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Objectives: The opioid neuropeptide pro-enkephalin A (PENK-A) may be a circulating marker of cardiovascular risk, with prior findings relevant to heart failure, kidney disease, and vascular dementia. Despite these findings, the association of PENK-A with ischemic stroke is unknown, so we examined this association in a prospective cohort study and analyzed differences by race and sex., Materials and Methods: The REasons for Geographic and Racial Differences in Stroke study (REGARDS) is a prospective cohort study of 30,239 Black and White adults. Plasma PENK-A was measured in 473 participants that developed first-time ischemic stroke over 5.9 years and 899 randomly selected participants. Cox models adjusted for demographics and stroke risk factors were used to calculate hazard ratios (HRs) of stroke by baseline PENK-A., Results: PENK-A was higher with increasing age, female sex, White race, lower body mass index, and antihypertensive medication use. Each SD higher increment of PENK-A was associated with an adjusted HR of 1.20 (95% CI 1.01-1.42) for stroke, with minimal confounding by stroke risk factors. Spline plots suggested a U-shaped relationship, particularly in White men, with an adjusted HR 3.88 (95% CI 1.94-7.77) for the 95 th versus 50 th percentile of PENK-A in White men., Conclusions: Higher baseline plasma PENK-A was independently associated with future stroke risk in REGARDS. This association was most apparent among White men. There was little confounding by established stroke risk factors, suggesting a possible causal role in stroke etiology. Further research is needed to understand the role of endogenous opioids in stroke pathogenesis., Competing Interests: Conflict of interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Previously we reported that ischemic stroke incidence is declining over time for men but not women. We sought to describe temporal trends of sex differences in incidence of transient ischemic attack (TIA) within the same large, biracial population., Methods: Among the population of 1.3 million in the Greater Cincinnati Northern Kentucky Stroke Study (GCNKSS) region, TIAs among area residents (≥20 years old) were identified at all local hospitals. Out of hospital cases were ascertained using a sampling scheme. First-ever cases and first within each study period for a patient was included in incidence rates. All cases were physician-adjudicated. Incidence rates (during July 93-June 94 and calendar years 1999, 2005, and 2010) were calculated using the age-, race-, and sex-specific number of TIAs divided by the GCNKSS population in that group; rates were standardized to the 2010 U.S., Population: t Tests with Bonferroni correction were used to compare rates over time., Results: There were a total of 4746 TIA events; 53% were female, and 12% were black. In males, incidence decreased from 153 (95% confidence interval [CI] 139-167) per 100,000 in 1993/4 to 117 (95% CI 107-128) in 2010 (P < .05 for trend test) but was similar over time among females (107 (95% CI 97-116) to 102 (95%CI 94-111), P > .05)., Conclusions: Within the GCNKSS population, TIA incidence decreased significantly over time in males but not females, data which parallels trends in ischemic stroke in the GCNKSS over the same time period. Future research is needed to determine if these sex differences in incidence over time continue past 2010., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Purpose: Antithrombotic medications are effective for ischemic stroke prevention, but stoppage of these medications is associated with an increased risk of thromboembolism. The frequency of antithrombotic withdrawal in the general population is unknown., Methods: We conducted a random phone sample of 2036 households in the Greater Cincinnati metropolitan area, representative of the stroke population by age, sex, and race, to determine the frequency of antithrombotic medication use and stoppage by physicians for medically indicated procedures., Results: Sixty-two percent of survey respondents reported that they were on an antithrombotic medication. Ten percent of participants reported that they had stopped taking their medication within the past 60 days for a medically indicated intervention. Of those who stopped taking the medication, it was more common for persons taking an anticoagulant to stop their medication (20%) than those taking an antiplatelet agent (9%). Colonoscopies and orthopedic surgeries were the most common reasons for withdrawal of antiplatelet agents, whereas orthopedic and vascular surgeries were the most