Early Versus Late Initiation of Direct Oral Anticoagulants After Ischemic Stroke in People With Atrial Fibrillation and Hemorrhagic Transformation: Prespecified Subanalysis of the Randomized Controlled ELAN Trial.

BACKGROUND: Whether hemorrhagic transformation (HT) modifies the treatment effect of early compared with late initiation of direct oral anticoagulation in people with ischemic stroke and atrial fibrillation is unknown. METHODS: This is a post hoc analysis of the ELAN trial (Early Versus Late Initiation of Direct Oral Anticoagulants in Post-Ischaemic Stroke Patients With Atrial Fibrillation). The primary outcome was a composite of recurrent ischemic stroke, symptomatic intracranial hemorrhage, major extracranial bleeding, systemic embolism, or vascular death within 30 days. Secondary outcomes were the individual components, 30- and 90-day functional outcome. We estimated outcomes based on HT, subclassified as hemorrhagic infarction (HI) or parenchymal hemorrhage (PH) on prerandomization imaging (core laboratory rating) using adjusted risk differences between treatment arms. RESULTS: Overall, 247 of 1970 participants (12.5%) had HT (114 HI 1, 77 HI 2, 34 PH 1, 22 PH 2). For the primary outcome, the estimated adjusted risk difference (early versus late) was -2.2% (95% CI, -7.8% to 3.5%) in people with HT (HI: -4.7% [95% CI, -10.8% to 1.4%]; PH: 6.1% [95% CI, -8.5% to 20.6%]) and -0.9% (95% CI, -2.6% to 0.8%) in people without HT. Numbers of symptomatic intracranial hemorrhage were identical in people with and without HT. With early treatment, the estimated adjusted risk difference for poor 90-day functional outcome (modified Rankin Scale score, 3-6) was 11.5% (95% CI, -0.8% to 23.8%) in participants with HT (HI: 7.4% [95% CI, -6.4% to 21.2%]; PH: 25.1% [95% CI, 0.2% to 50.0%]) and -2.6% (95% CI, -7.1% to 1.8%) in people without HT. CONCLUSIONS: We found no evidence of major treatment effect heterogeneity or safety concerns with early compared with late direct oral anticoagulation initiation in people with and without HT. However, early direct oral anticoagulation initiation may worsen functional outcomes in people with PH. REGISTRATION: URL: http://www.clinicaltrials.gov; Unique identifier: NCT03148457.

Increased Risk of Recurrent Stroke in Symptomatic Large Vessel Disease With Impaired BOLD Cerebrovascular Reactivity.

BACKGROUND: Impaired cerebrovascular reactivity (CVR) has been correlated with recurrent ischemic stroke. However, for clinical purposes, most CVR techniques are rather complex, time-consuming, and lack validation for quantitative measurements. The recent adaptation of a standardized hypercapnic stimulus in combination with a blood-oxygenation-level-dependent (BOLD) magnetic resonance imaging signal as a surrogate for cerebral blood flow offers a potential universally comparable CVR assessment. We investigated the association between impaired BOLD-CVR and risk for recurrent ischemic events. METHODS: We conducted a retrospective analysis of patients with symptomatic cerebrovascular large vessel disease who had undergone a prospective hypercapnic-challenged BOLD-CVR protocol at a single tertiary stroke referral center between June 2014 and April 2020. These patients were followed up for recurrent acute ischemic events for up to 3 years. BOLD-CVR (%BOLD signal change per mm Hg CO2) was calculated on a voxel-by-voxel basis. Impaired BOLD-CVR of the affected (ipsilateral to the vascular pathology) hemisphere was defined as an average BOLD-CVR, falling 2 SD below the mean BOLD-CVR of the right hemisphere in a healthy age-matched reference cohort (n=20). Using a multivariate Cox proportional hazards model, the association between impaired BOLD-CVR and ischemic stroke recurrence was assessed and Kaplan-Meier survival curves to visualize the acute ischemic stroke event rate. RESULTS: Of 130 eligible patients, 28 experienced recurrent strokes (median, 85 days, interquartile range, 5-166 days). Risk factors associated with an increased recurrent stroke rate included impaired BOLD-CVR, a history of atrial fibrillation, and heart insufficiency. After adjusting for sex, age group, and atrial fibrillation, impaired BOLD-CVR exhibited a hazard ratio of 10.73 (95% CI, 4.14-27.81; P<0.001) for recurrent ischemic stroke. CONCLUSIONS: Among patients with symptomatic cerebrovascular large vessel disease, those exhibiting impaired BOLD-CVR in the affected hemisphere had a 10.7-fold higher risk of recurrent ischemic stroke events compared with individuals with nonimpaired BOLD-CVR.

