Development of a Risk Prediction Nomogram for Carotid Restenosis in the One Year RECAST Registry.

OBJECTIVE: Long term benefit of carotid angioplasty and stenting (CAS) can be reduced by recurrent stroke related to in stent restenosis (ISR). An individualised predictive tool is needed to identify ISR events. A nomogram for individual risk assessment of ISR ≥ 70% after CAS is proposed. METHODS: A national observational, prospective, multicentre registry was conducted between January 2015 and December 2020. Cohorts of patients with symptomatic or asymptomatic severe carotid stenosis who underwent CAS were included with a follow up of at least 1 year after CAS. Duplex ultrasound was used to assess in stent restenosis. Pre-operative factors were compared between the non-ISR and ISR groups. Kaplan-Meier and Cox regression were used for variable selection. The nomogram was formulated and validated by concordance indices and calibration curves. An in stent restenosis risk table was generated for risk stratification. RESULTS: A total of 354 patients were included in the analysis. The ISR rate of ≥ 70% was 7.6% (n = 27). Peripheral arterial disease (hazard ratio [HR] 3.18, 95% confidence interval [CI] 1.23 - 8.24, p = .017), anterior communicating artery absence (HR 3.38, 95% CI 1.27 - 8.94, p = .016), diabetes mellitus (HR 3.34, 95% CI 1.21 - 9.26, p = .020), female sex (HR 2.99, 95% CI 1.04 - 8.60, p = .041), and pre-procedure pathologic ultrasound vasoreactivity (HR 3.87, 95% CI 1.43 -10.50, p = .008), as independent risk factors for ISR of ≥ 70%, were included in the nomogram. Concordance index at 12 and 24 months was 0.83. In low risk groups, ISR of ≥ 70% occurred in 4.8% of patients during follow up compared with 56.2% of patients in the high risk groups (p < .001). CONCLUSION: The nomogram and risk evaluation score have good predictive ability for ISR. They can be used as practical clinical tools for individualised risk assessment.

Predictive Factors for Stroke and TIA Following Carotid Artery Stenting.

PURPOSE: Carotid artery stenting (CAS) is an effective and minimally invasive method for the treatment of extracranial carotid artery stenosis. The aim of the present study was to explore independent risk factors to predict cerebrovascular events following CAS to identify high-risk patients and improve the safety of CAS in this population. MATERIALS AND METHODS: HISPANIAS is a national prospective multicenter study that included 14 hospitals that collected data from patients who underwent CAS. We analyzed morbidity and mortality within 30 days after CAS, looking for factors that might be associated with cerebrovascular events (stroke and transient ischemic attack [TIA]). RESULTS: The HISPANIAS cohort included 757 patients: 80.32% were men, the mean age was 70.73 years, and 82.96% underwent symptomatic CAS. Cerebrovascular complications occurred in 42 patients (5.6%), including TIA in 24 patients (70.8% ipsilateral; mean 2.79 days after CAS) and stroke in 18 patients (72.2% ipsilateral; mean 6.72 days after CAS). The main independent clinical predictors of stroke/TIA identified by logistic regression were female sex (odds ratio [OR] 2.29, 95% CI 1.15-4.54) and diabetes (OR 3.29, 95% CI 1.71-6.40). Survival analysis showed that diabetic women, compared with the rest of the patients, had a higher number of events concentrated mainly in the first days after the intervention (p=0.003). CONCLUSION: Cerebrovascular ischemic complications after CAS continue to be a challenge for the management of these patients. Although there are other factors, female sex and the presence of diabetes are emerging as strong risk factors for the development of complications after symptomatic CAS. CLINICAL IMPACT: Carotid artery stenting (CAS) is an effective and minimally invasive method for the treatment of extracranial carotid artery stenosis. Although CAS has been regarded as a reliable and safety approach, some studies reported that CAS was associated with a higher risk of procedure-related stroke. Cerebrovascular complications after CAS continue to be a main problem and a challenge for the management of these patients. Therefore, it is essential to identify the factors involved in the development of these complications. Our study shows that the combination of female sex and diabetes is associated with a clearly worse outcome, with a greater number of events concentrated mainly in the first days. This is different from other studies that have explored each factor separately. It would be interesting to perform separate interventions for this group given the increased risk of complications.

Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke.

During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke.

Intensive 90-day textile wearable Holter monitoring: an alternative to detect paroxysmal atrial fibrillation in selected patients with cryptogenic stroke.