common reason for withdrawal of anticoagulants., Conclusions: Recommended discontinuation of antithrombotic medication for surgical or diagnostic procedures is common practice for persons in the community representative of a stroke population. Because stoppage of these medications is associated with an increased risk of thromboembolic stroke, further clinical trials are needed to determine best management practices in this setting., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Some studies of stroke patients report longer prehospital delays in women, but others conflict; studies vary in their inclusion of factors including age and stroke severity. We aimed to investigate the relationship between gender and time to emergency department (ED) arrival and the influence of age and stroke severity on this relationship., Methods: Ischemic stroke patients 20 years old or older who presented to 15 hospitals within a 5-county region of Greater Cincinnati/Northern Kentucky during 2010 were included. Time from symptom onset to ED arrival and covariates were abstracted by study nurses and reviewed by study physicians. Data were analyzed using logistic regression with time to arrival dichotomized at 3 hours or less in the overall sample and then stratified by National Institutes of Health Stroke Scale (NIHSS) and age., Results: 1991 strokes (55% women) were included. Time to arrival was slightly longer in women (geometric mean 337 minutes [95% confidence interval {CI} 307-369] versus 297 [95% CI 268-329], P = .05), and 24% of women versus 27% of men arrived within 3 hours (P = .15). After adjusting for age, race, NIHSS, living situation, and other covariates, gender was not associated with delayed time to arrival (OR = 1.00, 95% CI .78-1.28). This did not change across age or NIHSS categories., Conclusions: After adjusting for factors including age, NIHSS score, and living alone, women and men with ischemic stroke had similar times to arrival. Arrival time is not likely a major contributor to differences in outcome between men and women., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Leukocytosis is associated with hemorrhage volume and early neurologic deterioration after intracerebral hemorrhage (ICH). We examined total white blood cell (WBC) count, absolute monocyte count (AMC), and absolute neutrophil count (ANC) as potential readily available prognostic biomarkers in human ICH., Methods: In a retrospective study, adult patients aged 18 years or older who presented to 1 of 2 local hospitals with nontraumatic ICH from July 2008 to December 2009 within 12 hours of symptom onset were identified. Demographics, Glasgow Coma Scale (GCS), ICH volume, ICH location, and 30-day case fatality rates were determined. Total WBC count, ANC, AMC, and hemoglobin concentration were determined. Linear and logistic regressions were used to evaluate factors associated with baseline ICH volume (log transformed) and 30-day case fatality, respectively., Results: Of the 186 patients, mean (±SD) age was 67.3 ± 14.8 years; 51% were men and 22% were black. Median (interquartile range) ICH volume was 12.8 (4.9, 29.4) mL. After adjusting for patient age and initial hemoglobin, higher initial WBC count (P = .0009) and higher ANC (P = .006) were associated with higher ICH volume, whereas AMC was not (P = .4). After adjusting for patient age, GCS, intraventricular hemorrhage (+/-), stroke location, and ICH volume, baseline AMC was associated with greater odds of 30-day case fatality (odds ratio 2.26, 95% confidence interval 1.10-4.65, P = .03)., Conclusions: The association of AMC with higher 30-day case fatality after ICH is hypothesis generating. Given the lack of association between presenting AMC and ICH volume, AMC may contribute to secondary injury after ICH (hematoma expansion and/or cerebral edema)., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Elevated blood pressure is common in patients with acute subarachnoid hemorrhage (SAH). American Heart Association guidelines do not specify a blood pressure target, but limited data suggest that systolic blood pressure (SBP)≥160 mmHg is associated with increased risk of rebleeding and neurologic decline. In a population-based study, we determined the frequency of antihypertensive therapy in emergency department (ED) patients with SAH and the proportion of those patients with SBP≥160 mmHg who received this therapy. In 2005, nontraumatic SAH cases were retrospectively ascertained at 16 hospitals in our region by screening for International Classification of Diseases Ninth Revision diagnostic codes 430-436. Blood pressure was recorded