Projections of Endovascular Therapy-Eligible Patients With Stroke for the US Population.

BACKGROUND: As stroke endovascular thrombectomy (EVT) treatment indications expand, understanding population-based EVT eligibility becomes critical for resource planning. We aimed to project current and future population-based EVT eligibility in the United States. METHODS: We conducted a post hoc analysis of the physician-adjudicated GCNKSS (Greater Cincinnati Northern Kentucky Stroke Study; 2015 epoch), a population-based, cross sectional, observational study of stroke incidence, treatment, and outcomes across a 5-county region. All hospitalized patients ≥18 years of age with acute ischemic stroke were ascertained using the International Classification of Diseases, Ninth Revision codes 430-436 and Tenth Revision codes I60-I67 and G45-G46 and extrapolated to the US adult census 2020. We determined the rate of EVT eligibility within the GCNKSS population using time from last known well to presentation (0-5 versus 5-23 hours), presenting National Institutes of Health Stroke Scale, and prestroke modified Rankin Scale. Both conservative and liberal estimates of prevalence of large vessel occlusion and large core were then applied based on literature review (unavailable within the 2015 GCNKSS). This eligibility was then extrapolated to the 2020 US population. RESULTS: Of the 1 057 183 adults within GCNKSS in 2015, 2741 had an ischemic stroke and 2176 had data available for analysis. We calculated that 8659 to 17 219 patients (conservative to liberal) meet the current guideline-recommended EVT criteria (nonlarge core, no prestroke disability, and National Institutes of Health Stroke Scale score ≥6) in the United States. Estimates (conservative to liberal) for expanded EVT eligibility subpopulations include (1) 5316 to 10 635 by large core; (2) 10 635 to 21 270 by mild presenting deficits with low National Institutes of Health Stroke Scale score; (3) 13 572 to 27 089 by higher prestroke disability; and (4) 7039 to 14 180 by >1 criteria. These expanded eligibility subpopulations amount to 36 562 to 73 174 patients. CONCLUSIONS: An estimated 8659 to 17 219 adult patients in the United States met strict EVT eligibility criteria in 2020. A 4-fold increase in population-based EVT eligibility can be anticipated with incremental adoption of recent or future positive trials. US stroke systems need to be rapidly optimized to handle all EVT-eligible patients with stroke.

Optic Nerve Sheath Diameter is not a predictor of functional outcomes in ICH Patients.

OBJECTIVES: Optic nerve sheath diameter (ONSD) may serve as an early marker of increasing intracranial pressure resulting from intracerebral hemorrhage (ICH). We investigated if changes in ONSD can predict 90-day functional outcomes in ICH patients. MATERIALS AND METHODS: We utilized ERICH (Ethnic/Racial Variations of Intracerebral Hemorrhage), a prospective, multi-center, case-control study of 3000 patients. We included patients with baseline and follow-up head CT with available outcomes. We measured change in ONSD from baseline and follow-up CT within a 6 (±1) hour window. Our primary outcome was the 90-day Modified Rankin (mRS) score. We compared patients with good (mRS 0-3) versus poor outcomes (mRS 4-6) to presence of significant change in ONSD using univariate analysis. We did an analysis of variance to assess for differences in ONSD. RESULTS: Of 93 ICH patients who fit the inclusion criteria, the mean age was 64.1 (SD +/- 14.6), with 36.6 % being females. Forty-nine patients (47.1 %) had significant ONSD change between baseline and follow-up CT. ONSD change in the poor outcome group was not significantly different than that of the good outcome group in both the right and left hemispheres (p = 0.21 and p = 0.63 respectively). CONCLUSIONS: We found that early change in the ONSD within the first 6 h of presentation in patients with ICH does not predict functional outcomes at three months.

Higher blood glucose is associated with the severity of hemorrhagic transformation after endovascular therapy for stroke.

