Publications by authors named "Wilfried Lang"

86 Publications

EXPRESS: Longer term patient management following stroke A systematic review.

Int J Stroke 2021 May 5:17474930211016963. Epub 2021 May 5.

Medical University of Innsbruck, Neurology, Innsbruck, Tirol, Austria.

Tremendous progress in acute stroke therapy has improved short-term outcome but part of this achievement may be lost in the long run. Concepts for a better long-term management of stroke survivors are needed to address their unmet needs and to reduce the burden of post-stroke complications, residual deficits and recurrent vascular events. This review summarizes current knowledge on post-hospital care and the scientific evidence supporting individual programs. A systematic search of electronic databases according to PRISMA guidelines identified 10,374 articles, 77 of which met the inclusion criteria. One large randomised controlled trial on a multifaceted care program delivered by the multidisciplinary stroke team reduced recurrent vascular events and improved quality of life and functional outcome one year after the event while a number of studies offer solutions for individual components of post-hospital disease management like patient education, counselling, and self-management or the management of post-stroke complications and residual deficits. A majority of studies, however, was small in size and limited by a short follow-up. Most initiatives with a narrow focus on risk factor control failed to lower the risk of recurrent events. The caregiversâ central role in post-stroke patient management is broadly neglected in research. Over the past years, first knowledge on how to best organize post-hospital care of stroke patients has emerged. Comprehensive and pragmatic programs operated by the multidisciplinary stroke team hold promise to reduce the long-term health burden of stroke. There is a clear need for further high-quality studies with both clinical endpoints and patient-reported outcomes to establish sustainable solutions in different settings and regions to improve life after stroke, a key priority of the Stroke Action Plan for Europe 2018-2030.
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http://dx.doi.org/10.1177/17474930211016963DOI Listing
May 2021

Intravenous thrombolysis in stroke with admission NIHSS score 0 or 1.

Int J Stroke 2021 Feb 10:1747493021991969. Epub 2021 Feb 10.

Medical Faculty, Sigmund Freud University Vienna, Austria.

Background: Up to 30% of stroke patients initially presenting with non-disabling or mild deficits may experience poor functional outcome. Despite, intravenous thrombolysis remains controversial in this subgroup of stroke patients due to its uncertain risk benefit ratio.

Aim: We aimed to analyze the real-world experience with intravenous thrombolysis in stroke patients presenting with very low NIHSS.

Methods: Data of stroke patients presenting with mild initial stroke severity (NIHSS 0-5) including vascular risk factors, stroke syndrome and etiology, early neurological deterioration, symptomatic intracerebral haemorrhage (sICH), and functional outcome by modified Rankin Scale were extracted from a large nationwide stroke registry and analysed. Patients were categorized and compared according to admission severity NIHSS 0-1 versus NIHSS 2-5 and intravenous thrombolysis use.

Results: Seven hundred and three (2%) of 35,113 patients presenting with NIHSS 0-1 and 6316 (13.9%) of 45,521 of patients presenting with NIHSS 2-5 underwent intravenous thrombolysis. In the NIHSS 0-1 group, intravenous thrombolysis was associated with early neurological deterioration (adjusted OR 8.84, CI 6.61-11.83), sICH (adjusted OR 9.32, CI 4.53-19.15) and lower rate of excellent outcome (mRS 0-1) at three months (adjusted OR 0.67, CI 0.5-0.9). In stroke patients with NIHSS 2-5, intravenous thrombolysis was associated with early neurological deterioration (adjusted OR 1.7, 1.47-1.98), sICH (adjusted OR 5.75, CI 4.45-7.45), and higher rate of excellent outcome (mRS 0-1) at three months (adjusted OR 1.21, CI 1.08-1.34).

Conclusions: Among patients with NIHSS 0-1, intravenous thrombolysis did not increase the likelihood of excellent outcome. Moreover, potential signals of harm were observed. Further research seems to be warranted.
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http://dx.doi.org/10.1177/1747493021991969DOI Listing
February 2021

Design and Derivation of the Austrian Prehospital Stroke Scale (APSS) to Predict Severe Stroke with Large Vessel Occlusion.

Prehosp Emerg Care 2021 Jan 12:1-9. Epub 2021 Jan 12.

Prediction of large vessel occlusion (LVO) is highly relevant for accurate prehospital transportation triage. The Austrian Prehospital Stroke Scale (APSS) score for LVO prediction was developed using critical synthesis of previously published LVO-scores. The aim of this study was to investigate the accuracy of the APSS and compare it to other LVO-scores. APSS consists of 5 items: "facial palsy," "motor arm," "language," "motor leg" and "gaze deviation." The score ranges from 0 to 9 points. Data from 741 consecutive stroke patients with acute vessel imaging admitted to an independent comprehensive stroke center was used to test the predictive performance of the APSS in context of other LVO-scores (CPSS, FAST-ED, G-FAST, sNIHSS-EMS and RACE). In the prediction of treatable LVO the APSS showed the highest area under the curve (0.834) with significant difference to CPSS (p = 0.010) and G-FAST (p = 0.006) and showed highest sensitivity (69%) as compared to other LVO scores. Specificity (85%), positive predictive value (75%), negative predictive value (81%) and accuracy (79%) were comparable to other LVO scores. Receiver operating curve analysis revealed an optimal cutoff for LVO prediction at APSS equal to 4 points. The easy assessable 5-item APSS score tended to outperform other LVO scores. Real-life prospective evaluation in prehospital setting is ongoing.
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http://dx.doi.org/10.1080/10903127.2020.1851329DOI Listing
January 2021

STROKE-CARD care to prevent cardiovascular events and improve quality of life after acute ischaemic stroke or TIA: A randomised clinical trial.

EClinicalMedicine 2020 Aug 28;25:100476. Epub 2020 Jul 28.

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

Background: Patients with ischaemic stroke or transient ischaemic attack (TIA) are at high risk of recurrent stroke and other cardiovascular diseases and commonly suffer from reduced quality of life. We aimed to determine whether the disease management programme STROKE-CARD can prevent cardiovascular diseases and improve quality of life in these patients.

Methods: In this pragmatic open-label two-centre randomised controlled trial with blinded outcome assessment, we randomly assigned patients with acute ischaemic stroke or TIA (ABCD score ≥3) in a 2:1 ratio to receive STROKE-CARD care or standard care. STROKE-CARD care is a disease management programme by a multidisciplinary stroke team that comprises a standardised 3-month visit and access to a web-based patient portal targeting risk factor management, post-stroke complications, comorbidities and cardiovascular warning signs, rehabilitation demands, and patient education, counselling, and self-empowerment. Co-primary outcomes were analysed on an intention-to-treat basis and were: (i) major cardiovascular disease events defined as nonfatal ischaemic or haemorrhagic stroke, nonfatal myocardial infarction, or vascular death occurring between hospital discharge and 12 months; and (ii) health-related quality of life at 12 months quantified with the EuroQol-5-Dimensions-3-Levels (EQ-5D-3L) overall utility score. This trial is registered with ClinicalTrials.gov, number NCT02156778.

Findings: Of 2149 patients enrolled between January 2014 and December 2017 (mean age 69 years, 41% female, 83% with ischaemic stroke, 17% with TIA), 1438 were assigned to STROKE-CARD care and 711 to standard care. Major cardiovascular disease events occurred in 78 patients in the STROKE-CARD care group (5.4%) and in 59 patients in the standard care group (8.3%) (hazard ratio, 0.63; 95% confidence interval: 0.45-0.88; P=0.007). STROKE-CARD care also led to a better EQ-5D-3L overall utility score at 12 months (P<0.001). Among pre-specified secondary outcomes, STROKE-CARD care improved all individual EQ-5D-3L dimensions and functional outcome on the modified Rankin Scale at 12 months. Post hoc explanatory analyses identified considerable demands for additional rehabilitation and refinement of preventive therapy regimes at the 3-month visit and high proportions of post-stroke complications and warning signs of imminent cardiovascular diseases within the first three months.