at ED presentation and also before and after any treatment with antihypertensives. Hypotension was defined as SBP<100 mmHg. The Mann-Whitney U test and χ2 test were used for comparisons. Our cohort comprised 82 patients with SAH presenting to an ED; 4 patients were excluded. The median age of the included patients was 54 years, 74.4% were female, 29.5% were black, and 31 (39.7%) had SBP≥160 mmHg. Antihypertensive therapy was given to 22 of 31 patients (70.9%) with SBP≥160 mmHg and to 4 of 47 patients (8.5%) with SBP<160 mmHg. No patients became hypotensive after receiving treatment. Age, sex, Glascow Coma Scale score, and National Institutes of Health Stroke Scale score were similar between treated and untreated patients. In the absence of definitive evidence, current blood pressure management in local EDs appears reasonable. Further studies of blood pressure management in acute SAH are warranted., (Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Recruitment challenges are common in acute stroke clinical trials. In a population-based study, we determined eligibility and actual enrollment for a successful, phase II acute stroke clinical trial. We hypothesized that missed opportunities for enrollment of eligible patients occurred frequently, despite the success of the trial., Methods: In 2005, acute ischemic stroke (AIS) cases in our region were identified at all 17 local hospitals as part of an epidemiologic study. The Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue Plasminogen Activator (CLEAR) trial assessed the safety of this combination in AIS patients within 3 hours of symptom onset. In 2005, we determined the proportion of AIS patients who were eligible for CLEAR and the proportion that were actually enrolled., Results: At 8 participating hospitals, 33 (2.8%) of 1175 AIS patients were eligible for CLEAR. Of 33 eligible patients, 18 (54.5%) were approached for enrollment, 4 (12.1%) refused, 1 (3.0%) was not consentable, and 13 (39.4%) were enrolled. Of the 15 not approached for enrollment in the trial, 10 were evaluated by the stroke team; 7 received recombinant tissue plasminogen activator. Enrollment was not associated with night or weekend presentation., Conclusions: Although the CLEAR trial was successful in meeting its delineated recruitment goals, our findings suggest enrollment could have been more efficient. Three out of 4 patients approached for enrollment participated in the trial. Eligible patients who were not approached and those treated with recombinant tissue plasminogen activator but not enrolled represent targets for improving enrollment rates., (Copyright © 2012 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Stroke survivors should recognize and control vascular risk factors to prevent recurrent strokes. We therefore assessed the prevalence, treatment, and control of hypertension, diabetes, and dyslipidemia among stroke survivors versus stroke-free control subjects., Methods: We conducted cross-sectional analysis from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study cohort, which includes oversampling from the Stroke Belt and African Americans. Patients were interviewed by telephone then visited for blood pressure, glucose, and lipid measurements. There were 2830 participants reporting a past stroke or transient ischemic attack (TIA) (stroke survivors) and 24,886 participants without past stroke or TIA (control subjects). Outcome measures included the recognition, treatment, and control of hypertension, diabetes, and dyslipidemia., Results: Stroke survivors were more likely to have unrecognized hypertension (18.7% v 13.5%, P < .0003), unrecognized stage 2 hypertension (4.4% v 2.2%, P < .0006), and unrecognized diabetes (4.2% v 3.2%, P < .026) versus control subjects. Stroke survivors were more likely to be treated for hypertension (92.4% v 89.0%, P < .0001), diabetes (88.3% v 81.4%, P < .0001), and dyslipidemia (76.3% v 61.9%, P < .0001). However, despite treatment, stroke survivors were more likely to have hypertension (33.3% v 30.4%, P=.0074) and stage 2 hypertension (9.1% v 7.6%, P=.017). Predictors of unrecognized and undertreated risk factors in stroke survivors include increasing body mass index, black race, and lower education., Conclusion: Despite having a past stroke or TIA, stroke survivors had higher rates of unrecognized hypertension, unrecognized diabetes, and undertreated hypertension. Better efforts are needed to help stroke survivors recognize and control vascular risk factors to prevent recurrent stroke., (Copyright (c) 2010 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: The Joint