Impact of Poverty on Stroke Recurrence: A Population-Based Study.

BACKGROUND AND OBJECTIVES: Poverty is associated with greater stroke incidence. The relationship between poverty and stroke recurrence is less clear. METHODS: In this population-based study, incident strokes within the Greater Cincinnati/Northern Kentucky region were ascertained during the 2015 study period and followed up for recurrence until December 31, 2018. The primary exposure was neighborhood socioeconomic status (nSES), defined by the percentage of households below the federal poverty line in each census tract in 4 categories (≤5%, >5%-10%, >10%-25%, >25%). Poisson regression models provided recurrence rate estimates per 100,000 residents using population data from the 2015 5-year American Community Survey, adjusting for age, sex, and race. In a secondary analysis, Cox models allowed for the inclusion of vascular risk factors in the assessment of recurrence risk by nSES among those with incident stroke. RESULTS: Of 2,125 patients with incident stroke, 245 had a recurrent stroke during the study period. Poorer nSES was associated with increased stroke recurrence, with rates of 12.5, 17.5, 25.4, and 29.9 per 100,000 in census tracts with ≤5%, >5%-10%, >10%-25%, and >25% below the poverty line, respectively (p < 0.01). The relative risk (95% CI) for recurrent stroke among Black vs White individuals was 2.54 (1.91-3.37) before adjusting for nSES, and 2.00 (1.47-2.74) after adjusting for nSES, a 35.1% decrease. In the secondary analysis, poorer nSES (HR 1.74, 95% CI 1.10-2.76 for lowest vs highest category) and Black race (HR 1.31, 95% CI 1.01-1.70) were both independently associated with recurrence risk, though neither retained significance after full adjustment. Age, diabetes, and left ventricular hypertrophy were associated with increased recurrence risk in fully adjusted models. DISCUSSION: Residents of poorer neighborhoods had a dose-dependent increase in stroke recurrence risk, and neighborhood poverty accounted for approximately one-third of the excess risk among Black individuals. These results highlight the importance of poverty, race, and the intersection of the 2 as potent drivers of stroke recurrence.

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.

Trends Over Time in Stroke Incidence by Race in the Greater Cincinnati Northern Kentucky Stroke Study.

BACKGROUND AND OBJECTIVES: Understanding the current status of and temporal trends of stroke epidemiology by age, race, and stroke subtype is critical to evaluate past prevention efforts and to plan future interventions to eliminate existing inequities. We investigated trends in stroke incidence and case fatality over a 22-year time period. METHODS: In this population-based stroke surveillance study, all cases of stroke in acute care hospitals within a 5-county population of southern Ohio/northern Kentucky in adults aged ≥20 years were ascertained during a full year every 5 years from 1993 to 2015. Temporal trends in stroke epidemiology were evaluated by age, race (Black or White), and subtype (ischemic stroke [IS], intracranial hemorrhage [ICH], or subarachnoid hemorrhage [SAH]). Stroke incidence rates per 100,000 individuals from 1993 to 2015 were calculated using US Census data and age-standardized, race-standardized, and sex-standardized as appropriate. Thirty-day case fatality rates were also reported. RESULTS: Incidence rates for stroke of any type and IS decreased in the combined population and among White individuals (any type, per 100,000, 215 [95% CI 204-226] in 1993/4 to 170 [95% CI 161-179] in 2015, p = 0.015). Among Black individuals, incidence rates for stroke of any type decreased over the study period (per 100,000, 349 [95% CI 311-386] in 1993/4 to 311 [95% CI 282-340] in 2015, p = 0.015). Incidence of ICH was stable over time in the combined population and in race-specific subgroups, and SAH decreased in the combined groups and in White adults. Incidence rates among Black adults were higher than those of White adults in all time periods, and Black:White risk ratios were highest in adults in young and middle age groups. Case fatality rates were similar by race and by time period with the exception of SAH in which 30-day case fatality rates decreased in the combined population and White adults over time. DISCUSSION: Stroke incidence is decreasing over time in both Black and White adults, an encouraging trend in the burden of cerebrovascular disease in the US population. Unfortunately, however, Black:White disparities have not decreased over a 22-year period, especially among younger and middle-aged adults, suggesting the need for more effective interventions to eliminate inequities by race.