Interpretation: The pragmatic and easily implementable STROKE-CARD care programme reduced cardiovascular risk and improved health-related quality of life and functional outcome in patients with acute ischaemic stroke or TIA.

Funding: Tirol Kliniken, Tyrolean Health Insurance Company, Tyrol Health Care Funds, Boehringer Ingelheim, Nstim Services, Sanofi, Bayer Healthcare.
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http://dx.doi.org/10.1016/j.eclinm.2020.100476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486330PMC
August 2020

Heart rate entropy is associated with mortality after intracereberal hemorrhage.

J Neurol Sci 2020 Nov 12;418:117033. Epub 2020 Jul 12.

Division of Neurosurgery, Department of Clinical Neurosciences, Cambridge University, Cambridge, United Kingdom.

Background: Autonomic nervous system changes have been associated with outcome after intracerebral hemorrhage (ICH) previously. We aimed to investigate the association of heart rate entropy (HRE) with mortality after ICH.

Methods: Sample HRE, heart rate variability and baroreflex sensitivity were examined in consecutive ICH patients. Hematoma volume, intraventricular hemorrhage, infratentorial origin, consciousness impairment and age were combined into standard ICH score.

Results: In 47 patients suffering ICH (mean age 61 years, median hemorrhage volume 38 mL) the areas under the curve (AUC) for mortality were 0.86, 0.83, 0.76, 0.74, 0.72 and 0.7 for HRE, ICH-score, normalized low frequency powers, low frequency/high frequency powers ratio, normalized high frequency powers and BRS, respectively. HRE and ICH score were associated with mortality independently (adjusted odd ratio (aOR) 0.09, 95% confidence interval (CI) 0.1-0.8, p = .03 and aOR 2.6, CI 1.03-6.6, p = .04). Combining ICH score with HRE into a novel score resulted in an AUC of 0.94, CI 0.88-0.99, p < .001.

Conclusion: Compared to several autonomic markers HRE seems to bear the largest amount of information on death probability after ICH. Moreover, HRE may predict mortality comparable to ICH score. Combining HRE with ICH score may increase the predictive performance for mortality after ICH.
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http://dx.doi.org/10.1016/j.jns.2020.117033DOI Listing
November 2020

Intracranial and systemic atherosclerosis in the NAVIGATE ESUS trial: Recurrent stroke risk and response to antithrombotic therapy.

J Stroke Cerebrovasc Dis 2020 Aug 8;29(8):104936. Epub 2020 Jun 8.

Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada.

Background: Non-stenotic intracranial and systemic atherosclerosis are associated with ischemic stroke. We report frequency and response to anticoagulant vs. antiplatelet prophylaxis of patients with embolic stroke of undetermined source (ESUS) who have non-stenotic intracranial atherosclerosis and/or systemic atherosclerosis.

Methods: Exploratory analysis of the international NAVIGATE ESUS randomized trial comparing rivaroxaban 15mg daily with aspirin 100mg daily in 7213 patients with recent ESUS. Among participants with results of intracranial arterial imaging with either computed tomographic angiography (CTA) or magnetic resonance angiography (MRA), the frequency and predictors of non-stenotic intracranial and systemic atherosclerosis and responses to antithrombotic therapy were assessed.

Results: Among 4723 participants with available intracranial CTA or MRA results (65% of the trial cohort), the prevalence of intracranial atherosclerosis was 16% (n=739). Patient features independently associated with intracranial atherosclerosis included East Asian region (odds ratio 2.7, 95%CI 2.2,3.3) and cervical carotid plaque (odds ratio 2.3, 95%CI 1.9,2.7), among others. The rate of recurrent ischemic stroke averaged 4.8%/year among those with intracranial atherosclerosis vs. 5.0.%/year for those without (HR 0.95, 95%CI 0.65, 1.4). Among those with intracranial atherosclerosis, the recurrent ischemic stroke rate was higher if assigned to rivaroxaban (5.8%/year) vs. aspirin (3.7%/year), but the difference was not statistically significant (HR 1.6, 95%CI 0.78, 3.3). There was trend for the effect of antithrombotic treatments to be different according to the presence or absence of intracranial atherosclerosis (p=0.09). Among participants with evidence of systemic atherosclerosis by either history or imaging (n=3820), recurrent ischemic stroke rates were similar among those assigned to rivaroxaban (5.5%/year) vs. aspirin (4.9%/year)(HR 1.1, 95%CI 0.84, 1.5).

Conclusions: East Asia region was the strongest factor associated with intracranial atherosclerosis. There were no statistically significant differences between rivaroxaban and aspirin prophylaxis for recurrent ischemic stroke in patients with non-stenotic intracranial atherosclerosis and/or systemic atherosclerosis.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.104936DOI Listing
August 2020

Trends of r-tPA (Recombinant Tissue-Type Plasminogen Activator) Treatment and Treatment-Influencing Factors in Acute Ischemic Stroke.

Stroke 2020 04 2;51(4):1240-1247. Epub 2020 Mar 2.

From the Department of Neurology, Medical University of Vienna, Austria (M.M., S. Szabo, S. Scharer, W.S., S.G.).

Background and Purpose- Frequencies of treatment with r-tPA (recombinant tissue-type plasminogen activator) are increasing over the past 15 years. However, published data on the influence of various demographic and clinical factors on r-tPA treatment as well as estimates of future trajectories are limited. We evaluated time trends and future trajectories of r-tPA treatment in patients with acute stroke and the influence of various factors on r-tPA treatment by analyzing data of 103 970 patients enrolled in the Austrian Stroke Unit Registry from 2006 to 2018, of which 18 953 were treated with r-tPA. Methods- Time trends of r-tPA-treatment were investigated in predefined subgroups (minor/major stroke, age, anterior/posterior circulation stroke); limited exponential time series models were calculated to estimate future trends of r-tPA-treatment. Logistic regression models were calculated to estimate the influence of clinical variables on r-tPA-treatment. Results- Overall, r-tPA treatment frequencies increased from 9.9% in 2006 to 21.8% in 2018. We observed a particular increase in patients >80 years, patients presenting with a National Institutes of Health Stroke Scale Score of 2 to 3, patients with posterior circulation stroke, patients with wake-up stroke, and patients without atrial fibrillation. Forecast of overall r-tPA frequencies predicted a further but flattened increase up to 24% by 2025. Logistic regression of time-dependent associations of clinical variables with r-tPA-treatment revealed increasing odds of r-tPA-treatment in patients with a posterior circulation stroke and decreasing odds of r-tPA-treatment in patients with atrial fibrillation. Conclusions- We observed a positive development of r-tPA-treatment frequencies mirroring increasing confidence with intravenous thrombolysis in clinical practice; however, decreasing odds of r-tPA-treatment over time in patients with atrial fibrillation deserve particular attention.
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http://dx.doi.org/10.1161/STROKEAHA.119.027921DOI Listing
April 2020

Thrombolysis in Stroke With Unknown Onset Based on Non-Contrast Computerized Tomography (TRUST CT).

J Am Heart Assoc 2020 02 12;9(4):e014265. Epub 2020 Feb 12.

Department of Neurology with Focus on Neurovascular Diseases and Neurooncology and Hertie Institute for Clinical Brain Research University Hospital Tübingen Germany.