Commission (JC) certifies primary stroke centers in the United States. Whether certification promotes enrollment of study subjects into stroke research studies is not known. We examined whether enrollment performance of centers was related to JC certification status., Methods: The 51 US Siblings with Ischemic Stroke Study (SWISS) centers were characterized by JC certification status, year of certification, year initiated into SWISS, center location, and whether the center had a vascular/stroke neurology fellowship program accredited by the Accreditation Council for Graduate Medical Education. Performance measures included days elapsed from initiation to first enrollment, total enrollments within 12 months after initiation, and annual rate of enrollment thereafter., Results: In all, 36 of 51 SWISS sites (71%) were JC certified. A total of 32 (63%) were initiated into the study from 2000 through 2002, and 19 (37%) were initiated from 2005 through May 2008. Comparison of certified and noncertified sites showed no significant difference in the time to first enrollment (median, 77.5 v 115 days; P = .90), total enrollees in the first year (median, 3 v 2 probands; P = .69), or annual enrollment rate (median, 1.9 v 1.8 probands; P = .72). The rate of enrollment or time to first enrollment was not different between 2000-to-2002 and 2005-to-2008 sites. Early-initiated centers tended to have better year-1 enrollment than later-initiated centers (3 v 2 probands; P = .056)., Conclusions: JC certification did not have a significant effect on SWISS center enrollment. The JC should encourage the research mission among certified stroke centers.

Background: A recent meta-analysis suggested that racial/ethnic status is not a major determinant of willingness to participate in observational studies or treatment trials. However, little is known about the predictors of enrollment in family-based observational genetic studies. We tested the hypothesis that proband race/ethnicity is a significant predictor of enrolling a pedigree., Methods: Univariable and multivariable logistic regression modeling was used to determine proband characteristics that predict DNA donation from both members of an affected sibling pair. A total of 619 adult male and female probands with first-time or recurrent ischemic stroke and a positive sibling history of stroke enrolled across 53 hospitals and clinics in the United States and Canada into the Siblings with Ischemic Stroke Study, a family-based prospective genomics study., Results: In univariable analysis, probands with siblings who agreed to a blood draw for DNA analyses were more likely to be male and less likely to be nonwhite. In multivariable analysis, only race/ethnicity was significantly associated with likelihood of a proband's having a sibling who agreed to a blood draw., Conclusions: Contrary to observational studies that are not family based, the willingness of family members to participate in observational genetics studies may be influenced by race/ethnicity. This result reinforces the need for improving methods for recruiting diverse populations into genetic studies of stroke.

Background: The reliability of the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system of stroke in siblings of stroke-affected probands has not been tested. Similarly, the reliability of using clinical medical records to classify ischemic stroke has not been assessed. The purpose of this study was to establish the interrater reliability of sibling stroke subtyping by applying the TOAST criteria to retrospectively obtained medical records., Methods: Thirty medical records were randomly sampled from among the records of all siblings previously classified as stroke affected by the Siblings with Ischemic Stroke Study (SWISS) Stroke Verification Committee. Blinded medical records for these individuals were sent to 6 physician reviewers who independently classified TOAST stroke subtype on the basis of record review., Results: Using the kappa statistic to assess interrater reliability, the overall reliability (SE) for assigning a TOAST subtype of stroke was 0.54 (0.03). Pair-wise comparisons between the original SWISS Stroke Verification Committee diagnoses and the diagnoses made by other reviewers exhibited moderate reliability (kappa range 0.41-0.56). The kappa statistics for common stroke subtypes were large vessel, 0.80 (0.06); cardioembolic, 0.80 (0.06); small vessel, 0.53 (0.06); and unknown cause, 0.40 (0.06)., Conclusion: We conclude that TOAST subtyping had moderate interrater reliability. Large-artery and cardioembolic subtype diagnoses seemed most reliable.

