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BackgroundThe aim of this study was to determine the effect of smoking status on subsequent stroke risk in patients with minor ischemic stroke or TIA and to determine whether smoking modifies the effect of clopidogrel-based DAPT on subsequent stroke risk.MethodsThis was a post-hoc analysis of the Platelet Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial, which had a 90-day follow-up period. We used multivariable Cox regression and subgroup interaction analysis to determine the effect of smoking on the risk of subsequent ischemic stroke and major hemorrhage, respectively.ResultsData from 4877 participants enrolled in the POINT trial were analyzed. Among these, 1004 were current smokers and 3873 were non-smokers at the time of index event. Smoking was associated with a non-significant trend toward an increased risk of subsequent ischemic stroke during follow up (adjusted HR, 1.31 (95% CI, 0.97-1.78), p = 0.076). The effect of clopidogrel on ischemic stroke did not differ between non-smokers (HR, 0.74 (95% CI, 0.56-0.98), p = 0.03) and smokers (HR, 0.63 (95% CI, 0.37-1.05), p = 0.078), p for interaction = 0.572. Similarly, the effect of clopidogrel on major hemorrhage did not differ between non-smokers (hazard ratio, 1.67 (95% CI, 0.40-7.00), p = 0.481) and smokers (HR, 2.59 (95% CI, 1.08-6.21), p = 0.032), p for interaction = 0.613.ConclusionsIn this post-hoc analysis of the POINT trial we found that the effect of clopidogrel on reducing subsequent ischemic stroke as well as risk of major hemorrhage did not depend on smoking status, indicating that smokers benefit to a similar degree from DAPT as non-smokers.

BACKGROUND: Clinical and neuroimaging measures incompletely explain behavioral deficits in the acute stroke setting. We hypothesized that electroencephalography (EEG)-based measures of neural function would significantly improve prediction of acute stroke deficits. METHODS: Patients with acute stroke (n=50) seen in the emergency department of a university hospital from 2017 to 2018 underwent standard evaluation followed by a 3-minute recording of EEG at rest using a wireless, 17-electrode, dry-lead system. Artifacts in EEG recordings were removed offline and then spectral power was calculated for each lead pair. A primary EEG metric was DTABR, which is calculated as a ratio of spectral power: [(Delta*Theta)/(Alpha*Beta)]. Bivariate analyses and least absolute shrinkage and selection operator (LASSO) regression identified clinical and neuroimaging measures that best predicted initial National Institutes of Health Stroke Scale (NIHSS) score. Multivariable linear regression was then performed before versus after adding EEG findings to these measures, using initial NIHSS score as the dependent measure. RESULTS: Age, diabetes status, and infarct volume were the best predictors of initial NIHSS score in bivariate analyses, confirmed using LASSO regression. Combined in a multivariate model, these 3 explained initial NIHSS score (adjusted r2=0.47). Adding any of several different EEG measures to this clinical model significantly improved prediction; the greatest amount of additional variance was explained by adding contralesional DTABR (adjusted r2=0.60, P

ObjectiveTo develop a simple and effective risk score for predicting which stroke patients will have persistent impairment of upper extremity motor function at 90 days.DesignPost hoc analysis of clinical trial patients hospitalized with acute ischemic stroke who were followed for 90 days to determine functional outcome.SettingPatient were hospitalized at facilities across the United States.ParticipantsWe created a harmonized cohort of individual patients (N=1653) from the NINDS tPA, ALIAS part 2, IMS-III, DEFUSE 3, and FAST-MAG trials. We split the cohort into balanced derivation and validation samples.InterventionsNot applicable.Main outcome measuresThe primary outcome was persistent arm impairment, defined as a National Institutes of Health Stroke Scale (NIHSS) arm domain score of 2 to 4 at 90 days in patients who had a 24-hour NIHSS arm score of 1 or more. We used least absolute shrinkage and selection operator regression to determine the elements of the persistent upper extremity impairment (PUPPI) index, which we validated as a predictive tool.ResultsWe included 1653 patients (827 derivation, 826 validation), of whom 803 (48.6%) had persistent arm impairment. The PUPPI index gives 1 point each for age 55 years or older and NIHSS values of worse arm (4), worse leg (>2), facial palsy (3), and total NIHSS (≥10). The optimal cutpoint for the PUPPI index was 3 or greater, at which the area under the curve was greater than 0.75 for the derivation and validation cohorts and when using NIHSS values from either 24 hours or in a subacute or discharge time window. Results were similar across different levels of stroke severity.ConclusionThe PUPPI index uses readily available information to accurately predict persistent upper extremity motor impairment at 90 days poststroke. The PUPPI index can be administered in minutes and could be used as inclusion criterion in recovery-related clinical trials or, with additional development, as a prognostic tool for patients, caregivers, and clinicians.