Implications for driving based on the risk of seizures after ischaemic stroke.

BACKGROUND: In addition to other stroke-related deficits, the risk of seizures may impact driving ability after stroke. METHODS: We analysed data from a multicentre international cohort, including 4452 adults with acute ischaemic stroke and no prior seizures. We calculated the Chance of Occurrence of Seizure in the next Year (COSY) according to the SeLECT2.0 prognostic model. We considered COSY<20% safe for private and <2% for professional driving, aligning with commonly used cut-offs. RESULTS: Seizure risks in the next year were mainly influenced by the baseline risk-stratified according to the SeLECT2.0 score and, to a lesser extent, by the poststroke seizure-free interval (SFI). Those without acute symptomatic seizures (SeLECT2.0 0-6 points) had low COSY (0.7%-11%) immediately after stroke, not requiring an SFI. In stroke survivors with acute symptomatic seizures (SeLECT2.0 3-13 points), COSY after a 3-month SFI ranged from 2% to 92%, showing substantial interindividual variability. Stroke survivors with acute symptomatic status epilepticus (SeLECT2.0 7-13 points) had the highest risk (14%-92%). CONCLUSIONS: Personalised prognostic models, such as SeLECT2.0, may offer better guidance for poststroke driving decisions than generic SFIs. Our findings provide practical tools, including a smartphone-based or web-based application, to assess seizure risks and determine appropriate SFIs for safe driving.

Skeletal Muscle Disorders: A Noncardiac Source of Cardiac Troponin T.

BACKGROUND: Cardiac troponin (cTn) T and cTnI are considered cardiac specific and equivalent in the diagnosis of acute myocardial infarction. Previous studies suggested rare skeletal myopathies as a noncardiac source of cTnT. We aimed to confirm the reliability/cardiac specificity of cTnT in patients with various skeletal muscle disorders (SMDs). METHODS: We prospectively enrolled patients presenting with muscular complaints (≥2 weeks) for elective evaluation in 4 hospitals in 2 countries. After a cardiac workup, patients were adjudicated into 3 predefined cardiac disease categories. Concentrations of cTnT/I and resulting cTnT/I mismatches were assessed with high-sensitivity (hs-) cTnT (hs-cTnT-Elecsys) and 3 hs-cTnI assays (hs-cTnI-Architect, hs-cTnI-Access, hs-cTnI-Vista) and compared with those of control subjects without SMD presenting with adjudicated noncardiac chest pain to the emergency department (n=3508; mean age, 55 years; 37% female). In patients with available skeletal muscle biopsies, TNNT/I1-3 mRNA differential gene expression was compared with biopsies obtained in control subjects without SMD. RESULTS: Among 211 patients (mean age, 57 years; 42% female), 108 (51%) were adjudicated to having no cardiac disease, 44 (21%) to having mild disease, and 59 (28%) to having severe cardiac disease. hs-cTnT/I concentrations significantly increased from patients with no to those with mild and severe cardiac disease for all assays (all P<0.001). hs-cTnT-Elecsys concentrations were significantly higher in patients with SMD versus control subjects (median, 16 ng/L [interquartile range (IQR), 7-32.5 ng/L] versus 5 ng/L [IQR, 3-9 ng/L]; P<0.001), whereas hs-cTnI concentrations were mostly similar (hs-cTnI-Architect, 2.5 ng/L [IQR, 1.2-6.2 ng/L] versus 2.9 ng/L [IQR, 1.8-5.0 ng/L]; hs-cTnI-Access, 3.3 ng/L [IQR, 2.4-6.1 ng/L] versus 2.7 ng/L [IQR, 1.6-5.0 ng/L]; and hs-cTnI-Vista, 7.4 ng/L [IQR, 5.2-13.4 ng/L] versus 7.5 ng/L [IQR, 6-10 ng/L]). hs-cTnT-Elecsys concentrations were above the upper limit of normal in 55% of patients with SMD versus 13% of control subjects (P<0.01). mRNA analyses in skeletal muscle biopsies (n=33), mostly (n=24) from individuals with noninflammatory myopathy and myositis, showed 8-fold upregulation of TNNT2, encoding cTnT (but none for TNNI3, encoding cTnI) versus control subjects (n=16, PWald<0.001); the expression correlated with pathological disease activity (R=0.59, Pt-statistic<0.001) and circulating hs-cTnT concentrations (R=0.26, Pt-statistic=0.031). CONCLUSIONS: In patients with active chronic SMD, elevations in cTnT concentrations are common and not attributable to cardiac disease in the majority. This was not observed for cTnI and may be explained in part by re-expression of cTnT in skeletal muscle. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03660969.