Association Between Body Mass Index and Functional Outcomes in Patients With Intracerebral Hemorrhage.

BACKGROUND AND OBJECTIVES: Evidence of the so-called "obesity paradox," which refers to the protective effect and survival benefit of obesity in patients with spontaneous intracerebral hemorrhage (ICH), remains controversial. This study aims to determine the association between body mass index (BMI) and functional outcomes in patients with ICH and whether it is modified by race/ethnicity. METHODS: Included individuals were derived from the Ethnic/Racial Variations of Intracerebral Hemorrhage study, which prospectively recruited 1,000 non-Hispanic White, 1,000 non-Hispanic Black, and 1,000 Hispanic patients with spontaneous ICH. Only patients with available BMI were included. The primary outcome was 90-day mortality. Secondary outcomes were mortality at discharge, modified Rankin Scale (mRS), Barthel Index, and self-reported health status measures at 90 days. Associations between BMI and ICH outcomes were assessed using univariable and multivariable logistic, ordinal, and linear regression models, as appropriate. Sensitivity analyses after excluding frail patients and by patient race/ethnicity were performed. RESULTS: A total of 2,841 patients with ICH were included. The median age was 60 years (interquartile range 51-73). Most patients were overweight (n = 943; 33.2%) or obese (n = 1,032; 36.3%). After adjusting for covariates, 90-day mortality was significantly lower among overweight and obese patients than their normal weight counterparts (adjusted odds ratio [aOR] = 0.71 [0.52-0.98] and aOR = 0.70 [0.50-0.97], respectively). Compared with patients with BMI <25 kg/m2, those with BMI ≥25 kg/m2 had better 90-day mRS (aOR = 0.80 [CI 0.67-0.95]), EuroQoL Group 5-Dimension (EQ-5D) (aß = 0.05 [0.01-0.08]), and EQ-5D VAS (aß = 3.80 [0.80-6.98]) scores. These differences persisted after excluding withdrawal of care patients. There was an inverse relationship between BMI and 90-day mortality (aOR = 0.97 [0.96-0.99]). Although non-Hispanic White patients had significantly higher 90-day mortality than non-Hispanic Black and Hispanic (26.6% vs 19.5% vs 18.0%, respectively; p < 0.001), no significant interactions were found between BMI and race/ethnicity. No significant interactions between BMI and age or sex for 90-day mortality were found, whereas for 90-day mRS, there was a significant interaction with age (pinteraction = 0.004). CONCLUSION: We demonstrated that a higher BMI is associated with decreased mortality, improved functional outcomes, and better self-reported health status at 90 days, thus supporting the paradoxical role of obesity in patients with ICH. The beneficial effect of high BMI does not seem to be modified by race/ethnicity or sex, whereas age may play a significant role in patient functional outcomes.

Can a best practice advisory improve anticoagulation prescribing to reduce stroke risk in patients with atrial fibrillation?

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac rhythm disorder and a risk factor for stroke. Randomized trials have demonstrated that anticoagulation can reduce strokes in AF patients. Yet, widespread underutilization of this therapy continues. To address this practice gap, we designed a study to implement and evaluate the effectiveness of a best practice advisory (BPA) for an Atrial Fibrillation Decision Support Tool (AFDST) embedded within our electronic health record. METHODS: Our intervention is provider-facing, focused on decision support. Clinical setting is ambulatory patients being seen by primary care physicians. We prospectively enrolled 608 patients in our health system who are currently receiving less than optimal anticoagulation therapy as determined by the AFDST and randomized them to one of two arms - 1) usual care, in which the AFDST is available for use; or 2) addition of a BPA to the AFDST notifying clinicians that their patient stands to gain significant benefit from a change in current therapy. Primary outcome was effectiveness of the BPA measured by change to "appropriate thromboprophylaxis" based on the AFDST recommendation at 3 months post-enrollment. Secondary endpoints included Reach and Adoption from the RE-AIM (Reach, Effectiveness, Adoption, Implementation, & Maintenance) framework for implementation studies. RESULTS: Among 562 patients with a minimum follow-up of 3 months, addition of a BPA to the AFDST resulted in significant improvement in anticoagulation therapy, 5 % (12/248) versus 11 % (33/314) p = 0.02, odds ratio 2.31 (95 % CI, 1.17-4.87). CONCLUSIONS: A BPA added to an AF decision support tool improved anticoagulation therapy among AF patients in a primary care academic health system setting.

