov NCT02204267\\u003c/p\\u003e\",\"manuscriptTitle\":\"Heart Failure, Recurrent Vascular Events and Death in Patients with Ischemic Stroke - Results of the MonDAFIS study\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2023-10-06 20:57:38\",\"doi\":\"10.21203/rs.3.rs-3303557/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"reviewerAgreed\",\"content\":\"\",\"date\":\"2023-10-04T06:19:32+00:00\",\"index\":0,\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2023-10-01T21:51:51+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2023-08-29T10:43:01+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Internal and Emergency Medicine\",\"date\":\"2023-08-28T09:41:15+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"internal-and-emergency-medicine\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"iaem\",\"sideBox\":\"Learn more about [Internal and Emergency Medicine](http://link.springer.com/journal/11739)\",\"snPcode\":\"11739\",\"submissionUrl\":\"https://www.editorialmanager.com/iaem/default.aspx\",\"title\":\"Internal and Emergency Medicine\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false}}],\"origin\":\"\",\"ownerIdentity\":\"483600eb-d2e0-4e6b-a95c-bf8b64b22a77\",\"owner\":[],\"postedDate\":\"October 6th, 2023\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"under-review\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2024-03-20T17:38:44+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2023-10-06 20:57:38\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-3303557\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-3303557\",\"identity\":\"rs-3303557\",\"version\":[\"v1\"]},\"buildId\":\"WrCJVZZCHTDjtuVLN7oU0\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}