Mechanical Thrombectomy Versus Best Medical Treatment in the Late Time Window in Non-DEFUSE-Non-DAWN Patients: A Multicenter Cohort Study.

BACKGROUND: We assessed the efficacy and safety of mechanical thrombectomy (MT) in adult stroke patients with anterior circulation large vessel occlusion presenting in the late time window not fulfilling the DEFUSE-3 (Thrombectomy for Stroke at 6 to 16 Hours With Selection by Perfusion Imaging trial) and DAWN (Thrombectomy 6 to 24 Hours After Stroke With a Mismatch Between Deficit and Infarct trial) inclusion criteria. METHODS: Cohort study of adults with anterior circulation large vessel occlusion admitted between 6 and 24 hours after last-seen-well at 5 participating Swiss stroke centers between 2014 and 2021. Mismatch was assessed by computer tomography or magnetic resonance imaging perfusion with automated software (RAPID or OLEA). We excluded patients meeting DEFUSE-3 and DAWN inclusion criteria and compared those who underwent MT with those receiving best medical treatment alone by inverse probability of treatment weighting using the propensity score. The primary efficacy end point was a favorable functional outcome at 90 days, defined as a modified Rankin Scale score shift toward lower categories. The primary safety end point was symptomatic intracranial hemorrhage within 7 days of stroke onset; the secondary was all-cause mortality within 90 days. RESULTS: Among 278 patients with anterior circulation large vessel occlusion presenting in the late time window, 190 (68%) did not meet the DEFUSE-3 and DAWN inclusion criteria and thus were included in the analyses. Of those, 102 (54%) received MT. In the inverse probability of treatment weighting analysis, patients in the MT group had higher odds of favorable outcomes compared with the best medical treatment alone group (modified Rankin Scale shift: acOR, 1.46 [1.02-2.10]; P=0.04) and lower odds of all-cause mortality within 90 days (aOR, 0.59 [0.37-0.93]; P=0.02). There were no significant differences in symptomatic intracranial hemorrhage (MT versus best medical treatment alone: 5% versus 2%, P=0.63). CONCLUSIONS: Two out of 3 patients with anterior circulation large vessel occlusion presenting in the late time window did not meet the DEFUSE-3 and DAWN inclusion criteria. In these patients, MT was associated with higher odds of favorable functional outcomes without increased rates of symptomatic intracranial hemorrhage. These findings support the enrollment of patients into ongoing randomized trials on MT in the late window with more permissive inclusion criteria.

Preventing Recurrent Cardioembolic Stroke: Right Approach, Right Patient (PRECISE) Study Protocol.

Cardiac rhythm monitoring is performed to search for atrial fibrillation (AF) after ischaemic stroke or transient ischaemic attack (TIA). Prolonged cardiac rhythm monitoring increases AF detection but is challenging to implement in many healthcare settings and is not needed for all people after ischaemic stroke/TIA. We aimed to develop and validate a model that includes clinical, electrocardiogram (ECG), blood-based, and genetic biomarkers to identify people with a low probability of AF detection after ischaemic stroke or TIA. We will recruit 675 consenting participants who are aged over 18 years, who were admitted with ischaemic stroke or TIA in the 5 days prior, who are not known to have AF, and who would be suitable for anticoagulation if AF is found. We will collect baseline demographic and clinical data, a 12-lead ECG, and a venous blood sample for blood biomarkers (including midregional pro-atrial natriuretic peptide, MRproANP) and genetic data. We will perform up to 28 days of cardiac rhythm monitoring using an R-test or patch device to search for AF in all participants. The sample size of 675 participants is based on true sensitivity of 92.5%, null hypothesis sensitivity of 80%, 80% power, and 5% significance. The primary outcome is AF detection ≥30 s duration during 28 days of cardiac rhythm monitoring. Secondary outcomes are AF detection at 1-year, recurrent cardiovascular events, and mortality and will be identified by electronic linkage and telephone follow-up. The results will guide the development of a more personalized care pathway to search for AF after ischaemic stroke or TIA. This could help to reduce cardiac rhythm monitoring for people with a low probability of AF detection and allow more intensive cardiac monitoring to be focused on people who are more likely to have AF and benefit. Participants will be consented for their data to be used in future research studies, providing a rich resource for stroke and cardiovascular research communities.