Time Course of Early Hematoma Expansion in Acute Spot-Sign Positive Intracerebral Hemorrhage: Prespecified Analysis of the SPOTLIGHT Randomized Clinical Trial.

BACKGROUND: In the SPOTLIGHT trial (Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy), patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral hemorrhage were randomized to rFVIIa (recombinant activated factor VIIa; 80 µg/kg) or placebo within 6 hours of onset, aiming to limit hematoma expansion. Administration of rFVIIa did not significantly reduce hematoma expansion. In this prespecified analysis, we aimed to investigate the impact of delays from baseline imaging to study drug administration on hematoma expansion. METHODS: Hematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total hematoma volume (intracerebral hemorrhage+intraventricular hemorrhage) change between the 3 scans was calculated as an estimate of how much hematoma expansion occurred before and after studying drug administration. RESULTS: Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2-2.6). Median time from baseline CT to study drug was 62.5 (55-80) minutes, and from study drug to early post-dose CT was 19 (14.5-30) minutes. Median (interquartile range) total hematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (-0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8-8.3) in the placebo arm (P=0.96). Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (-2.6 to 8.3) in the rFVIIa arm and 0.7 mL (-1.6 to 2.1) in the placebo arm (P=0.98). Total hematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted hematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI, 0.71-1.43]; P=0.99). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI, 0.994-1.003]; P=0.50; Table 3). CONCLUSIONS: In the SPOTLIGHT trial, the adjusted hematoma volume growth was not associated with Factor VIIa treatment. Most hematoma expansion occurred between the baseline CT and the early post-dose CT, limiting any potential treatment effect of hemostatic therapy. Future hemostatic trials must treat intracerebral hemorrhage patients earlier from onset, with minimal delay between baseline CT and drug administration. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01359202.

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.

Substance Use and Performance of Toxicology Screens in the Greater Cincinnati Northern Kentucky Stroke Study.

BACKGROUND: Though stroke risk factors such as substance use may vary with age, less is known about trends in substance use over time or about performance of toxicology screens in young adults with stroke. METHODS: Using the Greater Cincinnati Northern Kentucky Stroke Study, a population-based study in a 5-county region comprising 1.3 million people, we reported the frequency of documented substance use (cocaine/marijuana/opiates/other) obtained from electronic medical record review, overall and by race/gender subgroups among physician-adjudicated stroke events (ischemic and hemorrhagic) in adults 20 to 54 years of age. Secondary analyses included heavy alcohol use and cigarette smoking. Data were reported for 5 one-year periods spanning 22 years (1993/1994-2015), and trends over time were tested. For 2015, to evaluate factors associated with performance of toxicology screens, multiple logistic regression was performed. RESULTS: Overall, 2152 strokes were included: 74.5% were ischemic, mean age was 45.7±7.6, 50.0% were women, and 35.9% were Black. Substance use was documented in 4.4%, 10.4%, 19.2%, 24.0%, and 28.8% of cases in 1993/1994, 1999, 2005, 2010, and 2015, respectively (Ptrend<0.001). Between 1993/1994 and 2015, documented substance use increased in all demographic subgroups. Adjusting for gender, comorbidities, and National Institutes of Health Stroke Scale, predictors of toxicology screens included Black race (adjusted odds ratio, 1.58 [95% CI, 1.02-2.45]), younger age (adjusted odds ratio, 0.70 [95% CI, 0.53-0.91], per 10 years), current smoking (adjusted odds ratio, 1.62 [95% CI, 1.06-2.46]), and treatment at an academic hospital (adjusted odds ratio, 1.80 [95% CI, 1.14-2.84]). After adding chart-reported substance use to the model, only chart-reported substance abuse and age were significant. CONCLUSIONS: In a population-based study of young adults with stroke, documented substance use increased over time, and documentation of substance use was higher among Black compared with White individuals. Further work is needed to confirm race-based disparities and trends in substance use given the potential for bias in screening and documentation. Findings suggest a need for more standardized toxicology screening.