We aimed to demonstrate the feasibility of 90-day cardiac monitoring with an external Holter device and to find a target population able to benefit from such a technique. Cryptogenic stroke patients were continuously monitored for 90 days with a textile wearable Holter (TWH). Compliance and quality of the monitoring were assessed by the number of hours of ECG stored per month. Mean predictors of pAF, including age, gender, stroke severity, and atrial size (LAVI), were evaluated. One-year follow-up assessed pAF detection outside per protocol monitoring. Out of 224 patients included in 5 stroke centers, 163 patients (72.76%) fulfilled the criteria for the protocol. Median monitoring time was similar among the three months. Per protocol pAF detection reached 35.37% at 90 days. The age (OR 1.095; 95% CI 1.03-1.14) and the LAVI (OR 1.055; 95% CI 1.01-1.09) independently predicted pAF. The cut-off point of 70 years (AUC 0.68) (95% CI 0.60-0.76) predicted pAF with a sensitivity of 75.8% and specificity of 50.5%. The LAVI cut-off point of 28.5 (AUC 0.67) (95% CI 0.56-0.77) had a sensitivity of 63.6% and a specificity of 61.8% to detect pAF. The combination of both markers enhanced the validity of pAF detection sensitivity to 89.6%, with a specificity of 27.59%. These patients had increased risk of pAF during the 90-day monitoring HR 3.23 (χ2 7.15) and beyond 90 days (χ2 5.37). Intensive 90-days TWH monitoring detected a high percentage of pAF. However, a significant number of patients did not complete the monitoring. Patients older than 70 years and with enlarged left atria benefitted more from the protocol.

Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma.

Haemorrhagic transformation is a complication of recombinant tissue-plasminogen activator treatment. The most severe form, parenchymal haematoma, can result in neurological deterioration, disability, and death. Our objective was to identify single nucleotide variations associated with a risk of parenchymal haematoma following thrombolytic therapy in patients with acute ischaemic stroke. A fixed-effect genome-wide meta-analysis was performed combining two-stage genome-wide association studies (n = 1904). The discovery stage (three cohorts) comprised 1324 ischaemic stroke individuals, 5.4% of whom had a parenchymal haematoma. Genetic variants yielding a P-value < 0.05 1 × 10-5 were analysed in the validation stage (six cohorts), formed by 580 ischaemic stroke patients with 12.1% haemorrhagic events. All participants received recombinant tissue-plasminogen activator; cases were parenchymal haematoma type 1 or 2 as defined by the European Cooperative Acute Stroke Study (ECASS) criteria. Genome-wide significant findings (P < 5 × 10-8) were characterized by in silico functional annotation, gene expression, and DNA regulatory elements. We analysed 7 989 272 single nucleotide polymorphisms and identified a genome-wide association locus on chromosome 20 in the discovery cohort; functional annotation indicated that the ZBTB46 gene was driving the association for chromosome 20. The top single nucleotide polymorphism was rs76484331 in the ZBTB46 gene [P = 2.49 × 10-8; odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82-26.55]. In the replication cohort (n = 580), the rs76484331 polymorphism was associated with parenchymal haematoma (P = 0.01), and the overall association after meta-analysis increased (P = 1.61 × 10-8; OR: 5.84; 95% CI: 3.16-10.76). ZBTB46 codes the zinc finger and BTB domain-containing protein 46 that acts as a transcription factor. In silico studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conclusion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal haematoma following recombinant tissue-plasminogen activator treatment.

Association of blood-based biomarkers with radiologic markers and cognitive decline in atrial fibrillation patients.