Background Intravenous thrombolysis (IVT) in wake-up stroke (WUS) or stroke with unknown onset (SUO) has been recently proven to be safe and effective using advanced neuroimaging (magnetic resonance imaging or computerized tomography-perfusion) for patient selection. However, in most of the thrombolyzing centers advanced neuroimaging is not instantly available. We hypothesize that pragmatic non-contrast computed tomography-based IVT in WUS/SUO may be feasible and safe. Methods and Results TRUST-CT (Thrombolysis in Stroke With Unknown Onset Based on Non-Contrast Computerized Tomography) is an international multicenter registry-based study. WUS/SUO patients undergoing non-contrast computed tomography-based IVT with National Institute of Health Stroke Scale ≥4 and initial Alberta Stroke Program Early Computerized Tomography score ≥7 were included and compared with propensity score matched non-thrombolyzed WUS/SUO controls. Primary end point was the incidence of symptomatic intracranial hemorrhage; secondary end points included 24-hour National Institute of Health Stroke Scale improvement of ≥4 and modified Rankin Scale at 90 days. One hundred and seventeen WUS/SUO patients treated with non-contrast computed tomography-based IVT were included. As compared with 112 controls, the median admission National Institute of Health Stroke Scale was 10 and the median Alberta Stroke Program Early Computerized Tomography score was 10 in both groups. Four (3.4%) IVT patients and one control patient (0.9%) suffered symptomatic intracranial hemorrhage (adjusted odds ratio 7.9, 95% CI 0.65-96, =0.1). A decrease of ≥4 National Institute of Health Stroke Scale points was observed in 67 (57.3%) of IVT patients as compared with 25 (22.3%) in controls (adjusted odds ratio 5.8, CI 3.0-11.2, <0.001). A months, 39 (33.3%) IVT patients reached a modified Rankin Scale score of 0 or 1 versus 23 (20.5%) controls (adjusted odds ratio 1.94, CI 1.0-3.76, =0.05). Conclusions Non-contrast computed tomography-based thrombolysis in WUS/SUO seems feasible and safe and may be effective. Randomized prospective comparisons are warranted. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT03634748.
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http://dx.doi.org/10.1161/JAHA.119.014265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070213PMC
February 2020

Temporal trends in intracerebral hemorrhage: Evidence from the Austrian Stroke Unit Registry.

PLoS One 2019 20;14(11):e0225378. Epub 2019 Nov 20.

Department of Neurology, St. John's Hospital, Vienna, Austria.

Background: To assess changes in frequency, severity, complications, therapy and outcome of intracerebral hemorrhage in patients treated in stroke units in Austria, we evaluated data from the Austrian Stroke Unit Registry between 2008 and 2016.

Methods And Findings: Data of 6707 cases of ICH covering a time span of 9 years and including information on age, risk factors, pre-stroke modified Rankin Score (mRS), baseline stroke severity (NIHSS), complications, therapy, functional outcome, and mortality were extracted from the Austrian Stroke Unit Registry. A multivariate regularized logistic regression model and linear models for temporal dependence were computed for analyzing statistical inference and time trends. Bonferroni correction was applied to correct for multiple testing. Between 2008 and 2016, the proportion of ICH admissions to stroke units in Austria declined, with a shift among patients towards older age (>70 years, p = 0.04) and lower admission NIHSS scores. While no significant time trends in risk factors, pre-stroke mRS and medical complications were observed, therapeutic interventions declined significantly (p<0.001). Three-month mortality increased over the years independently (p = 0.003).

Conclusions: Despite declining incidence and clinical severity of ICH we observed a clear increase in three-month mortality. This effect seems to be independent of predictors including age, admission NIHSS, pre-morbid MRS, or medical complications. The observations from this large retrospective database cohort study underline an urgent call for action in the therapy of ICH.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225378PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867701PMC
March 2020

Regional, sex, and age differences in diagnostic testing among participants in the NAVIGATE-ESUS trial.

Int J Stroke 2021 Jan 20;16(1):55-62. Epub 2019 Oct 20.

Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada.

Background And Aim: The diagnosis of embolic stroke of undetermined source (ESUS) is based on excluding other more likely stroke etiologies, and therefore diagnostic testing plays an especially crucial role. Our objective was to compare the diagnostic testing by region, sex, and age among the participants of NAVIGATE-ESUS trial.

Methods: Participants were grouped according to five global regions (North America, Latin America, Western Europe, Eastern Europe and East Asia), age (<60, 60-74, and >75 years), and sex. Frequencies of each diagnostic test within areas of echocardiography, cardiac rhythm monitoring, and arterial imaging were described and compared across groups. A multivariable logistic regression model for each diagnostic test was fit to assess the independent influence of each of region, age, and sex and likelihood of testing.

Results: We included 6985 patients in the analysis (918 from North America; 746 from Latin America; 2853 from Western Europe; 1118 from Eastern Europe; 1350 from East Asia). Average age (highest in Western Europe (69 years), lowest in Eastern Europe (65 years)), % females (highest in Latin America (44%) and lowest in East Asia (31%)), and use of each diagnostic test varied significantly across regions. Region, but not sex, was independently associated with use of each diagnostic test examined. Transesophageal echocardiography and either CT or MR angiogram were more often used in younger patients.

Conclusion: Diagnostic testing differed by region, and less frequently by age, but not by sex. Our findings reflect the existing variations in global practice in diagnostic testing in ESUS patients.
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http://dx.doi.org/10.1177/1747493019884523DOI Listing
January 2021

Baroreflex sensitivity is associated with post-stroke infections. An open, prospective study.

J Neurol Sci 2019 Nov 3;406:116450. Epub 2019 Sep 3.

Institute of Electronic Systems, Warsaw University of Technology, Poland.

Background And Purpose: Autonomic nervous system (ANS) seems to play an important role in the post-stroke immunosuppression syndrome with increased susceptibility to infections. The aim of this study was to investigate if ANS activity measured at admission is associated with post-stroke infections.

Methods: We prospectively analyzed patients with acute ischemic stroke. ANS was measured using the cross-correlational baroreflex sensitivity (BRS) at admission. The occurrence and cause of in-hospital infections was assessed based on the clinical and laboratory examination. Demographic and clinical variables including initial stroke severity, dysphagia, procedures as nasogastric tubes, central venous and urinary catheters and mechanical ventilation were included in the analysis.

Results: We included 161 patients with ischemic stroke, of those 49 (30.4%) developed a nosocomial infection during the first 7 days of hospital stay. Patients with infections had significantly lower BRS (median 3 vs 5 ms/mmHg, p < .001) higher initial NIHSS (median 15 vs 5, p < .001), had more often non-lacunar etiology and underwent more invasive procedures. In the multivariable regression model decreased BRS (adjusted OR 1.21, 95% CI 1.03-1.41, p = .02), admission NIHSS (adjusted OR 1.10, 95% CI 1.02-1.19, p = .02) and invasive procedures (adjusted OR 1.46, 95% CI 1.03-2.06, p = .03) were independently associated with infection after ischemic stroke.

Conclusions: Decreased BRS was independently associated with infections after ischemic stroke. Autonomic shift may play an important role in increased susceptibility to infections after stroke. The possible diagnostic and therapeutic relevance of this finding deserves further research.
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http://dx.doi.org/10.1016/j.jns.2019.116450DOI Listing
November 2019

Aortic Arch Atherosclerosis in Patients With Embolic Stroke of Undetermined Source: An Exploratory Analysis of the NAVIGATE ESUS Trial.

Stroke 2019 11 17;50(11):3184-3190. Epub 2019 Sep 17.

Department of Medicine-Neurology (R.G.H.), McMaster University/Population Health Research Institute, Hamilton, Ontario, Canada.