Initial antihypertensive agent effects on acute blood pressure after intracerebral haemorrhage.

INTRODUCTION: Current guidelines recommend blood pressure (BP) lowering in patients after acute intracerebral haemorrhage (ICH) without guidance on initial choice of antihypertensive class. This study sought to determine if initial antihypertensive class differentially effects acute BP lowering in a large multiethnic ICH cohort. METHODS: Subjects enrolled in the Ethnic/Racial Variations in ICH study between August 2010 and August 2017 with elevated admission BP and who received labetalol, nicardipine or hydralazine monotherapy as initial antihypertensive were analysed. Primary outcomes were systolic and diastolic BP changes from baseline to first BP measurement after initial antihypertensive treatment. Secondary outcomes included haematoma expansion (HE), hospital length of stay (LOS) and modified Rankin Score (mRS) up to 12 months after ICH. Exploratory outcomes assessed effects of race/ethnicity. Linear and logistic regression analyses, adjusted for relevant covariates, were performed to determine associations of antihypertensive class with outcomes. RESULTS: In total, 1156 cases were used in analyses. Antihypertensive class was associated with diastolic BP change (p=0.003), but not systolic BP change (p=0.419). Initial dosing with nicardipine lowered acute diastolic BP than labetalol (least square mean difference (labetalol-nicardipine)=5.47 (2.37, 8.57), p<0.001). Initial antihypertensive class was also found to be associated with LOS (p=0.028), but not with HE (p=0.406), mortality (p=0.118), discharge disposition (p=0.083) or mRS score at discharge, 3, 6 and 12 months follow-up (p=0.262, 0.276, 0.152 and 0.36, respectively). Race/ethnicity variably affected multivariable models. CONCLUSION: In this large acute ICH cohort, initial antihypertensive class was associated with acute diastolic, but not systolic, BP-lowering suggesting differential effects of antihypertensive agents. TRIAL REGISTRATION NUMBER: NCT01202864.

Electronic health record-embedded decision support to reduce stroke risk in patients with atrial fibrillation - Study protocol.

BACKGROUND: Atrial fibrillation (AF) is the most common significant cardiac rhythm disorder and is a powerful common risk factor for stroke. Randomized trials have demonstrated that anticoagulation can reduce the risk of stroke in patients with AF. Yet, there continues to be widespread underutilization of this therapy. To address this practice gap locally and improve efforts to reduce the risk of stroke for patients with AF in our health system, we have designed a study to implement and evaluate the effectiveness of an Atrial Fibrillation Decision Support Tool (AFDST) embedded within our electronic health record. METHODS: Our intervention is provider-facing and focused on decision support. The clinical setting is ambulatory patients being seen by primary care physicians. Patients include those with both incident and prevalent AF. This randomized, prospective trial will enroll 800 patients in our University of Cincinnati Health System who are currently receiving less than optimal anticoagulation therapy as determined by the AFDST. Patients will be randomized to one of two arms - 1) usual care, in which the AFDST is available for use; 2) addition of a best practice advisory (BPA) to the AFDST notifying the clinician that their patient stands to gain a significant benefit from a change in their current thromboprophylactic therapy. RESULTS: The primary outcome is effectiveness of the BPA measured by change to "appropriate thromboprophylaxis" based on the AFDST recommendation at 3 months post randomization. Secondary endpoints include Reach and Adoption, from the RE-AIM framework for implementation studies. Sample size is based upon an improvement from inappropriate to appropriate anticoagulation therapy estimated at 4% in the usual care arm and ≥10% in the experimental arm. CONCLUSION: Our goal is to examine whether addition of a BPA to an AFDST focused on primary care physicians in an ambulatory care setting will improve "appropriate thromboprophylaxis" compared with usual care. Results will be examined at 3 months post randomization and at the end of the study to evaluate durability of changes. We expect to complete patient enrollment by the end of June 2022. TRIAL REGISTRATION: Clinicaltrials.gov NCT04099485.