BACKGROUND: Atrial fibrillation (AF) has been associated with an increased risk of silent brain infarcts (SBI) and cognitive impairment, even in patients with low embolic risk. We aimed to test the association between 11 blood-biomarkers representing different AF-related pathways, and SBI, white matter hyperintensities (WMH), and cognitive decline in patients with AF and low embolic risk. METHODS: The present study followed a cross-sectional design. 70 patients with a history of AF and CHADS2 score ≤1, and 10 controls with neither AF nor SBI were included. All patients underwent a 3T brain MRI. Cortical and large subcortical ischemic lesions were considered presumed embolic origin lesions. White matter hyperintensities (WMH) were measured according to the Fazekas scale. A subset of patients underwent cognitive evaluation with the MoCA test. Circulating proteins were measured under blind conditions in a laboratory at Roche Diagnostics, Germany. RESULTS: 45 patients presented SBI in the MRI, and 25 did not. Ang-2, FGF-23, and BMP-10 were increased in patients with SBI. Ang-2 was elevated only in patients with embolic infarcts, whereas FGF-23 and BMP-10 tended to be elevated in patients with both types of infarcts. Ang-2 (OR = 1.56 [0.94-2.59], p = 0.087), and BMP-10 (OR = 4.83 [0.99-23.60], p = 0.052) were the biomarkers that showed the highest association with SBI when entered in a multivariable logistic regression model corrected by age. No biomarker was found associated with WMH or mild cognitive impairment. CONCLUSIONS: BMP-10, and Ang-2 were increased in patients with SBI. Its usefulness to detect SBI in AF patients should be further explored.

Early Neurological Change After Ischemic Stroke Is Associated With 90-Day Outcome.

BACKGROUND AND PURPOSE: Large-scale observational studies of acute ischemic stroke (AIS) promise to reveal mechanisms underlying cerebral ischemia. However, meaningful quantitative phenotypes attainable in large patient populations are needed. We characterize a dynamic metric of AIS instability, defined by change in National Institutes of Health Stroke Scale score (NIHSS) from baseline to 24 hours baseline to 24 hours (NIHSSbaseline - NIHSS24hours = ΔNIHSS6-24h), to examine its relevance to AIS mechanisms and long-term outcomes. METHODS: Patients with NIHSS prospectively recorded within 6 hours after onset and then 24 hours later were enrolled in the GENISIS study (Genetics of Early Neurological Instability After Ischemic Stroke). Stepwise linear regression determined variables that independently influenced ΔNIHSS6-24h. In a subcohort of tPA (alteplase)-treated patients with large vessel occlusion, the influence of early sustained recanalization and hemorrhagic transformation on ΔNIHSS6-24h was examined. Finally, the association of ΔNIHSS6-24h with 90-day favorable outcomes (modified Rankin Scale score 0-2) was assessed. Independent analysis was performed using data from the 2 NINDS-tPA stroke trials (National Institute of Neurological Disorders and Stroke rt-PA). RESULTS: For 2555 patients with AIS, median baseline NIHSS was 9 (interquartile range, 4-16), and median ΔNIHSS6-24h was 2 (interquartile range, 0-5). In a multivariable model, baseline NIHSS, tPA-treatment, age, glucose, site, and systolic blood pressure independently predicted ΔNIHSS6-24h (R2=0.15). In the large vessel occlusion subcohort, early sustained recanalization and hemorrhagic transformation increased the explained variance (R2=0.27), but much of the variance remained unexplained. ΔNIHSS6-24h had a significant and independent association with 90-day favorable outcome. For the subjects in the 2 NINDS-tPA trials, ΔNIHSS3-24h was similarly associated with 90-day outcomes. CONCLUSIONS: The dynamic phenotype, ΔNIHSS6-24h, captures both explained and unexplained mechanisms involved in AIS and is significantly and independently associated with long-term outcomes. Thus, ΔNIHSS6-24h promises to be an easily obtainable and meaningful quantitative phenotype for large-scale genomic studies of AIS.

Break in the Stroke Chain of Survival due to COVID-19.

BACKGROUND AND PURPOSE: Emergency measures to treat patients with coronavirus disease 2019 (COVID-19) and contain the outbreak is the main priority in each of our hospitals; however, these measures are likely to result in collateral damage among patients with other acute diseases. Here, we investigate whether the COVID-19 pandemic affects acute stroke care through interruptions in the stroke chain of survival. METHODS: A descriptive analysis of acute stroke care activity before and after the COVID-19 outbreak is given for a stroke network in southern Europe. To quantify the impact of the pandemic, the number of stroke code activations, ambulance transfers, consultations through telestroke, stroke unit admissions, and reperfusion therapy times and rates are described in temporal relationship with the rising number of COVID-19 cases in the region. RESULTS: Following confinement of the population, our stroke unit activity decreased sharply, with a 25% reduction in admitted cases (mean number of 58 cases every 15 days in previous months to 44 cases in the 15 days after the outbreak, P<0.001). Consultations to the telestroke network declined from 25 every 15 days before the outbreak to 7 after the outbreak (P<0.001). The increasing trend in the prehospital diagnosis of stroke activated by 911 calls stopped abruptly in the region, regressing to 2019 levels. The mean number of stroke codes dispatched to hospitals decreased (78% versus 57%, P<0.001). Time of arrival from symptoms onset to stroke units was delayed >30 minutes, reperfusion therapy cases fell, and door-to-needle time started 16 minutes later than usual. CONCLUSIONS: The COVID-19 pandemic is disruptive for acute stroke pathways. Bottlenecks in the access and delivery of patients to our secured stroke centers are among the main challenges. It is critical to encourage patients to continue seeking emergency care if experiencing acute stroke symptoms and to ensure that emergency professionals continue to use stroke code activation and telestroke networks.