Background and Purpose- Aortic arch atherosclerosis (AAA) is a possible source of embolism in patients with embolic stroke of undetermined source. Previous studies reported high rates of embolic events in patients with AAA, especially those with high-risk AAA. This exploratory analysis of NAVIGATE ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) focused on patients with AAA and assessed their characteristics, stroke recurrence rates, and response to treatment. Methods- The detection of AAA and the assessment of its features were based on transesophageal echocardiography that was done in 19% of participants. AAA plaques were considered to have complex features when reported as complex or ulcerated or were ≥4 mm in thickness or had a mobile thrombus present. Results- Among 1382 participants who had transesophageal echocardiography, 397 (29%) had AAA and 112 (8%) had complex AAA. Mean (SD) age (63 [10] versus 67 [9] versus 69 [9]; <0.001), prevalence of diabetes mellitus (19% versus 26%, versus 32%; =0.002), and aortic valvulopathy (10 versus 20 versus 20; <0.001) increased across no versus noncomplex versus complex AAA, respectively. In multivariable analyses, increasing age, diabetes mellitus, aortic valvulopathy, statin use before randomization, chronic infarcts on imaging, and region were independently associated with any AAA versus no AAA and also with complex AAA versus no AAA. Multiterritorial qualifying infarcts rather than single-territory infarcts were observed in 21% with complex AAA versus 17% noncomplex versus 13% no AAA (=0.07). Annualized rates of ischemic stroke recurrence were 7.2% versus 4.2% versus 5.6% for complex versus noncomplex versus no AAA, respectively. While prevalence of complex AAA increased with increasing risk score, after adjusting for risk score, we did not observe increased risk of recurrent stroke for patients with complex AAA (hazard ratio, 1.1; 95% CI, 0.53-2.4), although the number of outcomes was limited. In patients with complex AAA, 4 strokes occurred among rivaroxaban-assigned patients and 4 strokes among aspirin-assigned patients. Conclusions- Complex AAA is prevalent in embolic stroke of undetermined source patients and is associated with atherosclerotic burden. Whether complex AAA independently increases recurrent stroke risk and whether a non-vitamin-K oral anticoagulant as compared with aspirin may be effective for reducing recurrent stroke requires additional study. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.
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http://dx.doi.org/10.1161/STROKEAHA.119.025813DOI Listing
November 2019

Efficacy and Safety of Rivaroxaban Versus Aspirin in Embolic Stroke of Undetermined Source and Carotid Atherosclerosis.

Stroke 2019 09 12;50(9):2477-2485. Epub 2019 Aug 12.

Department of Medicine (Neurology), Population Health Research Institute, McMaster University, Hamilton, ON, Canada. (R.G.H.).

Background and Purpose- The sources of emboli in patients with embolic stroke of undetermined source (ESUS) are multiple and may not respond uniformly to anticoagulation. In this exploratory subgroup analysis of patients with carotid atherosclerosis in the NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism)-ESUS trial, we assessed whether the treatment effect in this subgroup is consistent with the overall trial population and investigated the association of carotid atherosclerosis with recurrent ischemic stroke. Methods- Carotid atherosclerosis was analyzed either as the presence of mild (ie, 20%-49%) atherosclerotic stenosis or, separately, as the presence of carotid plaque. Primary efficacy outcome was ischemic stroke recurrence. Safety outcomes were major bleeding and symptomatic intracerebral bleeding. Results- Carotid plaque was present in 40% of participants and mild carotid stenosis in 11%. There was no significant difference in ischemic stroke recurrence between rivaroxaban- and aspirin-treated patients among 490 patients with carotid stenosis (5.0 versus 5.9/100 patient-years, respectively, hazard ratio [HR], 0.85; 95% CI, 0.39-1.87; P for interaction of treatment effect with patients without carotid stenosis 0.78) and among 2905 patients with carotid plaques (5.9 versus 4.9/100 patient-years, respectively, HR, 1.20; 95% CI, 0.86-1.68; P for interaction of treatment effect with patients without carotid stenosis 0.2). Among patients with carotid plaque, major bleeding was more frequent in rivaroxaban-treated patients compared with aspirin-treated (2.0 versus 0.5/100 patient-years, HR, 3.75; 95% CI, 1.63-8.65). Patients with carotid stenosis had similar rate of ischemic stroke recurrence compared with those without (5.4 versus 4.9/100 patient-years, respectively, HR, 1.11; 95% CI, 0.73-1.69), but there was a strong trend of higher rate of ischemic stroke recurrence in patients with carotid plaque compared with those without (5.4 versus 4.3/100 patient-years, respectively, HR, 1.23; 95% CI, 0.99-1.54). Conclusions- In ESUS patients with carotid atherosclerosis, we found no difference in efficacy between rivaroxaban and aspirin for prevention of recurrent stroke, but aspirin was safer, consistent with the overall trial results. Carotid plaque was much more often present ipsilateral to the qualifying ischemic stroke than contralateral, supporting an important etiological role of nonstenotic carotid disease in ESUS. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.
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http://dx.doi.org/10.1161/STROKEAHA.119.025168DOI Listing
September 2019

Predicting Early Mortality of Acute Ischemic Stroke.

Stroke 2019 02;50(2):349-356

From the Department of Neurology, Medical University of Graz, Austria (T.G., K.N., B.P., C.E., F.F.).

Background and Purpose- Several risk factors are known to increase mid- and long-term mortality of ischemic stroke patients. Information on predictors of early stroke mortality is scarce but often requested in clinical practice. We therefore aimed to develop a rapidly applicable tool for predicting early mortality at the stroke unit. Methods- We used data from the nationwide Austrian Stroke Unit Registry and multivariate regularized logistic regression analysis to identify demographic and clinical variables associated with early (≤7 days poststroke) mortality of patients admitted with ischemic stroke. These variables were then used to develop the Predicting Early Mortality of Ischemic Stroke score that was validated both by bootstrapping and temporal validation. Results- In total, 77 653 ischemic stroke patients were included in the analysis (median age: 74 years, 47% women). The mortality rate at the stroke unit was 2% and median stay of deceased patients was 3 days. Age, stroke severity measured by the National Institutes of Health Stroke Scale, prestroke functional disability (modified Rankin Scale >0), preexisting heart disease, diabetes mellitus, posterior circulation stroke syndrome, and nonlacunar stroke cause were associated with mortality and served to build the Predicting Early Mortality of Ischemic Stroke score ranging from 0 to 12 points. The area under the curve of the score was 0.879 (95% CI, 0.871-0.886) in the derivation cohort and 0.884 (95% CI, 0.863-0.905) in the validation sample. Patients with a score ≥10 had a 35% (95% CI, 28%-43%) risk to die within the first days at the stroke unit. Conclusions- We developed a simple score to estimate early mortality of ischemic stroke patients treated at a stroke unit. This score could help clinicians in short-term prognostication for management decisions and counseling.
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http://dx.doi.org/10.1161/STROKEAHA.118.022863DOI Listing
February 2019

Modified DWI-FLAIR mismatch guided thrombolysis in unknown onset stroke.

J Thromb Thrombolysis 2019 Feb;47(2):167-173

Department of Neurology, St. John's Hospital, Vienna, Austria.

DWI-FLAIR mismatch has been recently proven to identify patients with unknown onset stroke (UOS) eligible for thrombolysis. However, this concept may exclude patients from thrombolysis who may eventually benefit as well. We aimed to examine the feasibility, safety and potential efficacy of thrombolysis in wake-up stroke (WUS) and UOS patients using a modified DWI-FLAIR mismatch allowing for partial FLAIR positivity. WUS/UOS patients fulfilling the modified DWI-FLAIR mismatch and treated with intravenous thrombolysis (IVT) were compared to propensity score matched WUS/UOS patients excluded from IVT due to FLAIR positivity. The primary endpoint was a symptomatic intracranial hemorrhage (SICH), the secondary endpoints were improvement of ≥ 4 in NIHSS score and mRS score at 3 months. 64 IVT-treated patients (median NIHSS 9) and 64 controls (median NIHSS 8) entered the analysis (p = 0.2). No significant difference in SICH was found between the IVT group and the controls (3.1% vs. 1.6%, p = 0.9). An improvement of ≥ 4 NIHSS points was more frequent in IVT patients as compared to controls (40.6% vs. 18.8%, p = 0.01). 23.4% of IVT patients achieved a mRS score of 0-1 at 3 months as compared to 18.8% of the controls (p = 0.8). SICH, improvement of NIHSS ≥ 4 and mRS 0-1 at 3 months were comparable in thrombolyzed patients with negative FLAIR images versus those thrombolyzed with partial positive FLAIR images (3% vs. 3%, p = 0.9; 40% vs. 41%, p = 0.9; 19% vs. 22%, p = 0.8). Our study signalizes that thrombolysis may be feasible in selected WUS/UOS patients with partial FLAIR signal positivity.
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http://dx.doi.org/10.1007/s11239-018-1766-3DOI Listing
February 2019

Pragmatic trial of multifaceted intervention (STROKE-CARD care) to reduce cardiovascular risk and improve quality-of-life after ischaemic stroke and transient ischaemic attack -study protocol.