OBJECTIVES: Hyperglycemia is associated with poor outcome in large vessel occlusion (LVO) stroke, with mechanism for this effect unknown. MATERIALS AND METHODS: We used our prospective, multicenter, observational study, Blood Pressure After Endovascular Stroke Therapy (BEST), of anterior circulation LVO stroke undergoing endovascular therapy (EVT) from 11/2017-7/2018 to determine association between increasing blood glucose (BG) and intracerebral hemorrhage (ICH). Our primary outcome was degree of ICH, classified as none, asymptomatic ICH, or symptomatic ICH (≥4-point increase in National Institutes of Health Stroke Scale [NIHSS] at 24 h with any hemorrhage on imaging). Secondary outcomes included 24 h NIHSS, early neurologic recovery (ENR, NIHSS 0-1 or NIHSS reduction by ≥8 within 24 h), and 90-day modified Rankin Scale (mRS) using univariate and multivariable regression. RESULTS: Of 485 enrolled patients, increasing BG was associated with increasing severity of ICH (adjusted OR, aOR 1.06, 95 % CI 1.02-1.1, p < 0.001), higher 24 h NIHSS (aOR 1.22, 95 % CI 1.11-1.34, p < 0.001), ENR (aOR 0.90, 95 % CI 0.82-1.00, p < 0.002), and 90-day mRS (aOR 1.06, 95 % CI 1.03-1.09, p < 0.001) when adjusted for age, presenting NIHSS, ASPECTS, 24-hour peak systolic blood pressure, time from last known well, and successful recanalization. CONCLUSIONS: In the BEST study, increasing BG was associated with greater odds of increasing ICH severity. Further study is warranted to determine whether treatment of will decrease ICH severity following EVT.

Recruitment in Acute Stroke Trials: Challenges and Potential Solutions.

Randomized clinical trials of acute stroke have led to major advances in acute stroke therapy over the past decade. Despite these successes, recruitment in acute trials is often difficult. We outline challenges in recruitment for acute stroke trials and present potential solutions, which can increase the speed and decrease the cost of identifying new treatments for acute stroke. One of the largest opportunities to increase the speed of enrollment and make trials more generalizable is expansion of inclusion criteria whose impact on expected recruitment can be assessed by epidemiologic and registry databases. Another barrier to recruitment besides the number of eligible patients is availability of study investigators limited to business hours, which may be helped by financial support for after-hours call. The wider use of telemedicine has accelerated quicker stroke treatment at many hospitals and has the potential to accelerate research enrollment but requires training of clinical investigators who are often inexperienced with this approach. Other potential solutions to enhance recruitment include rapid prehospital notification of clinical investigators of potential patients, use of mobile stroke units, advances in the process of emergency informed consent, storage of study medication in the emergency department, simplification of study treatments and data collection, education of physicians to improve equipoise and enthusiasm for randomization of patients within a trial, and clear recruitment plans, and even potentially coenrollment, when there are competing trials at sites. Without successful recruitment, scientific advances and clinical benefit for acute stroke patients will lag.

Using Epidemiological Data to Inform Clinical Trial Feasibility Assessments: A Case Study.

BACKGROUND: Clinical trial enrollment and completion is challenging, with nearly half of all trials not being completed or not completed on time. In 2014, the National Institutes of Health StrokeNet in collaboration with stroke epidemiologists from GCNKSS (Greater Cincinnati/Northern Kentucky Stroke Study) began providing proposed clinical trials with formal trial feasibility assessments. Herein, we describe the process of prospective feasibility analyses using epidemiological data that can be used to improve enrollment and increase the likelihood a trial is completed. METHODS: In 2014, DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) trialists, National Institutes of Health StrokeNet, and stroke epidemiologists from GCNKSS collaborated to evaluate the initial inclusion/exclusion criteria for the DEFUSE 3 study. Trial criteria were discussed and an assessment was completed to evaluate the percent of the stroke population that might be eligible for the study. The DEFUSE 3 trial was stopped early with the publication of DAWN (Thrombectomy 6 to 24 Hours After Stroke With a Mismatch Between Deficit and Infarct), and the Wilcoxon rank-sum statistic was used to analyze whether the trial would have been stopped had the proposed changes not been made, following the DEFUSE 3 statistical analysis plan. RESULTS: After initial epidemiological analysis, 2.4% of patients with acute stroke in the GCNKSS population would have been predicted to be eligible for the study. After discussion with primary investigators and modifying 4 key exclusion criteria (upper limit of age increased to 90 years, baseline modified Rankin Scale broadened to 0-2, time since last well expanded to 16 hours, and decreased lower limit of National Institutes of Health Stroke Scale score to <6), the number predicted to be eligible for the trial increased to 4%. At the time of trial conclusion, 57% of the enrolled patients qualified only by the modified criteria, and the trial was stopped at an interim analysis that demonstrated efficacy. We estimated that the Wilcoxon rank-sum value for the unadjusted predicted enrollment would not have crossed the threshold for efficacy and the trial not stopped. CONCLUSIONS: Objectively assessing trial inclusion/exclusion criteria using a population-based resource in a collaborative and iterative process including epidemiologists can lead to improved recruitment and can increase the likelihood of successful trial completion.