Precision medicine in secondary prevention of ischemic stroke: how may blood-based biomarkers help in clinical routine? An expert opinion.

PURPOSE OF REVIEW: One in eight patients unfortunately suffers a new stroke within 5 years of their first stroke, even today. Research in precision medicine could lead to a more individualized treatment allocation, possibly achieving lower recurrence rates of ischemic stroke. In this narrative review, we aim to discuss potential clinical implementation of several promising candidate blood biomarkers. RECENT FINDINGS: We discuss specifically some promising blood-based biomarkers, which may improve the identification of underlying causes as well as risk stratification of patients according to their specific cerebrovascular risk factor pattern. SUMMARY: Multimodal profiling of ischemic stroke patients by means of blood biomarkers, in addition to established clinical and neuroradiological data, may allow in the future a refinement of decision algorithms for treatment allocation in secondary ischemic stroke prevention.

Seizures after Ischemic Stroke: A Matched Multicenter Study.

OBJECTIVE: The purpose of this study was to identify risk factors for acute symptomatic seizures and post-stroke epilepsy after acute ischemic stroke and evaluate the effects of reperfusion treatment. METHODS: We assessed the risk factors for post-stroke seizures using logistic or Cox regression in a multicenter study, including adults from 8 European referral centers with neuroimaging-confirmed ischemic stroke. We compared the risk of post-stroke seizures between participants with or without reperfusion treatment following propensity score matching to reduce confounding due to treatment selection. RESULTS: In the overall cohort of 4,229 participants (mean age 71 years, 57% men), a higher risk of acute symptomatic seizures was observed in those with more severe strokes, infarcts located in the posterior cerebral artery territory, and strokes caused by large-artery atherosclerosis. Strokes caused by small-vessel occlusion carried a small risk of acute symptomatic seizures. 6% developed post-stroke epilepsy. Risk factors for post-stroke epilepsy were acute symptomatic seizures, more severe strokes, infarcts involving the cerebral cortex, and strokes caused by large-artery atherosclerosis. Electroencephalography findings within 7 days of stroke onset were not independently associated with the risk of post-stroke epilepsy. There was no association between reperfusion treatments in general or only intravenous thrombolysis or mechanical thrombectomy with the time to post-stroke epilepsy or the risk of acute symptomatic seizures. INTERPRETATION: Post-stroke seizures are related to stroke severity, etiology, and location, whereas an early electroencephalogram was not predictive of epilepsy. We did not find an association of reperfusion treatment with risks of acute symptomatic seizures or post-stroke epilepsy. ANN NEUROL 2021;90:808-820.

Prior Anticoagulation in Patients with Ischemic Stroke and Atrial Fibrillation.

OBJECTIVE: The aim was to evaluate, in patients with atrial fibrillation (AF) and acute ischemic stroke, the association of prior anticoagulation with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) with stroke severity, utilization of intravenous thrombolysis (IVT), safety of IVT, and 3-month outcomes. METHODS: This was a cohort study of consecutive patients (2014-2019) on anticoagulation versus those without (controls) with regard to stroke severity, rates of IVT/mechanical thrombectomy, symptomatic intracranial hemorrhage (sICH), and favorable outcome (modified Rankin Scale score 0-2) at 3 months. RESULTS: Of 8,179 patients (mean [SD] age, 79.8 [9.6] years; 49% women), 1,486 (18%) were on VKA treatment, 1,634 (20%) on DOAC treatment at stroke onset, and 5,059 controls. Stroke severity was lower in patients on DOACs (median National Institutes of Health Stroke Scale 4, [interquartile range 2-11]) compared with VKA (6, [2-14]) and controls (7, [3-15], p < 0.001; quantile regression: ß -2.1, 95% confidence interval [CI] -2.6 to -1.7). The IVT rate in potentially eligible patients was significantly lower in patients on VKA (156 of 247 [63%]; adjusted odds ratio [aOR] 0.67; 95% CI 0.50-0.90) and particularly in patients on DOACs (69 of 464 [15%]; aOR 0.06; 95% CI 0.05-0.08) compared with controls (1,544 of 2,504 [74%]). sICH after IVT occurred in 3.6% (2.6-4.7%) of controls, 9 of 195 (4.6%; 1.9-9.2%; aOR 0.93; 95% CI 0.46-1.90) patients on VKA and 2 of 65 (3.1%; 0.4-10.8%, aOR 0.56; 95% CI 0.28-1.12) of those on DOACs. After adjustments for prognostic confounders, DOAC pretreatment was associated with a favorable 3-month outcome (aOR 1.24; 1.01-1.51). INTERPRETATION: Prior DOAC therapy in patients with AF was associated with decreased admission stroke severity at onset and a remarkably low rate of IVT. Overall, patients on DOAC might have better functional outcome at 3 months. Further research is needed to overcome potential restrictions for IVT in patients taking DOACs. ANN NEUROL 2021;89:42-53.