Intravenous Thrombolysis Guided by Perfusion CT with Alteplase in >4.5 Hours from Stroke Onset.

INTRODUCTION: The benefit of intravenous thrombolysis (IVT) in wake-up stroke (WUS), stroke of unknown time of onset (SUKO), or when time exceeds 4.5 h from last-seen-normal (LSN) guided by CT perfusion (CTP) or MRI has been recently suggested. However, there is limited information of IVT in those patients in real-world studies. OBJECTIVE: Our aim was to evaluate safety and efficacy of IVT selected by CTP in patients with WUS, SUKO, or stroke of time onset beyond 4.5 h. MATERIAL AND METHODS: We studied a prospective cohort of patients who underwent IVT from January 2010 to December 2017. Two groups were defined: standard of care group (SC) included patients with time onset <4.5 h and CTP group included patients with WUS, SUKO, or onset beyond >4.5 h from LSN with penumbra area in CTP. We evaluated baseline characteristics, functional outcomes according to modified Rankin Scale (mRS) at discharge and at 90 days, and intracranial hemorrhages rates. RESULTS: 657 patients were studied: 604 (92%) were treated in the SC group and 53 (8%) in the CTP group. The mean NIHSS score was 9.8 in the CTP group versus 13 in the SC group (p = 0.001). Seventeen patients in the CTP group (32.1%) received bridging therapy with mechanical thrombectomy (MT). Last time seen well-to-needle time was 538 versus 155 min (p < 0.001). The incidence of symptomatic intracranial hemorrhage was equal in both groups (3.8 vs. 3.8%, p = 1). Good functional outcome (mRS < 2) was achieved in both groups (72 vs. 60.4%, p = 0.107). CONCLUSIONS: IVT in patients with WUS, SUKO, or stroke beyond >4.5 h from LSN, with salvageable brain tissue on CTP, seems to be safe and has similar functional outcomes at 90 days to the standard therapeutic window, even when combined with MT.

Safety of Early Carotid Artery Stenting for Symptomatic Stenosis in Daily Practice.

OBJECTIVE/BACKGROUND: In 2006, the American Heart Association recommended that for preference carotid endarterectomy (CEA) or, alternatively, carotid angioplasty and stenting (CAS) for symptomatic carotid artery stenosis should ideally occur within 14 days of an ischaemic event. The aim was to determine the safety of CAS according to those recommendations in daily practice. METHODS: A retrospective analysis was performed of all consecutive patients (2000-16), with ipsilateral carotid symptoms who underwent CAS for extracranial carotid stenosis ≥70%, who were previously included in a prospective database. Thirty day morbidity was assessed (any stroke without transient ischaemic attack [TIA]/amaurosis fugax), along with mortality of the procedure in the early (≤14 days after stroke onset) and delayed phases (15-180 days after stroke onset). Patients who received CAS and/or mechanical thrombectomy for acute ischaemic stroke treatment were not included. RESULTS: In total, 1227 patients with symptomatic carotid stenosis who underwent CAS were identified. Early and delayed CAS was performed in 291 and 936 patients, respectively. Morbidity (any stroke) and mortality was 2.2% (n = 27) in the whole cohort (n = 8 [2.7%] in early vs. n = 19 [2%] in delayed CAS; p = .47). There were no differences in morbidity between early and delayed CAS regarding TIA (n = 15 vs. 36 [5.2% vs. 3.9%]; p = .33), minor stroke (n = 4 vs. 5 [1.4% vs. 0.5%]; p = .14), or major stroke (n = 2 vs. 6 [0.7% vs. 0.6%]; p = .59). Two patients (0.7%) died after early CAS and eight (0.9%) after delayed CAS (p = .56). CONCLUSION: CAS may be safely performed in the early phase after an ischaemic stroke with low clinical complication rates. Further studies are needed to validate CAS safety conducted even earlier in the acute phase of ischaemic stroke.