Association Between CT Angiogram Collaterals and CT Perfusion in Delayed Time Windows for Large Vessel Occlusion Ischemic Strokes.

OBJECTIVES: Recent endovascular trials have established the use of CT perfusion (CTP) in endovascular treatment selection for patients with large vessel occlusions (LVO). However, the relationship between CTP and collateral circulation is unclear in delayed time windows. We explored the relationship between CT Angiogram (CTA) collaterals and CTP parameters in delayed time windows (6-24 hours). MATERIALS AND METHODS: We utilized a single institutional, retrospective stroke registry of consecutive patients between May 2016 and May 2018 with anterior LVO with CTA and CTP imaging within 6-24 hours of stroke onset. We graded baseline collaterals on single phase CTA using modified Tan collateral score (0-3) and dichotomized into good (2-3) and poor (0-1) collaterals. We recorded automated CTP parameters, including estimated ischemic core (cerebral blood flow (CBF)<30%), penumbra (Tmax>6 s), and mismatch ratio. We used Mann-Whitney test and linear regression to assess associations. RESULTS: We included 48 patients with median age of 62 years (IQR= 52-72), median core of 17.5 mL (IQR=0-47), and median penumbra of 117.5 mL (IQR= 62-163.5). Patients with good collaterals had smaller median core (0 mL, IQR=0-12 mL vs. 40.5 mL, IQR=15-60 mL) (p < 0.001), smaller median penumbra (83.5 mL, IQR=43-135 mL vs. 142.5 mL, IQR=77-190 mL) (p = 0.04), larger median mismatch ratio (13.7, IQR=5.7-58.0 vs. 3.1, IQR=2.1-5.0) (p < 0.001), and lower median hypoperfusion intensity ratio (0.23, IQR=0-0.44 vs. 0.52, IQR=0.45-0.63) (p < 0.001) than patients with poor collaterals. CONCLUSIONS: In delayed time window LVO patients, good CTA collaterals are significantly associated with smaller CTP core, smaller penumbra, larger mismatch ratio, and lower hypoperfusion intensity ratio. CTA collateral assessment could be a potential valuable surrogate to perfusion imaging, particularly in stroke centers where CTP is unavailable.

Factors Associated With Premature Termination of Hyperacute Stroke Trials: A Review.

BACKGROUND: We performed a review of acute stroke trials to determine features associated with premature termination of trial enrollment, defined by the authors as not meeting preplanned sample size. METHODS AND RESULTS: MEDLINE was searched for randomized clinical stroke trials published in 9 major clinical journals between 2013 and 2022. We included randomized clinical trials that were phase 2 or 3 with a preplanned sample size ≥100 and a time-to-treatment within 24 hours of onset for transient ischemic attack, ischemic stroke, or intracerebral hemorrhage. Data were abstracted on trial features including trial design, inclusion criteria, imaging, location and number of sites, masking, treatment complexity, control group (standard therapy, placebo), industry involvement, and preplanned stopping rules (futility and efficacy). Least absolute shrinkage and selection operator regression was used to select the most important factors associated with premature termination; then, a multivariable logistic regression was fit including only the least absolute shrinkage and selection operator selected variables. Of 1475 studies assessed, 98 trials met eligibility criteria. Forty-five (46%) trials were prematurely terminated, of which 27% were stopped for benefit/efficacy, 20% for lack of money/slow enrollment, 18% for futility, 16% for newly available evidence, 17% for other reasons, and 4% due to harm. Complex trials (adjusted odds ratio [aOR], 2.76 [95% CI, 1.13-7.49]), presence of a futility rule (aOR, 4.43 [95% CI, 1.62-17.91]), and exclusion of prestroke dependency (none/slight disability only; aOR, 2.19 [95% CI, 0.84-6.72] versus dependency allowed) were identified as the strongest predictors. CONCLUSIONS: Nearly half of acute stroke trials were terminated prematurely. Broadening inclusion criteria and simplifying trial design may decrease the likelihood of unplanned termination, whereas planned futility analyses may appropriately terminate trials early, saving money and resources.