What is the median volume of intracerebral hemorrhage and is it changing?

OBJECTIVES: Population-level estimates of the median intracerebral hemorrhage (ICH) volume would allow for the evaluation of clinical trial external validity and determination of temporal trends. We previously reported the median ICH volume in 1988. However, differences in risk factor management, neuroimaging, and demographics may have affected ICH volumes. The goal of this study is to determine the median volume of ICH within a population-based cross-sectional study, including whether it has changed over time. METHODS: The Genetic and Environmental Risk Factors for Hemorrhagic Stroke study was a population-based study of ICH among residents of the Greater Cincinnati/Northern Kentucky region from 2008 through 2012. This study utilizes those data and compares with ICH cases from the same region in 1988. Initial computed tomography images of the head were reviewed, and ICH volumes were calculated using consistent methodology. RESULTS: From 2008 through 2012, we identified 1117 cases of ICH. The median volume of ICH was 14.0 mL and was lower in black (11.6) than in white (15.5) patients. Median volumes of lobar and deep ICH were 28.8 mL and 9.8 mL, respectively. Median ICH volume changed significantly from 1988 to 2008-2012, with age-and-race-adjusted volume decreasing from 18.3 mL to 13.76 mL (p = 0.025). CONCLUSIONS: Median volume of ICH was 13.76 mL, and this should be considered in clinical trial design. Median ICH volume has apparently decreased from 1988 to 2008-2012.

Racial and sex differences in optimizing anticoagulation therapy for patients with atrial fibrillation.

Study objective: Atrial fibrillation (AF) is the most common cardiac rhythm disorder, responsible for 15 % of strokes in the United States. Studies continue to document underuse of anticoagulation therapy in minority populations and women. Our objective was to compare the proportion of AF patients by race and sex who were receiving non-optimal anticoagulation as determined by an Atrial Fibrillation Decision Support Tool (AFDST). Design setting and participants: Retrospective cohort study including 14,942 patients within University of Cincinnati Health Care system. Data were analyzed between November 18, 2020, and November 20, 2021. Main outcomes and measures: Discordance between current therapy and that recommended by the AFDST. Results: In our two-category analysis 6107 (41 %) received non-optimal anticoagulation therapy, defined as current treatment category ≠ AFDST-recommended treatment category. Non-optimal therapy was highest in Black (42 % [n = 712]) and women (42 % [n = 2668]) and lower in White (39 % [n = 4748]) and male (40 % [n = 3439]) patients. Compared with White patients, unadjusted and adjusted odds ratios of receiving non-optimal anticoagulant therapy for Black patients were 1.13; 95 % CI, 1.02-1.30, p = 0.02; and 1.17; 95%CI, 1.04-1.31, p = 0.01; respectively, and 1.10; 95 % CI 1.03-1.18, p = 0.005; and 1.36; 95 % CI, 1.25-1.47, p < 0.001; for females compared with males. Conclusions and relevance: In patients with atrial fibrillation in the University of Cincinnati Health system, Black race and female sex were independently associated with an increased odds of receiving non-optimal anticoagulant therapy.

Ethnic and Racial Variation in Intracerebral Hemorrhage Risk Factors and Risk Factor Burden.