External Validation of the ISAN, A2DS2, and AIS-APS Scores for Predicting Stroke-Associated Pneumonia.

BACKGROUND: The Prestroke Independence, Sex, Age, National Institutes of Health Stroke Scale (ISAN), Age, Atrial Fibrillation, Dysphagia, male sex, and National Institutes of Health Stroke Scale (A2DS2), and acute ischemic stroke-associated pneumonia score (AIS-APS) scores were created to predict stroke-associated pneumonia (SAP), one of the most important medical stroke complications. External validation of all such scores in an acute stroke population was the aim of our study. METHODS: Patients with ischemic or hemorrhagic stroke were prospectively enrolled in the multicenter Stroke-Induced Pneumonia in Andalucía project between October 2014 and May 2016. Receiver operating characteristic curves and linear regression analyses were used to determine discrimination ability of the scores. The Hosmer-Lemeshow goodness-of-fit test and the plot of observed versus predicted SAP risk were used to assess model calibration. RESULTS: Among 201 included patients, SAP rate was 15.5% (31). Higher ISAN, A2DS2, and AIS-APS scores were related to SAP (all P < .001). The C statistic was .83 (95% confidence interval [CI], .76-.91) for the ISAN score, .80 (95% CI, .70-.89) for the A2DS2 score, and .82 (95% CI, .74-.90) for the AIS-APS score, suggesting good discrimination. The ISAN and AIS-APS scores showed good calibration (Cox and Snell R2 = .206 and .174, respectively). The A2DS2 score showed the highest sensitivity (87%), and the AIS-APS score showed the highest specificity (92.8%). CONCLUSIONS: In our cohort, the external validation of ISAN, A2DS2, and AIS-APS scores have demonstrated their accurate prediction of SAP and the ability of these scores as screening tools to better manage SAP. The AIS-APS score would be recommendable for the development of future clinical trials.

GRECOS Project (Genotyping Recurrence Risk of Stroke): The Use of Genetics to Predict the Vascular Recurrence After Stroke.

BACKGROUND AND PURPOSE: Vascular recurrence occurs in 11% of patients during the first year after ischemic stroke (IS) or transient ischemic attack. Clinical scores do not predict the whole vascular recurrence risk; therefore, we aimed to find genetic variants associated with recurrence that might improve the clinical predictive models in IS. METHODS: We analyzed 256 polymorphisms from 115 candidate genes in 3 patient cohorts comprising 4482 IS or transient ischemic attack patients. The discovery cohort was prospectively recruited and included 1494 patients, 6.2% of them developed a new IS during the first year of follow-up. Replication analysis was performed in 2988 patients using SNPlex or HumanOmni1-Quad technology. We generated a predictive model using Cox regression (GRECOS score [Genotyping Reurrence Risk of Stroke]) and generated risk groups using a classification tree method. RESULTS: The analyses revealed that rs1800801 in the MGP gene (hazard ratio, 1.33; P=9×10-03), a gene related to artery calcification, was associated with new IS during the first year of follow-up. This polymorphism was replicated in a Spanish cohort (n=1.305); however, it was not significantly associated in a North American cohort (n=1.683). The GRECOS score predicted new IS (P=3.2×10-09) and could classify patients, from low risk of stroke recurrence (1.9%) to high risk (12.6%). Moreover, the addition of genetic risk factors to the GRECOS score improves the prediction compared with previous Stroke Prognosis Instrument-II score (P=0.03). CONCLUSIONS: The use of genetics could be useful to estimate vascular recurrence risk after IS. Genetic variability in the MGP gene was associated with vascular recurrence in the Spanish population.

Predictors of Restenosis Following Carotid Angioplasty and Stenting.