Asymptomatic Intracerebral Hemorrhage Following Endovascular Stroke Therapy Is Not Benign: A Systematic Review and Meta-Analysis.

BACKGROUND: Asymptomatic intracerebral hemorrhage (aICH) occurs in approximately 35% of patients with acute ischemic stroke after endovascular thrombectomy. Unlike symptomatic ICH, studies evaluating the effect of aICH on outcomes have been inconclusive. We performed a systematic review and meta-analysis to evaluate the long-term effects of postendovascular thrombectomy aICH. METHODS AND RESULTS: The meta-analysis protocol was submitted to the International Prospective Register of Systematic Reviews a priori. PubMed, Scopus, and Web of Science were searched from inception through September 2023, yielding 312 studies. Two authors independently reviewed all abstracts. Included studies contained adult patients with ischemic stroke undergoing endovascular thrombectomy with follow-up imaging assessment of ICH reporting comparative outcomes according to aICH versus no ICH. After screening, 60 papers were fully reviewed, and 10 studies fulfilled inclusion criteria (n=5723 patients total, 1932 with aICH). Meta-analysis was performed using Cochrane RevMan v5.4. Effects were estimated by a random-effects model to estimate summary odds ratio (OR) of the effect of aICH versus no ICH on primary outcomes of 90-day modified Rankin Scale 3 to 6 and mortality. The presence of aICH was associated with a higher odds of 90-day mRS 3 to 6 (OR, 2.17 [95% CI, 1.81-2.60], P<0.0001, I2 46% Q 19.15) and mortality (OR, 1.72 [95% CI, 1.17-2.53], P:0.005, I2 79% Q 27.59) compared with no ICH. This difference was maintained following subgroup analysis according to hemorrhage classification and recanalization status. CONCLUSIONS: The presence of aICH is associated with worse 90-day functional outcomes and higher mortality. Further studies to evaluate the factors predicting aICH and treatments aimed at reducing its occurrence are warranted.

Racial Disparities in Blood Pressure at Time of Acute Ischemic Stroke Presentation: A Population Study.

BACKGROUND: Hypertension is a stroke risk factor with known disparities in prevalence and management between Black and White patients. We sought to identify if racial differences in presenting blood pressure (BP) during acute ischemic stroke exist. METHODS AND RESULTS: Adults with acute ischemic stroke presenting to an emergency department within 24 hours of last known normal during study epochs 2005, 2010, and 2015 within the Greater Cincinnati/Northern Kentucky Stroke Study were included. Demographics, histories, arrival BP, National Institutes of Health Stroke Scale score, and time from last known normal were collected. Multivariable linear regression was used to determine differences in mean BP between Black and White patients, adjusting for age, sex, National Institutes of Health Stroke Scale score, history of hypertension, hyperlipidemia, smoking, stroke, body mass index, and study epoch. Of 4048 patients, 853 Black and 3195 White patients were included. In adjusted analysis, Black patients had higher presenting systolic BP (161 mm Hg [95% CI, 159-164] versus 158 mm Hg [95% CI, 157-159], P<0.01), diastolic BP (86 mm Hg [95% CI, 85-88] versus 83 mm Hg [95% CI, 82-84], P<0.01), and mean arterial pressure (111 mm Hg [95% CI, 110-113] versus 108 mm Hg [95% CI, 107-109], P<0.01) compared with White patients. In adjusted subanalysis of patients <4.5 hours from last known normal, diastolic BP (88 mm Hg [95% CI, 86-90] versus 83 mm Hg [95% CI, 82-84], P<0.01) and mean arterial pressure (112 mm Hg [95% CI, 110-114] versus 108 mm Hg [95% CI, 107-109], P<0.01) were also higher in Black patients. CONCLUSIONS: This population-based study suggests differences in presenting BP between Black and White patients during acute ischemic stroke. Further study is needed to determine whether these differences influence clinical decision-making, outcome, or clinical trial eligibility.

Hyperglycemia, Ischemic Lesions, and Functional Outcomes After Intracerebral Hemorrhage.