Importance: Black and Hispanic individuals have an increased risk of intracerebral hemorrhage (ICH) compared with their White counterparts, but no large studies of ICH have been conducted in these disproportionately affected populations. Objective: To examine the prevalence, odds, and population attributable risk (PAR) percentage for established and novel risk factors for ICH, stratified by ICH location and racial/ethnic group. Design, Setting, and Participants: The Ethnic/Racial Variations of Intracerebral Hemorrhage Study was a case-control study of ICH among 3000 Black, Hispanic, and White individuals who experienced spontaneous ICH (1000 cases in each group). Recruitment was conducted between September 2009 and July 2016 at 19 US sites comprising 42 hospitals. Control participants were identified through random digit dialing and were matched to case participants by age (±5 years), sex, race/ethnicity, and geographic area. Data analyses were conducted from January 2019 to May 2020. Main Outcomes and Measures: Case and control participants underwent a standardized interview, physical measurement for body mass index, and genotyping for the ɛ2 and ɛ4 alleles of APOE, the gene encoding apolipoprotein E. Prevalence, multivariable adjusted odds ratio (OR), and PAR percentage were calculated for each risk factor in the entire ICH population and stratified by racial/ethnic group and by lobar or nonlobar location. Results: There were 1000 Black patients (median [interquartile range (IQR)] age, 57 [50-65] years, 425 [42.5%] women), 1000 Hispanic patients (median [IQR] age, 58 [49-69] years; 373 [37.3%] women), and 1000 White patients (median [IQR] age, 71 [59-80] years; 437 [43.7%] women). The mean (SD) age of patients with ICH was significantly lower among Black and Hispanic patients compared with White patients (eg, lobar ICH: Black, 62.2 [15.2] years; Hispanic, 62.5 [15.7] years; White, 71.0 [13.3] years). More than half of all ICH in Black and Hispanic patients was associated with treated or untreated hypertension (PAR for treated hypertension, Black patients: 53.6%; 95% CI, 46.4%-59.8%; Hispanic patients: 46.5%; 95% CI, 40.6%-51.8%; untreated hypertension, Black patients: 45.5%; 95% CI, 39.%-51.1%; Hispanic patients: 42.7%; 95% CI, 37.6%-47.3%). Lack of health insurance also had a disproportionate association with the PAR percentage for ICH in Black and Hispanic patients (Black patients: 21.7%; 95% CI, 17.5%-25.7%; Hispanic patients: 30.2%; 95% CI, 26.1%-34.1%; White patients: 5.8%; 95% CI, 3.3%-8.2%). A high sleep apnea risk score was associated with both lobar (OR, 1.68; 95% CI, 1.36-2.06) and nonlobar (OR, 1.62; 95% CI, 1.37-1.91) ICH, and high cholesterol was inversely associated only with nonlobar ICH (OR, 0.60; 95% CI, 0.52-0.70); both had no interactions with race and ethnicity. In contrast to the association between the ɛ2 and ɛ4 alleles of APOE and ICH in White individuals (eg, presence of APOE ɛ2 allele: OR, 1.84; 95% CI, 1.34-2.52), APOE alleles were not associated with lobar ICH among Black or Hispanic individuals. Conclusions and Relevance: This study found sleep apnea as a novel risk factor for ICH. The results suggest a strong contribution from inadequately treated hypertension and lack of health insurance to the disproportionate burden and earlier onset of ICH in Black and Hispanic populations. These findings emphasize the importance of addressing modifiable risk factors and the social determinants of health to reduce health disparities.

Risk of intracerebral haemorrhage from hypertension is greatest at an early age.