BACKGROUND AND PURPOSE: Restenosis after carotid angioplasty (with or without stent) is associated with increased rate of stroke and death. Our aim was to determine risk and predictive factors related to carotid restenosis post carotid angioplasty and its association to recurrent cerebrovascular events. METHODS: All consecutive patients with carotid stenosis treated with angioplasty (n=1060) in a single University Hospital were included (from 2002 to 2013). Follow-up was done prospectively evaluating restenosis, ipsilateral stroke, or death. Restenosis was defined as a narrowing of ≥70% of a previously treated vessel evaluated by ultrasonography. RESULTS: Of the 1060 patients treated, 9.2% (97) of patients experienced restenosis during follow up (median 12 [9-32] months). Occurrence of restenosis was associated with ipsilateral stroke during follow-up (P=0.049). After Cox regression analysis, hypertension (hazard ratio, 6.2 [1.9-19.9]; P=0.002), impaired vasoreactivity (hazard ratio, 1.7 [1.09-2.8]; P=0.019), and angioplasty without stent (hazard ratio, 2.9 [1.2-6.8]; P=0.012) were independent risk predictors of >70% restenosis. CONCLUSIONS: Carotid restenosis after carotid angioplasty is associated with ipsilateral stroke occurrence. In our sample, hypertension, angioplasty without stent, and impaired vasoreactivity identify patients at high risk of restenosis and could help to select patients for follow-up ultrasonography imaging.

Combination of Thrombolysis and Statins in Acute Stroke Is Safe: Results of the STARS Randomized Trial (Stroke Treatment With Acute Reperfusion and Simvastatin).

BACKGROUND AND PURPOSE: The STARS trial (Stroke Treatment With Acute Reperfusion and Simvastatin) was conducted to demonstrate the efficacy and safety of simvastatin treatment in acute stroke. METHODS: STARS07 was a multicentre, phase IV, prospective, randomized, double-blind, placebo-controlled trial. Patients with Acute ischemic stroke recruited within 12 hours from symptom onset were randomized to oral simvastatin 40 mg or placebo, once daily for 90 days. Primary outcome was proportion of independent patients (modified Rankin Scale score of ≤2) at 90 days. Safety end points were hemorrhagic transformation, hemorrhagic events, death, infections, and serious adverse events. RESULTS: From April 2009 to March 2014, 104 patients were included. Fifty-five patients received intravenous tissue-type plasminogen activator. No differences were found between treatment arms regarding the primary outcome (adjusted odds ratio, 0.99 [0.35-2.78]; P=0.98). Concerning safety, no significant differences were found in the rate of hemorrhagic transformation of any type, nor symptomatic hemorrhagic transformation. There were no differences in other predefined safety outcomes. In post hoc analyses, for patients receiving tissue-type plasminogen activator, a favorable effect for simvastatin treatment was noted with higher proportion of patients experiencing major neurological recovery (adjusted odds ratio, 4.14 [1.18-14.4]; P=0.02). CONCLUSIONS: Simvastatin plus tissue-type plasminogen activator combination seems safe in acute stroke, with low rates of bleeding complications. Because of the low recruitment, the STARS trial was underpowered to detect differences in simvastatin efficacy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01073007.

Antiplatelet effects of clopidogrel dose adjustment (75 mg/d vs 150 mg/d) after carotid stenting.

OBJECTIVE: Clopidogrel plays a central role in the treatment of patients undergoing carotid artery stenting (CAS). The objective was to evaluate the effect of clopidogrel (75 mg/d) on platelet reactivity in responders and nonresponders and the antiplatelet effect of different doses of clopidogrel in patients with high on-treatment reactivity (OTR) after CAS. METHODS: Patients with high OTR (defined by VerifyNow (Accumetrics, San Diego, Calif) assay as ≥230 P2Y12 reaction units [PRU]) were randomly assigned in a 1:1 ratio to group 1 (standard-dose clopidogrel therapy: 75 mg/d for 30 days) or group 2 (high-dose clopidogrel: 150 mg/d for 30 days). RESULTS: The study enrolled 214 patients. Of these, 115 (53.7%) were clopidogrel responders (group 0), and 99 (46.3%) had high OTR (clopidogrel nonresponders); of which, 50 were randomly assigned to group 1 and 49 to group 2. At baseline, the PRU value did not differ between group 1 (288.50 ± 46) and group 2 (295.45 ± 47.2; P = .308). Patients displayed reduced mean platelet reactivity levels at 30 days in group 1 (238.96 ± 72.25; P < .001) and group 2 (201.85 ± 77.8; P < .001). Although high-dose clopidogrel resulted in more intense platelet function inhibition, the differences between median 30-day PRU values (P = .483) and the percentage change of PRU (P = .442) for groups 1 and 2 were not significant. The incidences of transient ischemic attack, stroke, or death at up to 30 days after CAS in the high-OTR patients were similar between groups 1 and 2 (P = .481). CONCLUSIONS: Patients with high OTR undergoing CAS treated with standard-dose and double-dose clopidogrel had significantly reduced platelet reactivity after 30 days. The double dose did not result in statistically significantly greater reductions in reactivity compared with the standard dose.