Aetiology, secondary prevention strategies and outcomes of ischaemic stroke despite oral anticoagulant therapy in patients with atrial fibrillation.

OBJECTIVE: To investigate the aetiology, subsequent preventive strategies and outcomes of stroke despite anticoagulation in patients with atrial fibrillation (AF). METHODS: We analysed consecutive patients with AF with an index imaging-proven ischaemic stroke despite vitamin K-antagonist (VKA) or direct oral anticoagulant (DOAC) treatment across 11 stroke centres. We classified stroke aetiology as: (i) competing stroke mechanism other than AF-related cardioembolism; (ii) insufficient anticoagulation (non-adherence or low anticoagulant activity measured with drug-specific assays); or, (iii) AF-related cardioembolism despite sufficient anticoagulation. We investigated subsequent preventive strategies with regard to the primary (composite of recurrent ischaemic stroke, intracranial haemorrhage, death) and secondary endpoint (recurrent ischaemic stroke) within 3 months after index stroke. RESULTS: Among 2946 patients (median age 81 years; 48% women; 43% VKA, 57% DOAC), stroke aetiology was competing mechanism in 713 patients (24%), insufficient anticoagulation in 934 (32%) and cardioembolism despite sufficient anticoagulation in 1299 (44%). We found high rates of the primary (27% of patients; completeness 91.6%) and secondary endpoint (4.6%; completeness 88.5%). Only DOAC (vs VKA) treatment after index stroke showed lower odds for both endpoints (primary: adjusted OR (aOR) (95% CI) 0.49 (0.32 to 0.73); secondary: 0.44 (0.24 to 0.80)), but not switching between different DOAC types. Adding antiplatelets showed higher odds for both endpoints (primary: aOR (95% CI) 1.99 (1.25 to 3.15); secondary: 2.66 (1.40 to 5.04)). Only few patients (1%) received left atrial appendage occlusion as additional preventive strategy. CONCLUSIONS: Stroke despite anticoagulation comprises heterogeneous aetiologies and cardioembolism despite sufficient anticoagulation is most common. While DOAC were associated with better outcomes than VKA, adding antiplatelets was linked to worse outcomes in these high-risk patients. Our findings indicate that individualised and novel preventive strategies beyond the currently available anticoagulants are needed. TRIAL REGISTRATION NUMBER: ISRCTN48292829.

Blood Pressure Variability Indices for Outcome Prediction After Thrombectomy in Stroke by Using High-Resolution Data.

BACKGROUND: Blood pressure variability (BPV) is associated with outcome after endovascular thrombectomy in acute large vessel occlusion stroke. We aimed to provide the optimal sampling frequency and BPV index for outcome prediction by using high-resolution blood pressure (BP) data. METHODS: Patient characteristics, 3-month outcome, and BP values measured intraarterially at 1 Hz for up to 24 h were extracted from 34 patients treated at a tertiary care center neurocritical care unit. Outcome was dichotomized (modified Rankin Scale 0-2, favorable, and 3-6, unfavorable) and associated with systolic BPV (as calculated by using standard deviation, coefficient of variation, averaged real variability, successive variation, number of trend changes, and a spectral approach using the power of specific BP frequencies). BP values were downsampled by either averaging or omitting all BP values within each prespecified time bin to compare the different sampling rates. RESULTS: Out of 34 patients (age 72 ± 12.7 years, 67.6% men), 10 (29.4%) achieved a favorable functional outcome and 24 (70.6%) had an unfavorable functional outcome at 3 months. No group differences were found in mean absolute systolic BP (SBP) (130 ± 18 mm Hg, p = 0.82) and diastolic BP (DBP) (59 ± 10 mm Hg, p = 1.00) during the monitoring time. BPV only reached predictive significance when using successive variation extracted from downsampled (averaged over 5 min) SBP data (median 4.8 mm Hg [range 3.8-7.1]) in patients with favorable versus 7.1 mmHg [range 5.5-9.7] in those with unfavorable outcome, area under the curve = 0.74 [confidence interval (CI) 0.57-0.85; p = 0.031], or the power of midrange frequencies between 1/20 and 1/5 min [area under the curve = 0.75 (CI 0.59-0.86), p = 0.020]. CONCLUSIONS: Using high-resolution BP data of 1 Hz, downsampling by averaging all BP values within 5-min intervals is essential to find relevant differences in systolic BPV, as noise can be avoided (confirmed by the significance of the power of midrange frequencies). These results demonstrate how high-resolution BP data can be processed for effective outcome prediction.