INTRODUCTION: The risk of intracerebral haemorrhage (ICH) associated with hypertension (HTN) is well documented. While the prevalence of HTN increases with age, the greatest odds ratio (OR) for HTN as a risk for ischemic stroke is at an early age. We sought to evaluate if the risk for ICH from HTN was higher in the youngest patients of each race. PATIENTS AND METHODS: The Ethnic/Racial Variations of ICH (ERICH) study is a prospective multicenter case-control study of ICH among whites, blacks, and Hispanics. Participants were divided into age groups based on race-specific quartiles. Cases in each race/age group were compared to controls using logistic regression (i.e., cases and controls unmatched). The probability of ICH among cases and controls for each race were compared against independent variables of HTN, quartile of age and interaction of quartile and age also using logistic regression. RESULTS: Overall, 2033 non-lobar ICH cases and 2060 controls, and 913 lobar ICH cases with 927 controls were included. ORs were highest in the youngest age quartile for non-lobar haemorrhage for blacks and Hispanics and highest in the youngest quartile for lobar haemorrhage for all races. The formal test of interaction between age and HTN was significant in all races for all locations with the exception of lobar ICH in whites (p = 0.2935). DISCUSSION: Hypertension is a strong independent risk factor for ICH irrespective of location among persons of younger age, consistent with the hypothesis that first exposure to HTN is a particularly sensitive time for all locations of ICH.

Contribution of Racial and Ethnic Differences in Cerebral Small Vessel Disease Subtype and Burden to Risk of Cerebral Hemorrhage Recurrence.

OBJECTIVE: Black and Hispanic survivors of intracerebral hemorrhage (ICH) are at higher risk of recurrent intracranial bleeding. MRI-based markers of chronic cerebral small vessel disease (CSVD) are consistently associated with recurrent ICH. We therefore sought to investigate whether racial/ethnic differences in MRI-defined CSVD subtype and severity contribute to disparities in ICH recurrence risk. METHODS: We analyzed data from the Massachusetts General Hospital ICH study (n = 593) and the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study (n = 329). Using CSVD markers derived from MRIs obtained within 90 days of index ICH, we classified ICH cases as cerebral amyloid angiopathy (CAA)-related, hypertensive arteriopathy (HTNA)-related, and mixed etiology. We quantified CSVD burden using validated global, CAA-specific, and HTNA-specific scores. We compared CSVD subtype and severity among White, Black, and Hispanic ICH survivors and investigated its association with ICH recurrence risk. RESULTS: We analyzed data for 922 ICH survivors (655 White, 130 Black, 137 Hispanic). Minority ICH survivors had greater global CSVD (p = 0.011) and HTNA burden (p = 0.021) on MRI. Furthermore, minority survivors of HTNA-related and mixed-etiology ICH demonstrated higher HTNA burden, resulting in increased ICH recurrence risk (all p < 0.05). CONCLUSIONS: We uncovered significant differences in CSVD subtypes and severity among White and minority survivors of primary ICH, with direct implication for known disparities in ICH recurrence risk. Future studies of racial/ethnic disparities in ICH outcomes will benefit from including detailed MRI-based assessment of CSVD subtypes and severity and investigating social determinants of health.

Exome Array Analysis of Early-Onset Ischemic Stroke.

BACKGROUND AND PURPOSE: The genetic contribution to ischemic stroke may include rare- or low-frequency variants of high-penetrance and large-effect sizes. Analyses focusing on early-onset disease, an extreme-phenotype, and on the exome, the protein-coding portion of genes, may increase the likelihood of identifying such rare functional variants. To evaluate this hypothesis, we implemented a 2-stage discovery and replication design, and then addressed whether the identified variants also associated with older-onset disease. METHODS: Discovery was performed in UMD-GEOS Study (University of Maryland-Genetics of Early-Onset Stroke), a biracial population-based study of first-ever ischemic stroke cases 15 to 49 years of age (n=723) and nonstroke controls (n=726). All participants had prior GWAS (Genome Wide Association Study) and underwent Illumina exome-chip genotyping. Logistic-regression was performed to test single-variant associations with all-ischemic stroke and TOAST (Trial of ORG 10172 in Acute Stroke Treatment) subtypes in Whites and Blacks. Population level results were combined using meta-analysis. Gene-based aggregation testing and meta-analysis were performed using seqMeta. Covariates included age and gender, and principal-components for population structure. Pathway analyses were performed across all nominally associated genes for each stroke outcome. Replication was attempted through lookups in a previously reported meta-analysis of early-onset stroke and a large-scale stroke genetics study consisting of primarily older-onset cases. RESULTS: Gene burden tests identified a significant association with NAT10 in small-vessel stroke (P=3.79×10-6). Pathway analysis of the top 517 genes (P<0.05) from the gene-based analysis of small-vessel stroke identified several signaling and metabolism-related pathways related to neurotransmitter, neurodevelopmental notch-signaling, and lipid/glucose metabolism. While no individual SNPs reached chip-wide significance (P<2.05×10-7), several were near, including an intronic variant in LEXM (rs7549251; P=4.08×10-7) and an exonic variant in TRAPPC11 (rs67383011; P=5.19×10-6). CONCLUSIONS: Exome-based analysis in the setting of early-onset stroke is a promising strategy for identifying novel genetic risk variants, loci, and pathways.