Tirofiban versus aspirin to prevent in-stent thrombosis after emergent carotid artery stenting in acute ischemic stroke.

BACKGROUND: Several antithrombotic treatments during emergent carotid artery stenting (eCAS) have been proposed, but an appropriate protocol to balance risk-benefit is not well known. OBJECTIVE: To investigate the efficacy and safety of tirofiban compared with aspirin in patients with acute ischemic stroke undergoing eCAS. METHODS: We conducted a retrospective single-center study of the prospective ARTISTA Registry, including patients with atherosclerotic internal carotid artery occlusion treated with eCAS. Two groups, according to antiplatelet drug, were studied: aspirin (250-500 mg single-dose) versus tirofiban (500 µg bolus+200 µg/h). Primary outcomes were the rate of in-stent thrombosis and symptomatic intracranial hemorrhage (sICH) within the first 24 hours. RESULTS: During the period 2019-2023, 181 patients were included, 103 received aspirin, 78 tirofiban; 149 (82.3%) had tandem lesions. The primary efficacy outcome occurred in 9 (9.4%) in the aspirin group, as compared with 1 (1.3%) in the tirofiban group (adjusted odds ratio (aOR)=0.11, 95% CI 0.01 to 0.98; P=0.048). The primary safety outcome was detected in 12 (11.7%) in the aspirin group, as compared with 2 (2.6%) in the tirofiban group (aOR=0.16, 95% CI 0.03 to 0.87; P=0.034). The tirofiban group presented a lower risk of parenchymal hemorrhage (18 (17.4%) vs 4 (5.2%), aOR=0.27, 95% CI 0.09 to 0.88; P=0.029) and an increased rate of excellent recanalization (expanded Treatment in Cerebral Infarction (eTICI) 2c-3) (50 (48.5%) vs 54 (69.2%); aOR=2.15, 95% CI 1.12 to 4.13; P=0.02). There were no differences in functional outcomes or mortality at 3 months. CONCLUSIONS: Periprocedural antithrombotic therapy with tirofiban was associated with a lower risk of in-stent thrombosis and sICH at 24 hours from eCAS compared with aspirin. Prospective randomized clinical trials are needed to confirm our results.

Stroke-associated pneumonia according to mCDC criteria: impact on prognosis and antibiotic therapy.

Objective: The modified Centers for Disease Control and Prevention (mCDC) criteria have been proposed for diagnosing and managing stroke-associated pneumonia (SAP). The objective was to investigate the impact of SAP on stroke outcome depending on whether or not it conforms to mCDC criteria. Our secondary objective was to identify the responsible factors for antibiotic initiation in stroke patients. Methods: We conducted a prospective, multicenter, observational study of ischemic stroke patients with moderate to severe stroke (NIHSS≥4) admitted within 24 h. For 7 days, mCDC criteria were assessed daily, and infections and antibiotics were recorded. Pneumonias were divided into those fulfilling mCDC criteria (mCDC-SAP) or not (other pneumonias, OPn). The effect of each type of pneumonia on 3-month outcome was evaluated in separated logistic regression models. Factors associated with antibiotic initiation were explored using a random forest analysis. Results: Of the 342 patients studied, infections were diagnosed in 72 (21.6%), including 39 (11.7%) cases of pneumonia. Of them, 25 (7.5%) fulfilled mCDC criteria. Antibiotics were used in 92% of mCDC-SAP and 64.3% of OPn. In logistic regression analysis, mCDC-SAP, but not OPn, was an independent predictor of poor outcome [OR, 4.939 (1.022-23.868)]. The random forest analysis revealed that fever had the highest importance for antibiotic initiation. Interpretation: The mCDC criteria might be useful for detecting clinically relevant SAP, which is associated with poor outcomes. Isolated signs of infection were more important for antibiotic initiation than compliance with pre-defined criteria. Therefore, adherence to mCDC criteria might result in antibiotic saving without compromising clinical outcome.

Early automated cerebral edema assessment following endovascular therapy: impact on stroke outcome.