Lipoprotein(a) is associated with large artery atherosclerosis stroke aetiology and stroke recurrence among patients below the age of 60 years: results from the BIOSIGNAL study.

AIMS: Lipoprotein(a) [Lp(a)] is a recognized causal risk factor for atherosclerotic cardiovascular disease but its role for acute ischaemic stroke (AIS) is controversial. In this study, we evaluated the association of Lp(a) with large artery atherosclerosis (LAA) stroke and risk of recurrent cerebrovascular events in AIS patients. METHODS AND RESULTS: For this analysis of the prospective, observational, multicentre BIOSIGNAL cohort study we measured Lp(a) levels in plasma samples of 1733 primarily Caucasian (98.6%) AIS patients, collected within 24 h after symptom onset. Primary outcomes were LAA stroke aetiology and recurrent cerebrovascular events (ischaemic stroke or transient ischaemic attack) within 1 year. We showed that Lp(a) levels are independently associated with LAA stroke aetiology [adjusted odds ratio 1.48, 95% confidence interval (CI) 1.14-1.90, per unit log10Lp(a) increase] and identified age as a potent effect modifier (Pinteraction =0.031) of this association. The adjusted odds ratio for LAA stroke in patients aged <60 years was 3.64 (95% CI 1.76-7.52) per unit log10Lp(a) increase and 4.04 (95% CI 1.73-9.43) using the established cut-off ≥100 nmol/l. For 152 recurrent cerebrovascular events, we did not find a significant association in the whole cohort. However, Lp(a) levels ≥100 nmol/l were associated with an increased risk for recurrent events among patients who were either <60 years [adjusted hazard ratio (HR) 2.40, 95% CI 1.05-5.47], had evident LAA stroke aetiology (adjusted HR 2.18, 95% CI 1.08-4.40), or had no known atrial fibrillation (adjusted HR 1.60, 95% CI 1.03-2.48). CONCLUSION: Elevated Lp(a) was independently associated with LAA stroke aetiology and risk of recurrent cerebrovascular events among primarily Caucasian individuals aged <60 years or with evident arteriosclerotic disease.

External Validation of Five Scores to Predict Stroke-Associated Pneumonia and the Role of Selected Blood Biomarkers.

BACKGROUND AND PURPOSE: Several clinical scoring systems as well as biomarkers have been proposed to predict stroke-associated pneumonia (SAP). We aimed to externally and competitively validate SAP scores and hypothesized that 5 selected biomarkers would improve performance of these scores. METHODS: We pooled the clinical data of 2 acute stroke studies with identical data assessment: STRAWINSKI and PREDICT. Biomarkers (ultrasensitive procalcitonin; mid-regional proadrenomedullin; mid-regional proatrionatriuretic peptide; ultrasensitive copeptin; C-terminal proendothelin) were measured from hospital admission serum samples. A literature search was performed to identify SAP prediction scores. We then calculated multivariate regression models with the individual scores and the biomarkers. Areas under receiver operating characteristic curves were used to compare discrimination of these scores and models. RESULTS: The combined cohort consisted of 683 cases, of which 573 had available backup samples to perform the biomarker analysis. Literature search identified 9 SAP prediction scores. Our data set enabled us to calculate 5 of these scores. The scores had area under receiver operating characteristic curve of 0.543 to 0.651 for physician determined SAP, 0.574 to 0.685 for probable and 0.689 to 0.811 for definite SAP according to Pneumonia in Stroke Consensus group criteria. Multivariate models of the scores with biomarkers improved virtually all predictions, but mostly in the range of an area under receiver operating characteristic curve delta of 0.05. CONCLUSIONS: All SAP prediction scores identified patients who would develop SAP with fair to strong capabilities, with better discrimination when stricter criteria for SAP diagnosis were applied. The selected biomarkers provided only limited added predictive value, currently not warranting addition of these markers to prediction models. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01264549 and NCT01079728.