BMC Neurol 2018 Nov 6;18(1):187. Epub 2018 Nov 6.

Department of Neurology, Medical University of Innsbruck, Anichstraße 35, A-6020, Innsbruck, Austria.

Background: Patients with ischaemic stroke or transient ischaemic attack (TIA) are at high risk of future cardiovascular events. Despite compelling evidence about the efficacy of secondary prevention, a substantial gap exists between risk factor management in real life and that recommended by international guidelines. Moreover, stroke is a leading cause of disability and morbidity which partly emerges from post-stroke complications.

Methods/design: We designed a block-randomised (2:1 ratio) open pragmatic trial [NCT02156778] with blinded outcome assessment comparing STROKE-CARD to usual post-stroke-patient care. STROKE-CARD is a multifaceted post-stroke disease management program with the objective of reducing recurrent cardiovascular events and improving quality of life in ischaemic stroke and TIA-patients. It combines intensified multi-domain secondary prevention, systematic detection and treatment of post-stroke complications, and patient self-empowerment. Enrolment of 2160 patients with acute ischaemic stroke or TIA (ABCD2-Score ≥ 3) is planned at two study centres in Austria. The co-primary efficacy endpoints are (i) the composite of major recurrent cardiovascular events (nonfatal stroke, nonfatal myocardial infarction, and vascular death) occurring within 12 months after the index event and (ii) one-year health-related quality-of-life measured with the European Quality of Life-5 Dimensions (EQ-5D-3 L) questionaire. Secondary endpoints include all-cause mortality, functional outcome, and target-level achievement in risk factor management.

Discussion: This trial will provide evidence on whether the pragmatic post-stroke intervention program STROKE-CARD can help prevent cardiovascular events and improve quality-of-life within the setting of a high-quality acute stroke care system. In case of success, STROKE-CARD may be implemented in daily clinical routine and serve as a model for other disease management initiatives.

Trial Registration: ClinicalTrials.gov: NCT02156778 . (June 5, 2014, retrospectively registered).
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http://dx.doi.org/10.1186/s12883-018-1185-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219064PMC
November 2018

Is Functional Outcome Different in Posterior and Anterior Circulation Stroke?

Stroke 2018 11;49(11):2728-2732

Department of Neurology, Medical University of Vienna, Austria (W.S., M.M., S. Scharer, S. Szabo, S.G.).

Background and Purpose- Posterior circulation stroke (PCS) account for 20% of all ischemic strokes. There is limited evidence whether functional outcome of PCS is comparable to that of anterior circulation stroke (ACS). We aimed to analyze whether 3-month functional outcome is different in PCS and ACS. Methods- Patients with acute ischemic stroke prospectively enrolled within the Austrian Stroke Unit Registry were stratified by infarct localization according to the Oxfordshire Community Stroke Project Classification. Propensity score matching was used to control for covariate imbalances and to match patients with PCS and ACS. Patients were matched for stroke severity, recombinant tissue-type plasminogen activator treatment, and demographic and vascular risk factors. Main outcomes were the distribution of modified Rankin Scale after 3 months and multiple proportional odds models to estimate the influence of the infarct localization on the functional outcome. Results- From a total of 90 484 patients enrolled within the Austrian Stroke Unit Registry, 9208 (4604 PCS/4604 ACS) were matched, of those 954 (477 in each group) were treated with recombinant tissue-type plasminogen activator. We detected a significant shift towards better 3-month functional outcome in patients with ACS compared with PCS (odds ratio [OR], 1.19; 95% CI, 1.1-1.28; P<0.0001). In particular, functional outcome was worse in PCS with onset-to-door-time >270 minutes (OR, 1.34; 95% CI, 1.17-1.54; P<0.0001) and in PCS with unknown onset-to-door-time (OR, 1.26; 95% CI, 1.13-1.42; P<0.0001); however, we did not detect any difference in functional outcome between ACS and PCS in patients with an onset-to-door-time ≤270 minutes (1-180 minutes: OR, 0.92, 95% CI, 0.78-1.09, P=0.3554; 181-270 minutes: OR, 1.04, 95% CI, 0.79-1.37, P=0.7689). In patients treated with recombinant tissue-type plasminogen activator, functional outcome was not significantly different between PCS and ACS. Conclusions- PCS was associated with worse outcome compared with ACS in patients arriving later than 4.5 hours at hospital or in those with unknown onset of symptoms. Our results urge for implementation of symptoms found in the posterior circulation into preclinical patient-triage tools.
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http://dx.doi.org/10.1161/STROKEAHA.118.021785DOI Listing
November 2018

Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source.

N Engl J Med 2018 Jun 16;378(23):2191-2201. Epub 2018 May 16.

From the Departments of Medicine-Neurology (R.G.H., M.S., A.S.), Health Research Methods, Evidence, and Impact (S.I.B.), Pathology and Molecular Medicine (G. Pare), and Medicine-Cardiology (S.J.C.), Population Health Research Institute (B.S., P.S., E.T.), and the Thrombosis and Atherosclerosis Research Institute and McMaster University (J.I.W.), Hamilton, ON, the Vancouver Stroke Program, University of British Columbia, Vancouver (O.R.B.), and Sunnybrook Health Sciences Centre, University of Toronto, Toronto (C.J.) - all in Canada; Bayer, Wuppertal (H.M.), Klinik für Neurologie, Charité-Universitätsmedizin Berlin (M.E.), and Bayer (B.K.), Berlin, and Bayer, Leverkusen (C.P.) - all in Germany; the Department of Neurology, University of Pennsylvania, Philadelphia (S.E.K.), and Janssen Research and Development, Spring House (G. Peters) - both in Pennsylvania; Bayer U.S., Pharmaceuticals Clinical Development Thrombosis, Whippany, NJ (S.D.B.); Clínica Alemana de Santiago, Santiago, Chile (P.L.); the Department of Neurology and Stroke Center, Beijing Tiantan Hospital, Beijing (Yongjun Wang, Yilong Wang); Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona (A.D.); Pirogov Russian National Research Medical University, Moscow (N.S.); International Clinical Research Center and Neurology Department, St. Anne's University Hospital, Brno, Czech Republic (R.M.); Centro Hospitalar e Universitário de Coimbra, Hospitais da Universidade de Coimbra, Coimbra, Portugal (L.C.); the Department of Clinical Sciences (Neurology), Lund University, and the Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund (A.L.), and the Department of Clinical Neuroscience-Neurology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg (T.T.) - all in Sweden; Instituto Nacional de Neurología y Neurocirugía, Mexico City (A.A.); Hospital St. John of God, Sigmund Freud Private University, Medical Faculty, Vienna (W.L.); the 2nd Department of Neurology, Institute of Psychiatry and Neurology, and the Department of Pharmacology, Medical University of Warsaw, Warsaw, Poland (A.C.); the Department of Internal Medicine, University Hospital Basel, Basel, Switzerland (J.E.); Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo (R.J.G.); Assistance Publique-Hôpitaux de Paris, Bichat Hospital, Paris-Diderot, Sorbonne Paris Cité University, Paris (P.A.); Institute for Neurological Research-Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Buenos Aires (S.F.A.); the Department of Neurology, Helsinki University Central Hospital, Helsinki (T.T.); Imperial College London, London (R.V.); Medical School, University of Western Australia, and Sir Charles Gairdner Hospital, Perth, Australia (G.J.H.); the Department of Human Neurosciences, Sapienza University of Rome, Rome (D.T.); the Department of Neurology, Semmelweis University, Budapest, Hungary (D.B.); International University of Health and Welfare, Sanno Hospital and Sanno Medical Center, Tokyo (S.U.); the Department of Medicine, University of Thessaly, Larissa, Greece (G.N.); Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea (B.-W.Y.); the Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels (R.B.); the Department of Neurology, ZorgSaam Hospital, Terneuzen, the Netherlands (R.B.); Institute of Neuroscience and Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, United Kingdom (K.W.M.); Shaare Zedek Medical Center, Jerusalem (N.B.); the Department of Neurology, Selcuk University, Konya, Turkey (S.O.); Health Research Board Clinical Research Facility, National University of Ireland, Galway (M.J.O.); Tiervlei Trial Centre and Head of Internal Medicine Karl Bremer Hospital, Bellville, South Africa (M.M.D.V.B.); and Baylor College of Medicine, Houston (W.F.P.).