Effect of COVID-19 on Emergent Stroke Care: A Regional Experience.

BACKGROUND AND PURPOSE: Anecdotal evidence suggests that the coronavirus disease 2019 (COVID-19) pandemic mitigation efforts may inadvertently discourage patients from seeking treatment for stroke with resultant increased morbidity and mortality. Analysis of regional data, while hospital capacities for acute stroke care remained fully available, offers an opportunity to assess this. We report regional Stroke Team acute activations and reperfusion treatments during COVID-19 mitigation activities. METHODS: Using case log data prospectively collected by a Stroke Team exclusively serving ≈2 million inhabitants and 30 healthcare facilities, we retrospectively reviewed volumes of consultations and reperfusion treatments for acute ischemic stroke. We compared volumes before and after announcements of COVID-19 mitigation measures and the prior calendar year. RESULTS: Compared with the 10 weeks prior, stroke consultations declined by 39% (95% CI, 32%-46%) in the 5 weeks after announcement of statewide school and restaurant closures in Ohio, Kentucky, and Indiana. Results compared with the prior year and time trend analyses were consistent. Reperfusion treatments also appeared to decline by 31% (95% CI, 3%-51%), and specifically thrombolysis by 33% (95% CI, 4%-55%), but this finding had less precision. CONCLUSIONS: Upon the announcement of measures to mitigate COVID-19, regional acute stroke consultations declined significantly. Reperfusion treatment rates, particularly thrombolysis, also appeared to decline qualitatively, and this finding requires further study. Urgent public education is necessary to mitigate a possible crisis of avoiding essential emergency care due to COVID-19.

White Matter Lesion Severity is Associated with Intraventricular Hemorrhage in Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Intraventricular hemorrhage (IVH) and white matter lesion (WML) severity are associated with higher rates of death and disability in intracerebral hemorrhage (ICH). A prior report identified an increased risk of IVH with greater WML burden but did not control for location of ICH. We sought to determine whether a higher degree of WML is associated with a higher risk of IVH after controlling for ICH location. METHODS: Utilizing the patient population from 2 large ICH studies; the Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS III) Study and the Ethnic/Racial Variations of Intracerebral Hemorrhage study, we graded WML using the Van Swieten Scale (0-1 for mild, 2 for moderate, and 3-4 for severe WML) and presence or absence of IVH in baseline CT scans. We used multivariable regression models to adjust for relevant covariates. RESULTS: Among 3023 ICH patients, 1260 (41.7%) had presence of IVH. In patients with IVH, the proportion of severe WML (28.6%) was higher compared with patients without IVH (21.8%) (P < .0001). Multivariable analysis demonstrated that moderate-severe WML, deep ICH, and increasing ICH volume were independently associated with presence of IVH. We found an increased risk of IVH with moderate-severe WML (OR = 1.38; 95%Cl 1.03-1.86, P = .0328) in the subset of lobar hemorrhages. CONCLUSIONS: Moderate to severe WML is a risk for IVH. Even in lobar ICH hemorrhages, severe WML leads to an independent increased risk for ventricular rupture.