[Secondary prevention of ischemic stroke: laboratory and imaging biomarkers]. / Sekundärprävention des Hirnschlags: Laborchemische und bildgebende Biomarker beim ischämischen Schlaganfall.

Secondary prevention of ischemic stroke: laboratory and imaging biomarkers Abstract. Identifying the cause of stroke is pivotal to prevent stroke recurrence. Large artery atherosclerosis, cardiac embolism, small vessel disease or other, rarer pathologies can induce ischemic stroke. Recently, laboratory and imaging biomarkers have been proposed to contribute to a better stratification of stroke etiology. This article summarizes current knowledge in the field of biomarkers in secondary prevention of stroke; and highlights the potential for future application in clinical stroke patient care.

Independent Prognostic Value of MRproANP (Midregional Proatrial Natriuretic Peptide) Levels in Patients With Stroke Is Unaltered Over Time.

Background and Purpose- MRproANP (midregional proatrial natriuretic peptide) is known to be independently associated with cardioembolic stroke cause and to improve risk stratification for 90-day mortality when measured within 24 to 72 hours after symptom onset in patients with acute ischemic stroke. However, the optimal time point for assessment remains unclear. This study aimed to evaluate prognostic utility of MRproANP at different time points during the first 5 days of hospitalization in patients with acute ischemic stroke. Methods- Samples of MRproANP were collected on admission (<72 hours after onset) and at multiple time points during the first 5 days of hospitalization in 348 consecutively enrolled patients with acute ischemic stroke. The prognostic value for 90-day mortality, 90-day functional outcome, and the association with cardioembolic stroke cause was assessed regarding the time of measurement, and change over time was modeled using generalized estimating equations. Results- MRproANP levels modestly decease over the initial 5 days but remain highly predictive for cardioembolic stroke cause (odds ratio, 9.75 [95% CI, 3.2-29]; 10.62 [95% CI, 3.4-33.3]; 10.8 [95% CI, 3.1-37.1]; 19.4 [95% CI, 5.49-68.7] on admission, day 1, 3 and 5) and 90-day mortality (odds ratio, 59.4 [95% CI, 7.4-480.7]; 78.3 [95% CI, 7.9-772.6]; 14.5 [95% CI, 1.4-145]; 19.81 [95% CI, 2.7-143.4] on admission, day 1, 3, and 5). Change over time does not significantly modify the prognostic value of MRproANP (P=0.65 and P=0.56 for the interaction term in the multivariate model). Conclusions- Independent prognostic value of MRproANP remains unaltered in the acute phase of stroke at least up to 5 days; repeated measurements do not improve the prognostic value.

SAA (Serum Amyloid A): A Novel Predictor of Stroke-Associated Infections.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate and independently validate SAA (serum amyloid A)-a recently discovered blood biomarker-to predict poststroke infections. METHODS: The derivation cohort (A) was composed of 283 acute ischemic stroke patients and the independent validation cohort (B), of 367 patients. The primary outcome measure was any stroke-associated infection, defined by the criteria of the US Centers for Disease Control and Prevention, occurring during hospitalization. To determine the association of SAA levels on admission with the development of infections, logistic regression models were calculated. The discriminatory ability of SAA was assessed, by calculating the area under the receiver operating characteristic curve. RESULTS: After adjusting for all predictors that were significantly associated with any infection in the univariate analysis, SAA remained an independent predictor in study A (adjusted odds ratio, 1.44 [95% CI, 1.16-1.79]; P=0.001) and in study B (adjusted odds ratio, 1.52 [1.05-2.22]; P=0.028). Adding SAA to the best regression model without the biomarker, the discriminatory accuracy improved from 0.76 (0.69-0.83) to 0.79 (0.72-0.86; P<0.001; likelihood ratio test) in study A. These results were externally validated in study B with an improvement in the area under the receiver operating characteristic curve, from 0.75 (0.70-0.81) to 0.76 (0.71-0.82; P<0.038). CONCLUSIONS: Among patients with ischemic stroke, blood SAA measured on admission is a novel independent predictor of infection after stroke. SAA improved the discrimination between patients who developed an infection compared with those who did not in both derivation and validation cohorts. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00390962.