Background: Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin.

Methods: We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding.

Results: A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001).

Conclusions: Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).
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http://dx.doi.org/10.1056/NEJMoa1802686DOI Listing
June 2018

Characterization of Patients with Embolic Strokes of Undetermined Source in the NAVIGATE ESUS Randomized Trial.

J Stroke Cerebrovasc Dis 2018 Jun 7;27(6):1673-1682. Epub 2018 Mar 7.

Shaare-Zedek Medical Center, Jerusalem, Israel.

Background: The New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs. ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) trial is a randomized phase-III trial comparing rivaroxaban versus aspirin in patients with recent ESUS.

Aims: We aimed to describe the baseline characteristics of this large ESUS cohort to explore relationships among key subgroups.

Methods: We enrolled 7213 patients at 459 sites in 31 countries. Prespecified subgroups for primary safety and efficacy analyses included age, sex, race, global region, stroke or transient ischemic attack prior to qualifying event, time to randomization, hypertension, and diabetes mellitus.

Results: Mean age was 66.9 ± 9.8 years; 24% were under 60 years. Older patients had more hypertension, coronary disease, and cancer. Strokes in older subjects were more frequently cortical and accompanied by radiographic evidence of prior infarction. Women comprised 38% of participants and were older than men. Patients from East Asia were oldest whereas those from Latin America were youngest. Patients in the Americas more frequently were on aspirin prior to the qualifying stroke. Acute cortical infarction was more common in the United States, Canada, and Western Europe, whereas prior radiographic infarctions were most common in East Asia. Approximately forty-five percent of subjects were enrolled within 30 days of the qualifying stroke, with earliest enrollments in Asia and Eastern Europe.

Conclusions: NAVIGATE-ESUS is the largest randomized trial comparing antithrombotic strategies for secondary stroke prevention in patients with ESUS. The study population encompasses a broad array of patients across multiple continents and these subgroups provide ample opportunities for future research.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2018.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701183PMC
June 2018

ABCD3-I score and the risk of early or 3-month stroke recurrence in tissue- and time-based definitions of TIA and minor stroke.

J Neurol 2018 Mar 11;265(3):530-534. Epub 2018 Jan 11.

Department of Neurology, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.

Changing definition of TIA from time to a tissue basis questions the validity of the well-established ABCD3-I risk score for recurrent ischemic cerebrovascular events. We analyzed patients with ischemic stroke with mild neurological symptoms arriving < 24 h after symptom onset in a phase where it is unclear, if the event turns out to be a TIA or minor stroke, in the prospective multi-center Austrian Stroke Unit Registry. Patients were retrospectively categorized according to a time-based (symptom duration below/above 24 h) and tissue-based (without/with corresponding brain lesion on CT or MRI) definition of TIA or minor stroke. Outcome parameters were early stroke during stroke unit stay and 3-month ischemic stroke. Of the 5237 TIA and minor stroke patients with prospectively documented ABCD3-I score, 2755 (52.6%) had a TIA by the time-based and 2183 (41.7%) by the tissue-based definition. Of the 2457 (46.9%) patients with complete 3-month followup, corresponding numbers were 1195 (48.3%) for the time- and 971 (39.5%) for the tissue-based definition of TIA. Early and 3-month ischemic stroke occurred in 1.1 and 2.5% of time-based TIA, 3.8 and 5.9% of time-based minor stroke, 1.2 and 2.3% of tissue-based TIA as well as in 3.1 and 5.5% of tissue-based minor stroke patients. Irrespective of the definition of TIA and minor stroke, the risk of early and 3-month ischemic stroke steadily increased with increasing ABCD3-I score points. The ABCD3-I score performs equally in TIA patients in tissue- as well as time-based definition and the same is true for minor stroke patients.
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http://dx.doi.org/10.1007/s00415-017-8720-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834555PMC
March 2018

Effects of SSRI exposure on hemorrhagic complications and outcome following thrombolysis in ischemic stroke.

Int J Stroke 2018 07 14;13(5):511-517. Epub 2017 Nov 14.

Department of Neurology, St. John's Hospital, Medical Faculty, Sigmund Freud University Vienna, Vienna, Austria.

Background Selective serotonin reuptake inhibitors (SSRI) may interfere with platelet function, and pre-stroke SSRI treatment has been associated with increased hematoma volumes and mortality in hemorrhagic stroke patients. The effects of SSRI on the risk of hemorrhagic complications after thrombolysis in ischemic stroke patients are unclear. Aims To examine the effects of pre-stroke SSRI exposure on bleeding complications, functional outcome, and mortality following thrombolysis in ischemic stroke. Methods Data including standard demographic and clinical variables as well as baseline and follow-up stroke severity (measured by National Institutes of Health Stroke Score), functional outcome (measured by modified Rankin Scale) at 3 months, and mortality at 7 and 90 days were extracted from the Virtual International Stroke Trials Archive. Multivariable binary logistic regression was used for statistical analyses. Results Out of 1114 ischemic stroke patients treated with recombinant tissue-type plasminogen activator, 135 (12.1%) had previous SSRI exposure. Symptomatic intracranial hemorrhage occurred in 30 (2.7%) patients. Of those, 2 (1.5%, n = 135) were in the SSRI pretreatment group and 28 (2.9%, n = 979) were SSRI naive patients. Pre-stroke SSRI exposure in thrombolysed patients showed association with neither bleeding complications ( P = .58) nor functional outcome ( P = .38) nor mortality ( P = .65). Conclusions Results from this large retrospective ad hoc database cohort study indicate that pre-stroke SSRI exposure in ischemic stroke patients who receive thrombolytic treatment is not associated with bleeding complications, functional outcome, or mortality.
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http://dx.doi.org/10.1177/1747493017743055DOI Listing
July 2018

Do Women With Atrial Fibrillation Experience More Severe Strokes? Results From the Austrian Stroke Unit Registry.

Stroke 2017 03 1;48(3):778-780. Epub 2017 Feb 1.

From the Department of Neurology, Hospital St. John of God, Vienna, Austria (C.L., J.F., S. Krebs, W.L.); Austrian Institute for Health Care (Österreichisches Bundesinstitut für Gesundheitswesen), Vienna, Austria (L.S.); Department of Neurology, Medical University of Graz, Austria (T.G.); Department of Neurology, Medical University Vienna, Austria (S.G.); Department for Clinical Neurosciences, Danube University, Krems, Austria (M.B.); Department of Neurology, Medical University of Innsbruck, Austria (K.W., T.T, S. Kiechl, J.W., M.K.); and Medical Faculty, Sigmund Freud University, Vienna, Austria (W.L.).

Background And Purpose: Ischemic strokes associated with atrial fibrillation (AF) are more severe than those of other cause. We aim to study potential sex effects in this context.

Methods: In this cross-sectional study, 74 425 adults with acute ischemic stroke from the Austrian Stroke Unit Registry were included between March 2003 and January 2016. In 63 563 patients, data on the National Institutes of Health Stroke Scale on admission to the stroke unit, presence of AF, vascular risk factors, and comorbidities were complete. Analysis was done by a multivariate regression model.

Results: Stroke severity in general increased with age. AF-related strokes were more severe than strokes of other causes. Sex-related differences in stroke severity were only seen in stroke patients with AF. Median (Q,) National Institutes of Health Stroke Scale score points were 9 (4,17) in women and 6 (3,13) in men (<0.001). The interaction between AF and sex on stroke severity was independent of age, previous functional status, vascular risk factors, and vascular comorbidities and remained significant in various subgroups.