Background Ischemic lesions observed on diffusion-weighted imaging (DWI) magnetic resonance imaging are associated with poor outcomes after intracerebral hemorrhage (ICH). We evaluated the association between hyperglycemia, ischemic lesions, and functional outcomes after ICH. Methods and Results This was a retrospective observational analysis of 1167 patients who received magnetic resonance imaging in the ERICH (Ethnic and Racial Variations in Intracerebral Hemorrhage) study. A machine learning strategy using the elastic net regularization and selection procedure was used to perform automated variable selection to identify final multivariable logistic regression models. Sensitivity analyses with alternative model development strategies were performed, and predictive performance was compared. After covariate adjustment, white matter hyperintensity score, leukocyte count on admission, and non-Hispanic Black race (compared with non-Hispanic White race) were associated with the presence of DWI lesions. History of ICH and ischemic stroke, presence of DWI lesions, deep ICH location (versus lobar), ICH volume, age, lower Glasgow Coma Score on admission, and medical history of diabetes were associated with poor 6-month modified Rankin Scale outcome (4-6) after covariate adjustment. Inclusion of interactions between race and ethnicity and variables included in the final multivariable model for functional outcome improved model performance; a significant interaction between race and ethnicity and medical history of diabetes and serum blood glucose on admission was observed. Conclusions No measure of hyperglycemia or diabetes was associated with presence of DWI lesions. However, both medical history of diabetes and presence of DWI lesions were independently associated with poor functional outcomes after ICH.

Transcirculation Embolization to New Territory During Mechanical Thrombectomy for Acute Ischemic Stroke.

Embolization in new territories (ENT) is a known complication of mechanical thrombectomy with incidence dependent upon a variety of procedural factors. We present 2 cases of anterior circulation to posterior circulation ENT. These cases were managed with manual aspiration thrombectomy with excellent radiographic and clinical outcome. We present the available literature involving ENT along with our experience in management.

Reflection on the Past, Present, and Future of Thrombolytic Therapy for Acute Ischemic Stroke.

More than 25 years have passed since the US Food and Drug Administration approved IV recombinant tissue plasminogen activator (alteplase) for the treatment of acute ischemic stroke. This landmark decision brought a previously untreatable disease into a new therapeutic landscape, providing inspiration for clinicians and hope to patients. Since that time, the use of alteplase in the clinical setting has become standard of care, continually improving with quality measures such as door-to-needle times and other metrics of specialized stroke unit care. The past decade has seen more widespread use of alteplase in the prehospital setting with mobile stroke units and telestroke and beyond initial time windows via the use of CT perfusion or MRI. Simultaneously, the position of alteplase is being challenged by new lytics and by the concept of its bypass altogether in the era of endovascular therapy. We provide an overview of alteplase, including its earliest trials and how they have shaped the current therapeutic landscape of ischemic stroke treatment, and touch on new frontiers for thrombolytic therapy. We highlight the critical role of thrombolytic therapy in the past, present, and future of ischemic stroke care.

A strategy for the generation, characterization and distribution of animal models by The Michael J. Fox Foundation for Parkinson's Research.

Progress in Parkinson's disease (PD) research and therapeutic development is hindered by many challenges, including a need for robust preclinical animal models. Limited availability of these tools is due to technical hurdles, patent issues, licensing restrictions and the high costs associated with generating and distributing these animal models. Furthermore, the lack of standardization of phenotypic characterization and use of varying methodologies has made it difficult to compare outcome measures across laboratories. In response, The Michael J. Fox Foundation for Parkinson's Research (MJFF) is directly sponsoring the generation, characterization and distribution of preclinical rodent models, enabling increased access to these crucial tools in order to accelerate PD research. To date, MJFF has initiated and funded the generation of 30 different models, which include transgenic or knockout models of PD-relevant genes such as Park1 (also known as Park4 and SNCA), Park8 (LRRK2), Park7 (DJ-1), Park6 (PINK1), Park2 (Parkin), VPS35, EiF4G1 and GBA. The phenotypic characterization of these animals is performed in a uniform and streamlined manner at independent contract research organizations. Finally, MJFF created a central repository at The Jackson Laboratory (JAX) that houses both non-MJFF and MJFF-generated preclinical animal models. Funding from MJFF, which subsidizes the costs involved in transfer, rederivation and colony expansion, has directly resulted in over 2500 rodents being distributed to the PD community for research use.