BACKGROUND: Cerebral edema (CED) is associated with poorer outcome in patients with acute ischemic stroke (AIS). The aim of the study was to investigate the factors contributing to greater early CED formation in patients with AIS who underwent endovascular therapy (EVT) and its association with functional outcome. METHODS: We conducted a multicenter cohort study of patients with an anterior circulation AIS undergoing EVT. The volume of cerebrospinal fluid (CSF) was extracted from baseline and 24-hour follow-up CT using an automated algorithm. The severity of CED was quantified by the percentage reduction in CSF volume between CT scans (∆CSF). The primary endpoint was a shift towards an unfavorable outcome, assessed by modified Rankin Scale (mRS) score at 3 months. Multivariable ordinal logistic regression analyses were performed. The ∆CSF threshold that predicted unfavorable outcome was selected using receiver operating characteristic curve analysis. RESULTS: We analyzed 201 patients (mean age 72.7 years, 47.8% women) in whom CED was assessable for 85.6%. Higher systolic blood pressure during EVT and failure to achieve modified Thrombolysis In Cerebral Infarction (mTICI) 3 were found to be independent predictors of greater CED. ∆CSF was independently associated with the probability of a one-point worsening in the mRS score (common odds ratio (cOR) 1.05, 95% CI 1.03 to 1.08) after adjusting for age, baseline mRS, National Institutes of Health Stroke Scale (NIHSS), and number of passes. Displacement of more than 25% of CSF was associated with an unfavorable outcome (OR 6.09, 95% CI 3.01 to 12.33) and mortality (OR 6.72, 95% CI 2.94 to 15.32). CONCLUSIONS: Early CED formation in patients undergoing EVT was affected by higher blood pressure and incomplete reperfusion. The extent of early CED, measured by automated ∆CSF, was associated with worse outcomes.

A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment.

BACKGROUND: Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient's prognosis. OBJECTIVES: To investigate the association between genetically determined natural hemostatic factors' levels and increased risk of HT after r-tPA treatment. METHODS: Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT. RESULTS: Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10-11. Multitrait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), P = 8.80 × 10-10; rs1421067 (CHD9), P = 1.81 × 10-14; and rs34780449, near ROBO1 gene, P = 1.64 × 10-8. Multitrait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), P = 1.81 × 10-14. Mendelian randomization analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse-variance weighted estimate [SE], 0.07 [-0.29 to 0.00]; odds ratio, 0.87; 95% CI, 0.75-1.00; raw P = .05). CONCLUSION: We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed.

Relevance of Carotid Reocclusion in Tandem Lesions.

AIMS: Carotid reocclusion (CRO) after mechanical thrombectomy (MT) in acute ischemic stroke (AIS) due to tandem lesion (TL) or isolated internal carotid occlusion (ICO) is associated with worse clinical outcomes. Our aim was to analyze the predictors and clinical impact of CRO. METHODS: A retrospective single-center analysis of all patients with anterior circulation strokes who underwent MT prospectively included in a registry between 2017 and 2020 was performed. ICO and TL as stroke causes were included. Stent deployment was left to the discretion of the interventionist. All patients received at least intravenous aspirin during MT. CRO was assessed using ultrasound within the first 24 h after MT. Efficacy and safety of stenting were assessed. RESULTS: Among 1304 AIS cases, 218 (16.7%) were related to TL or ICO. Of them, 5% (n=11) were associated with internal CRO 24 h after the endovascular procedure. After adjusting per confounders, multivariate analysis showed that the independent variables associated with CRO were the TICI recanalization grade [TICI 2b-3; OR 0.1, 95% confidence interval (CI) 0.01-0.89, p=0.040], pial collateral circulation presence (OR 0.09, 95% CI 0.02-0.45, p=0.03), stent deployment during MT (OR 0.17, 95% CI 0.03-0.84, p=0.030), and general anesthesia use (OR 2.92, 95% CI 1.13-7.90, p=0.034). CRO showed a trend toward worst outcomes (modified Rankin scale 3-6) at 3 months (OR 3.4, 95% CI 0.96-12, p=0.057). After multivariate analysis, variables independently associated with worse outcomes at 90 days were intrastent platelet aggregation phenomena during endovascular therapy, admission National Institute of Health Stroke Scale, and age. Conversely, intravenous thrombolysis and TICI 2b-3 recanalization grade were identified as independent predictors of good outcomes at 90 days. CONCLUSIONS: CRO has a relevant clinical impact in our study, associating lower rates of good functional outcomes at 3 months. Independent factors of CRO were the recanalization degree, presence of pial collateral circulation, use of a stent as a protective factor, and use of general anesthesia during thrombectomy.