BACKGROUND AND PURPOSE: Dual antiplatelet therapy has been shown to reduce the risk of recurrent stroke in patients with minor stroke or transient ischemic attack. However, whether the effect of dual antiplatelet therapy is modified by pretreatment antiplatelet status is unclear. METHODS: This is a post hoc analysis of the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke). Patients were divided into 2 groups based on pretreatment antiplatelet use. The primary outcome was ischemic stroke within 90 days of randomization. RESULTS: We included 4881 patients of whom 41% belonged to the no pretreatment antiplatelet. Ischemic stroke occurred in 6% and 5% in the antiplatelet pretreatment and no antiplatelet pretreatment, respectively. Antiplatelet pretreatment was not associated with the risk of ischemic stroke (adjusted hazard ratio, 1.05 [95% CI, 0.81-137]) or risk of major hemorrhage (hazard ratio, 1.10 [95% CI, 0.55-2.21]; P=0.794). The effect of dual antiplatelet therapy on recurrent ischemic stroke risk was not different in patients who were on antiplatelet before randomization (adjusted hazard ratio, 0.69 [95% CI, 0.50-0.94]) as opposed to those who were not (adjusted hazard ratio, 0.75 [95% CI, 0.50-1.12]), P for interaction = 0.685. CONCLUSIONS: In patients with minor stroke and high-risk transient ischemic attack, dual antiplatelet therapy reduces the risk of ischemic stroke regardless of premorbid antiplatelet use.

BACKGROUND: The benefit of endovascular thrombectomy for acute ischemic stroke with M2 segment middle cerebral artery occlusion remains controversial, with uncertainty and paucity of data specific to this population. OBJECTIVE: To compare outcomes between M1 and M2 occlusions in the Analysis of Revascularization in Ischemic Stroke with EmboTrap (ARISE II) trial. METHODS: We performed a prespecified analysis of the ARISE II trial with the primary outcome of 90-day modified Rankin Scale score of 0-2, which we termed good outcome. Secondary outcomes included reperfusion rates and major adverse events. The primary predictor was M2 occlusion, which we compared with M1 occlusion. RESULTS: We included 183 patients, of whom 126 (69%) had M1 occlusion and 57 (31%) had M2 occlusion. There was no difference in the reperfusion rates or adverse events between M2 and M1 occlusions. The rate of good outcome was not different in M2 versus M1 occlusions (70.2% vs 69.7%, p=0.946). In a logistic regression model adjusted for age, sex, and baseline National Institutes of Health Stroke Scale score, M2 occlusions did not have a significantly different odds of good outcome compared with M1 occlusions (OR 0.94, 95% CI 0.47 to 1.88, p=0.87). CONCLUSION: In ARISE II, M2 occlusions achieved a 70.2% rate of good outcome at 90 days, which is above published rates for untreated M2 occlusions and superior to prior reports of M2 occlusions treated with endovascular thrombectomy. We also report similar rates of good outcome, successful reperfusion, death, and other adverse events when comparing the M1 and M2 occlusions.