Conclusions: Women with AF do not only have an increased risk of stroke when compared with men but also experience more severe strokes.
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http://dx.doi.org/10.1161/STROKEAHA.116.015900DOI Listing
March 2017

Prehospital and intra-hospital time delays in posterior circulation stroke: results from the Austrian Stroke Unit Registry.

J Neurol 2017 Jan 7;264(1):131-138. Epub 2016 Nov 7.

Department of Neurology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Therapeutic effect of recombinant tissue-plasminogen activator (rt-PA) is time dependent. There is limited evidence whether localization of stroke within the posterior circulation (PCS) is associated with a treatment delay. We aimed to analyze within a nationwide multicenter cohort whether duration of pre- and intra-hospital patient management differs between patients with PCS and anterior circulation strokes (ACS). We studied onset-to-door-times (ODT) and door-to-needle-times (DNT) of all patients with acute ischemic stroke (IS) enrolled in the Austrian Stroke Unit Registry according to infarct localization. Classification into PCS and ACS was based on clinical presentation applying the criteria used in the Oxfordshire Community Stroke Project. Relationships between ODT, respectively, DNT and explanatory variables were modeled by multivariate linear regression. Between 2003 and 2015, 71010 patients with IS were enrolled, 11,924 with PCS and 59,086 with ACS. Overall, the ODT was significantly longer in PCS: median (IQR): 170 (25th, 75th‰: 79,420) min versus 110 (60,240); p < 0.001; this finding held true in multivariable analysis. In 10535 rt-PA-treated patients (1022 PCS/9832 ACS), ODT and DNT were significantly longer among those with PCS: ODT: median: 80 min (55,120) versus 72 (50,110), p < 0.001; DNT: 57 (35.90) versus 45 (30.67), p < 0.001. In the multivariate model, PCS was significantly associated with delay in the DNT. In conclusion, in this large nationwide cohort, patient management was significantly slower in PCS as compared to ACS. Increasing awareness about these delays and further elaboration of the underlying causes may translate into higher proportions of patients with PCS receiving rt-PA.
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http://dx.doi.org/10.1007/s00415-016-8330-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225195PMC
January 2017

Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: Design of the NAVIGATE ESUS randomized trial.

Eur Stroke J 2016 Sep 3;1(3):146-154. Epub 2016 Aug 3.

Department of Clinical Sciences (Neurology), Department of Neurology and Rehabilitation Medicine, Skane University Hospital, Lund University, Lund, Sweden.

Background: Embolic strokes of undetermined source comprise up to 20% of ischemic strokes. The stroke recurrence rate is substantial with aspirin, widely used for secondary prevention. The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source international trial will compare the efficacy and safety of rivaroxaban, an oral factor Xa inhibitor, versus aspirin for secondary prevention in patients with recent embolic strokes of undetermined source.

Main Hypothesis: In patients with recent embolic strokes of undetermined source, rivaroxaban 15 mg once daily will reduce the risk of recurrent stroke (both ischemic and hemorrhagic) and systemic embolism (primary efficacy outcome) compared with aspirin 100 mg once daily.

Design: Double-blind, randomized trial in patients with embolic strokes of undetermined source, defined as nonlacunar cryptogenic ischemic stroke, enrolled between seven days and six months from the qualifying stroke. The planned sample size of 7000 participants will be recruited from approximately 480 sites in 31 countries between 2014 and 2017 and followed for a mean of about two years until at least 450 primary efficacy outcome events have occurred. The primary safety outcome is major bleeding. Two substudies assess (1) the relative effect of treatments on MRI-determined covert brain infarcts and (2) the biological underpinnings of embolic strokes of undetermined source using genomic and biomarker approaches.

Summary: The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source trial is evaluating the benefits and risks of rivaroxaban for secondary stroke prevention in embolic strokes of undetermined source patients. Main results are anticipated in 2018.
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http://dx.doi.org/10.1177/2396987316663049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301240PMC
September 2016

Predictive value of ABCD2 and ABCD3-I scores in TIA and minor stroke in the stroke unit setting.

Neurology 2016 Aug 29;87(9):861-9. Epub 2016 Jul 29.

From the Department of Neurology (M.K., B.M., T.T., S. Kiechl, J.W.), Innsbruck Medical University; Department of Neurology (W.L., S. Krebs, J.F.), Hospital Barmherzige Brueder; Danube University Krems and Gesundheit Österreich GmbH/BIQG (L.S.); Department of Neurology (E.F.), Hospital Rudolfstiftung, Vienna; Department of Neurology (S.O.), University Clinic St Pölten; Department of Neurology (G.D.), Hospital Wilhelminenspital, Wien; Department of Neurology (T.S.-H.), Medical University of Graz; Department of Clinical Neurosciences and Preventive Medicine (M.B.), Danube University Krems; and Department of Neurology (M.B.), Karl Landsteiner University Hospital Tulln, Austria.

Objective: It is not clear whether risk scores for early stroke recurrence after TIA that have been mainly established in outpatient and emergency department settings are valid on the background of highly specialized stroke unit care.

Methods: ABCD2 and ABCD3-I scores have been prospectively documented in a cohort of patients admitted to Austrian stroke units within 24 hours of symptom onset with TIA or minor stroke (NIH Stroke Scale score <4).

Results: A total of 5,237 TIA and minor stroke patients met inclusion criteria, with 3-month follow-up data available on 2,457. Early and 3-month stroke were observed in 2.4% and 4.2% of the study population. The probability of early stroke during the stroke unit stay (median 2 [interquartile range 1-3] days) steadily increased from 0% to 4.8% and 0% to 16.7% with increasing ABCD2 and ABCD3-I score points, respectively. On 3-month follow-up, stroke risk increased from 0% to 8.0% and 0% to 23.8% with increasing ABCD2 and ABCD3-I score points, respectively. Of the individual score components, age, blood pressure, and diabetes were not related to early or 3-month stroke, whereas clinical presentation (C), symptom duration (D), and cerebral as well as carotid imaging (I) were and accounted for the information provided by the full scores.

Conclusions: Standard ABCD2 and ABCD3-I scores are useful instruments to estimate the probability of early and 3-month stroke in TIA and minor stroke patients treated at specialized stroke units, with C, D, and I being the most important score components in this setting.
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http://dx.doi.org/10.1212/WNL.0000000000003033DOI Listing
August 2016

IV thrombolysis in patients with ischemic stroke and alcohol abuse.

Neurology 2015 Nov 7;85(18):1592-7. Epub 2015 Oct 7.

From the Department of Neurology (T.G., C.E., R.F., K.N., M.K., F.F.) and Division of Neuroradiology, Department of Radiology (C.E.), Medical University of Graz; Center of Clinical Neurosciences (L.S., M.B.), Danube University of Krems; Department of Neurology (J.F., W.L.), Hospital Barmherzige Brueder Vienna; Department of Neurology (M.B.), University Hospital Tulln; and Department of Neurology (J.W.), Medical University of Innsbruck, Austria.

Objective: To determine whether chronic alcohol consumption or acute alcohol intoxication affects the rate of IV thrombolysis (IVT) and associated risk of symptomatic intracranial hemorrhage (SICH) in patients with acute ischemic stroke (IS).

Methods: We analyzed data from the nationwide Austrian Stroke Unit Registry for all patients with IS admitted to one of 35 stroke units between 2004 and 2014. We compared demographic and clinical characteristics for patients with chronic alcohol consumption (>2 drinks/d) or acute intoxication and for patients without these factors and their rates of IVT and associated SICH.

Results: We identified 47,422 patients with IS. Of these patients, 3,999 (8.5%) consumed alcohol chronically and 216 (0.5%) presented with acute intoxication. Alcohol abusers were younger, more frequently men, and less often functionally disabled before the index event. Stroke severity was comparable between alcoholic and nonalcoholic IS patients. Nevertheless, patients who abused alcohol were less likely to receive IVT (16.6% vs 18.9%) and this difference remained after accounting for possible confounders. Rates of SICH after IVT were not increased in patients who abused alcohol (2.1% vs 3.7%, p = 0.04). Multivariate analysis including age, NIH Stroke Scale score, and time from symptom onset to IVT treatment showed that alcohol abuse was not an independent risk factor for SICH and was not protective (odds ratio 0.73, 95% confidence interval 0.43-1.25, p = 0.2).