Global Burden of Stroke.

Stroke is the second leading cause of death and a major cause of disability worldwide. Its incidence is increasing because the population ages. In addition, more young people are affected by stroke in low- and middle-income countries. Ischemic stroke is more frequent but hemorrhagic stroke is responsible for more deaths and disability-adjusted life-years lost. Incidence and mortality of stroke differ between countries, geographical regions, and ethnic groups. In high-income countries mainly, improvements in prevention, acute treatment, and neurorehabilitation have led to a substantial decrease in the burden of stroke over the past 30 years. This article reviews the epidemiological and clinical data concerning stroke incidence and burden around the globe.

Procalcitonin and Midregional Proatrial Natriuretic Peptide as Biomarkers of Subclinical Cerebrovascular Damage: The Northern Manhattan Study.

BACKGROUND AND PURPOSE: Chronic infections and cardiac dysfunction are risk factors for stroke. We hypothesized that blood biomarkers of infection (procalcitonin) and cardiac dysfunction (midregional proatrial natriuretic peptide [MR-proANP]), previously associated with small vessel stroke and cardioembolic stroke are also associated with subclinical cerebrovascular damage, including silent brain infarcts and white matter hyperintensity volume. METHODS: The NOMAS (Northern Manhattan Study) was designed to assess risk factors for incident vascular disease in a multiethnic cohort. A subsample underwent brain magnetic resonance imaging and had blood samples available for biomarker measurement (n=1178). We used logistic regression models to estimate the odds ratios and 95% confidence intervals (95% CIs) for the association of these biomarkers with silent brain infarcts after adjusting for demographic, behavioral, and medical risk factors. We used linear regression to assess associations with log-white matter hyperintensity volume. RESULTS: Mean age was 70±9 years; 60% were women, 66% Hispanic, 17% black, and 15% were white. After adjusting for risk factors, subjects with procalcitonin or MR-proANP in the top quartile, compared with the lowest quartile were more likely to have silent brain infarcts (adjusted odds ratio for procalcitonin, 2.2; 95% CI, 1.3-3.7 and for MR-proANP, 3.3; 95% CI, 1.7-6.3) and increased white matter hyperintensity volume (adjusted mean change in log-white matter hyperintensity volume for procalcitonin, 0.29; 95% CI, 0.13-0.44 and for MR-proANP, 0.18; 95% CI, 0.004-0.36). CONCLUSIONS: Higher concentrations of procalcitonin, a marker of infection, and MR-proANP, a marker of cardiac dysfunction, are independently associated with subclinical cerebrovascular damage. If further studies demonstrate an incremental value for risk stratification, biomarker-guided primary prevention studies may lead to new approaches to prevent cerebrovascular disease.

C-reactive protein in the detection of post-stroke infections: systematic review and individual participant data analysis.

We conducted a systematic review and individual participant data meta-analysis to explore the role of C-reactive protein (CRP) in early detection or prediction of post-stroke infections. CRP, an acute-phase reactant binds to the phosphocholine expressed on the surface of dead or dying cells and some bacteria, thereby activating complement and promoting phagocytosis by macrophages. We searched PubMed up to May-2015 for studies measuring CRP in stroke and evaluating post-stroke infections. Individual participants' data were merged into a single database. CRP levels were standardized and divided into quartiles. Factors independently associated with post-stroke infections were determined by logistic regression analysis and the additional predictive value of CRP was assessed by comparing areas under receiver operating characteristic curves and integrated discrimination improvement index. Data from seven studies including 699 patients were obtained. Standardized CRP levels were higher in patients with post-stroke infections beyond 24 h. Standardized CRP levels in the fourth quartile were independently associated with infection in two different logistic regression models, model 1 [stroke severity and dysphagia, odds ratio = 9.70 (3.10-30.41)] and model 2 [age, sex, and stroke severity, odds ratio = 3.21 (1.93-5.32)]. Addition of CRP improved discrimination in both models [integrated discrimination improvement = 9.83% (0.89-18.77) and 5.31% (2.83-7.79), respectively], but accuracy was only improved for model 1 (area under the curve 0.806-0.874, p = 0.036). In this study, CRP was independently associated with development of post-stroke infections, with the optimal time-window for measurement at 24-48 h. However, its additional predictive value is moderate over clinical information. Combination with other biomarkers in a panel seems a promising strategy for future studies.