Global outcome measures that are widely used in stroke clinical trials, such as the modified Rankin Scale (mRS), lack sufficient detail to detect changes within specific domains (e.g., sensory, motor, visual, linguistic, or cognitive function). Yet such data are vital for understanding stroke recovery and its mechanisms. Poststroke deficits in specific domains differ in their rate and degree of recovery and in their effects on overall independence and quality of life. For example, even in a patient with complete recovery of strength, persistent deficits in the nonmotor domains such as language and cognition may make a return to independent living impossible. In such cases, global measures based solely on the patient's degree of independence would overlook a complete recovery in the motor domain. Capturing these important aspects of recovery demands a domain-specific approach. If stroke outcomes trials are to incorporate finer-grained recovery metrics-which can require substantial time, effort, and expertise to implement-efficiency must be a priority. In this article, we discuss how commonly collected clinical data from the NIH Stroke Scale can guide the judicious selection of relevant recovery domains for more detailed testing. Our overarching goal is to make the implementation of domain-specific testing more feasible for large-scale clinical trials on stroke recovery.

Background and purposeRandomized trials demonstrated the benefit of dual antiplatelet therapy in patients with minor ischemic stroke or high-risk transient ischemic attack. We sought to determine whether the presence of carotid stenosis was associated with increased risk of ischemic stroke and whether the addition of clopidogrel to aspirin was associated with more benefit in patients with versus without carotid stenosis.MethodsThis is a post-hoc analysis of the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) that randomized patients with minor ischemic stroke or high-risk transient ischemic attack within 12 hours from last known normal to receive either clopidogrel plus aspirin or aspirin alone. The primary predictor was the presence of ≥50% stenosis in either cervical internal carotid artery. The primary outcome was ischemic stroke. We built Cox regression models to determine the association between carotid stenosis and ischemic stroke and whether the effect of clopidogrel was modified by ≥50% carotid stenosis.ResultsAmong 4881 patients enrolled POINT, 3941 patients met the inclusion criteria. In adjusted models, ≥50% carotid stenosis was associated with ischemic stroke risk (hazard ratio, 2.45 [95% CI, 1.68-3.57], P

ObjectiveStudies indicate that the functional outcome evolves in the year after ischemic stroke onset. However, the traditional outcome measure in stroke trials is the modified Rankin Scale (mRS) at 90 days from onset. To determine mRS fluctuations in the first year after stroke, we examined data from 3 major stroke trials.MethodsIn a secondary analysis, we evaluated intrapatient mRS between 90 days and 1 year from stroke onset, the mRS shift (∆mRS = 1 year-day 90), and the trials' primary outcome at day 90 and 1 year.ResultsWe included 624 patients from the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study, 587 from Albumin Treatment for Acute Ischaemic Stroke, and 611 from Interventional Management of Stroke III, for which the proportion of patients with a ∆mRS change between day 90 and 1 year was 36.5%, 41.7%, and 36.0%. However, the trials' primary outcomes did not differ at 1 year vs 90 days. Similar findings were seen in a second cohort where we pooled the trials and excluded patients with recurrent stroke or death during the follow-up. In those 1,314 patients, 544 (41.4%) had a ∆mRS change, of which 379 (28.9%) had improvement and 165 (12.5%) had worsening, apart from death.ConclusionWe describe the patient-level spectrum of mRS change from day 90 to 1 year after ischemic stroke in 3 high-quality randomized trials. The patient-level shifts consisted of a sufficiently counterbalanced number of mRS improvements and declines, which masked clinical evolution occurring in over one-third of patients. These results may have important implications, both for clinical trial design and outcome adjudication in stroke research and duration of rehabilitative therapy.

Intracranial atherosclerotic disease (ICAD) has been characterized by the degree of arterial stenosis and downstream hypoperfusion, yet microscopic derangements of endothelial shear stress at the luminal wall may be key determinants of plaque growth, vascular remodeling and thrombosis that culminate in recurrent stroke. Platelet interactions have similarly been a principal focus of treatment, however, the mechanistic basis of anti-platelet strategies is largely extrapolated rather than directly investigated in ICAD. Platelet FcγRIIa expression has been identified as a potent risk factor in cardiovascular disease, as elevated expression markedly increases the risk of recurrent events. Differential activation of the platelet FcγRIIa receptor may also explain the variable response of individual patients to anti-platelet medications. We review existing data on endothelial shear stress and potential interactions with the platelet FcγRIIa receptor that may alter the evolving impact of ICAD, based on local pathophysiology at the site of arterial stenosis. Current methods for quantification of endothelial shear stress and platelet activation are described, including tools that may be readily adapted to the clinical realm for further understanding of ICAD.