Conclusions: IS patients with chronic alcohol consumption or acute intoxication have decreased likelihood of receiving IVT and are not at an increased risk of associated SICH. This supports current practice guidelines, which do not list chronic alcohol consumption or acute intoxication as an exclusion criterion.
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http://dx.doi.org/10.1212/WNL.0000000000002078DOI Listing
November 2015

Weather as physiologically equivalent was not associated with ischemic stroke onsets in Vienna, 2004-2010.

Environ Sci Pollut Res Int 2015 Jun 16;22(11):8756-62. Epub 2015 Apr 16.

Department of Neurology, St. John of God Hospital, Vienna, Austria.

Stroke rates were found to have seasonal variations. However, previous studies using air temperature, humidity, or air pressure separately were not adequate, and the study catchment was not clearly drawn. Therefore, here we proposed to use a thermal index called physiologically equivalent temperature (PET) that incorporates air temperature, humidity, wind speed, cloud cover, air pressure and radiation flux from a biometeorological approach to estimate the effect of weather as physiologically equivalent on ischemic stroke onsets in an Austrian population. Eight thousand four hundred eleven stroke events in Vienna registered within the Austrian Stroke Unit Register from January 1, 2004 to December 31, 2010 were included and were correlated with the weather data, obtained from the Central Institute for Meteorology and Geodynamics in the same area and study time period and calculated as PET (°C). Statistical analysis involved Poisson regression modeling. The median age was 74 years, and men made up 49 % of the entire population. Eighty percent had hypertension while 25.4 % were current smokers. Of note, 26.5 % had diabetes mellitus, 28.9 % had pre-stroke, and 11.5 % had pre-myocardial infarction. We have observed that onsets were higher on the weekdays than on the weekend. However, we did not find any significant association between PETs and ischemic stroke onsets by subtypes in Vienna. We did not observe any significant associations between PETs and ischemic stroke onsets by subtypes in Vienna. Hospital admission peaks on the weekdays might be due to hospital administration reasons.
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http://dx.doi.org/10.1007/s11356-015-4494-7DOI Listing
June 2015

[Consensus statement: Stroke prevention in nonvalvular atrial fibrillation in special consideration of the new direct oral anticoagulants].

Wien Klin Wochenschr 2014 Dec 3;126(23-24):792-808. Epub 2014 Oct 3.

Klin. Abt. für Hämatologie u. Hämostaseologie, Univ.-Klin. f. Innere Medizin I, MedUni Wien, Währinger Gürtel 18-20, 1090, Wien, Österreich,

The introduction of new direct oral anticoagulants has changed the treatment of nonvalvular atrial fibrillation. However, these changes are not yet fully reflected in current guidelines.This consensus statement, endorsed by six Austrian medical societies, provides guidance to current prophylactic approaches of thromboembolic events in nonvalvular atrial fibrillation on the basis of current evidence and published guidelines. Furthermore, some special subjects are treated, like changes in laboratory parameters and their interpretation under treatment with direct oral anticoagulants, treatment of bleedings, approach to operations, cardioversion and ablation, and specific neurological aspects. For a CHA2DS2-VASc-Score of ≥ 2, anticoagulation is recommended with a high level of evidence (1A). At the end of the consensus statement, recommendations for a number of specific patient subgroups can be found, in order to help treating physicians to arrive at appropriate therapeutic decisions.
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http://dx.doi.org/10.1007/s00508-014-0586-5DOI Listing
December 2014

Sex-related differences of acute stroke unit care: results from the Austrian stroke unit registry.

Stroke 2014 Jun 15;45(6):1632-8. Epub 2014 Apr 15.

From the Department of Neurology (T.G., S.H., K.N., V.C., M.B., C.E., F.F.) and Division of Neuroradiology, Department of Radiology (C.E.), Medical University of Graz, Graz, Austria; Department of Neurology, Hospital Barmherzige Brueder, Vienna, Austria (J.F., W.L.); Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria (M.K.); and Center of Clinical Neurosciences, Danube University of Krems, Krems, Austria (L.S.).

Background And Purpose: Sex-related differences in quality of acute stroke care are an important concern with limited data available, specifically regarding stroke unit (SU) setting. We used the prospective nationwide Austrian SU registry to address this issue.

Methods: Our analysis covered an 8-year time period (January 2005 to December 2012) during which all patients with transient ischemic attack or ischemic stroke admitted to 1 of 35 Austrian SU had been captured in the registry. These data were analyzed for age-adjusted preclinical and clinical characteristics and quality of acute stroke care in men and women. In addition, we assessed the outcome at 3 months in multivariate analysis.

Results: A total of 47 209 individuals (47% women) had received SU care. Women were significantly older (median age: 77.9 versus 70.3 years), had higher pre-existing disability and more severe strokes. Correcting for age, no significant sex-related differences in quality of care were identified with comparable onset-to-door times, times to and rates of neuroimaging, as well as door-to-needle times and rates of intravenous thrombolysis (14.5% for both sexes). Despite equal acute stroke care and a comparable rate of neurorehabilitation, women had a worse functional outcome at 3-month follow-up (modified Rankin scale 3-5: odds ratio, 1.26; 95% confidence interval [1.17-1.36]), but a lower mortality (odds ratio, 0.70; 95% confidence interval [0.78-0.88]) after correcting for confounders.

Conclusions: We identified no disproportions in quality of care in the acute SU setting between men and women, but the outcome was significantly different. Further studies on the poststroke period including socioeconomic aspects are needed to clarify this finding.
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http://dx.doi.org/10.1161/STROKEAHA.114.004897DOI Listing
June 2014

Thrombolysis in patients with mild stroke: results from the Austrian Stroke Unit Registry.

Stroke 2014 Mar 30;45(3):765-9. Epub 2014 Jan 30.

From the Department of Neurology, Medical University of Vienna, Vienna, Austria (S.G.); Danube University Krems and Gesundheit Österreich GmbH/BIQG, Vienna, Austria (L.S.); Department of Neurology, Innsbruck Medical University, Innsbruck, Austria (S.K.); and Department of Neurology, Krankenhaus Barmherzige Brüder, Vienna, Austria (W.L., J.F.).

Background And Purpose: Apart from missing the approved time window of 4.5 hours, one frequent cause for withholding recombinant tissue plasminogen activator (rt-PA) treatment in patients with ischemic stroke is presentation with mild deficit on admission. We analyzed in a large cohort of patients whether rt-PA treatment is beneficial for this group of patients.

Methods: From a total of 54 917 patients with ischemic stroke prospectively enrolled in the Austrian Stroke Unit Registry, 890 patients with mild deficit defined as ≤5 points in the National Institutes of Health Stroke Scale treated with and without rt-PA were matched for age, sex, prestroke disability, stroke severity, hypertension, diabetes mellitus, hypercholesterolemia, stroke cause, and clinical stroke syndrome. Functional outcome was assessed using the modified Rankin Scale at 3 months. For data visualization, weighted averages of outcome differences were computed for all age severity combinations and mapped to a color. For quantification of effect sizes, numbers need to treat were calculated.

Results: rt-PA-treated patients with mild deficit had a better outcome after 3 months compared with matched cases without rt-PA treatment (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.17-1.89; P<0.001). In rt-PA-treated patients with mild deficit, the numbers need to treat ranged from 8 to 14. Improvement achieved by rt-PA treatment was observed along the entire age range.

Conclusions: In our study, intravenous rt-PA treatment was beneficial for patients with mild deficit. Given the observational nature of these results, our data might serve as an incentive for future randomized controlled trials to provide a basis for optimal patient selection.
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http://dx.doi.org/10.1161/STROKEAHA.113.003827DOI Listing
March 2014