Objective: Quantifying stroke severity is essential for interpreting outcomes in stroke studies; severity impacts outcomes. Because outcome studies often enroll patients some time after stroke and there is little standardization of the history and physical examination, objective measurement of stroke severity is limited. A method for retrospectively scoring the National Institutes of Health Stroke Scale (NIHSS) based on history and physical examination has been proposed, but has yet to be validated in patients with higher NIHSS score. We evaluate the validity of this scoring method across the spectrum of the NIHSS scores., Methods: The retrospective scoring algorithm was applied to history and physical examinations documented for 58 patients with ischemic stroke presenting to any of 17 regional acute care facilities who had a NIHSS score recorded by a stroke team physician. The retrospective NIHSS score was obtained by standardized chart review. Linear regression was used to estimate scale-dependent and scale-independent bias. Limits of agreement quantify deviation of the retrospective NIHSS score from the prospective NIHSS score., Results: Mean (SD) age at stroke was 66 (14) years; 27 (46.6%) patients were men, and 38 (65.5%) were white. The mean (SD) prospective NIHSS score was 13.6 (7.8); the mean (SD) retrospective NIHSS score was 13.7 (7.8). There were 23 (40%) prospective NIHSS scores above 15, and 13 scores (22%) above 20. The linear regression constant was 0.290 (95% confidence interval -0.107, 0.687); the slope was 0.987 (95% confidence interval 0.962, 1.013). The R(2) for the model was 0.991. Limits of agreement were -1.35 and 1.59., Conclusion: The retrospective NIHSS appears valid across the entire spectrum of scores.

We have previously reported that family history of intracerebral hemorrhage (ICH) was associated with both lobar and nonlobar ICH. We sought to further examine this finding by analyzing differences by age and by apolipoprotein E (Apo E) genotype. All cases of hemorrhagic stroke in the greater Cincinnati area were identified through retrospective screening, and a subset was invited to undergo a direct interview and genetic testing. Interviewed subjects were matched to 2 controls by age, race, and sex. Conditional stepwise logistic regression modeling was used to determine whether having a first-degree relative with an ICH (FHICH) was an independent risk factor for ICH. Between May 1997 and December 2002, we recruited 333 cases of ICH. FHICH was found to be an independent risk factor for both lobar ICH (odds ratio [OR] = 3.9; P = .04) and nonlobar ICH (OR ratio = 5.4; P = .01) after controlling for the presence of numerous variables. Among nonlobar ICH cases, the risk appeared to be predominately in those age < 70 years. The presence of Apo E4 was associated with lobar ICH at age >/= 70 years but not at age < 70 years. Family history of ICH appears to be a significant risk factor for nonlobar ICH at age < 70 years. The presence of Apo E4 appears to be a risk factor for lobar ICH at age >/= 70 years but not at age < 70 years. Family history of ICH is a risk factor for lobar ICH after controlling for the presence of Apo E4.

To date, there have been no population-based data published regarding the influence of the patient's demographic factors on rt-PA use. We present preliminary data regarding the effect of race and gender on patterns of rt-PA use in the pre-FDA approval era, in a population with demographic and socioeconomic characteristics similar to the United States. All ischemic strokes within a biracial population of 1.3 million were identified by review of all primary and secondary hospital ICD-9-CM codes 430-438 from July 1993 to June 1994 at all hospitals in the region. The number of patients treated with rt-PA or placebo as part of the blinded NINDS rt-PA trial, as well as demographic characteristics, were recorded and analyzed. There were a total of 1973 hospitalized ischemic strokes that occurred at a hospital participating in the NINDS rt-PA trial. Patients that received rt-PA were significantly younger than those that did not (mean age 67 v 72, respectively, P = .01). Of the 413 strokes that occurred in African Americans, 2.2% were treated with rt-PA vs. 2.6% of the 1560 non-African Americans. Women (2.0%) and men (3.0%) were equally likely to receive rt-PA. The single academic center was as likely to give rt-PA as the community medical centers. In the Greater Cincinnati/Northern Kentucky population, patterns of rt-PA use in 1993-94 did not appear to vary according to race or gender, or type of medical center. These findings may be in part because of the regionally-based method of stroke care delivery in the area.