Effect of Alteplase on Ischemic Stroke Mortality Is Dependent on Stroke Severity.

OBJECTIVE: Although intravenous alteplase (IV-tPA) has a beneficial effect on functional outcome after ischemic stroke (IS), prior studies of IV-tPA's impact on post-stroke mortality did not have sufficient representation of more severe stroke. METHODS: We determined if the interaction between the baseline National Institutes of Health (NIH) Stroke Scale (NIHSS) and IV-tPA modified the risk of mortality after IS in two cohorts: (1) National Inpatient Sample 2016-2020, and (2) a harmonized cohort of IS patients from the NINDS IV-tPA, ALIAS part 2, SHINE, FAST-MAG, IMS-III, POINT, and DEFUSE 3 trials. We fit logistic regression models to the outcome of in-hospital mortality (National Inpatient Sample [NIS] cohort) or mortality within 90 days (harmonized cohort), adjusted for baseline variables. RESULTS: We included 198,668 patients in the NIS cohort, of which 14.0% received IV-tPA and 3.4% died in hospital. We included 7,138 patients in the harmonized cohort, of which 33.2% received IV-tPA and 9.4% died by 90 days. Mortality in the NIS cohort was associated with older age, female sex, non-Hispanic white race, atrial fibrillation, and higher NIHSS. In the harmonized cohort, mortality was associated with older age, diabetes, atrial fibrillation, and higher NIHSS. In both cohorts, the interaction between NIHSS and IV-tPA was significant. In the NIS cohort, the separation became significant at NIHSS 15 and in the harmonized cohort at NIHSS 23, at which point, IV-tPA began to have a significant benefit for both in-hospital and 90-day mortality, respectively. INTERPRETATION: IV-tPA is associated with a reduction in both in-hospital and 90-day mortality for patients with more severe IS. ANN NEUROL 2023;93:1106-1116.

Association Between Hospital-Documented Atrial Fibrillation and Central Retinal Artery Occlusion.

BACKGROUND: Carotid stenosis is thought to be the primary risk factor for central retinal artery occlusion (CRAO); however, it is not known whether atrial fibrillation (AF)-a cardiac arrhythmia that underlies over 25% of cerebral ischemic strokes-predisposes patients to CRAO. METHODS: A retrospective, observational, cohort study was performed using data from the State Inpatient Databases and State Emergency Department Databases from New York (2006-2015), California (2003-2011), and Florida (2005-2015) to determine the association between AF and CRAO. The primary exposure was hospital-documented AF. The primary end point was hospital-documented CRAO, defined as having an International Classification of Diseases, Ninth Revision, Clinical Modification, code 362.31 in the primary diagnosis position. Cause-specific hazard models were used to model CRAO-free survival among patients according to hospital-documented AF status. RESULTS: Of 39 834 885 patients included in the study, 2 723 842 (median age, 72.7 years; 48.5% women) had AF documented during the exposure window. The median follow-up duration was 6 years and 1 month. Patients with AF were older, more likely to be of non-Hispanic White race/ethnicity, and had a higher burden of cardiovascular comorbidities compared with patients without AF. The cumulative incidence of CRAO determined prospectively after exclusions was 8.69 per 100 000 at risk in those with AF and 2.39 per 100 000 at risk in those without AF over the study period. Before adjustment, AF was associated with higher risk of CRAO (hazard ratio, 2.55 [95% CI, 2.15-3.03]). However, after adjustment for demographics, state, and cardiovascular comorbidities, there was an inverse association between AF and risk of CRAO (adjusted hazard ratio, 0.72 [95% CI, 0.60-0.87]). These findings were robust in our prespecified sensitivity analyses. By contrast, positive control outcomes of embolic and ischemic stroke showed an expected strong relationship between AF and risk of stroke. CONCLUSIONS: We found an inverse association between AF and CRAO in a large, representative study of hospitalized patients; however, this cohort did not ascertain AF or CRAO occurring outside of hospital or emergency department settings.

Effect of Antihypertensives by Class on Cerebral Small Vessel Disease: A Post Hoc Analysis of SPRINT-MIND.

BACKGROUND: Treatment of uncontrolled arterial hypertension reduces the risk of cerebral small vessel disease (CSVD) progression, although it is unclear whether this reduction occurs due to blood pressure control or class-specific pleiotropic effects, such as improved beat-to-beat arterial pressure variability with calcium channel blockers. The goal of this study was to investigate the influence of antihypertensive medication class, particularly with calcium channel blocker, on accumulation of white matter hyperintensities (WMH), a radiographic marker of CSVD, within a cohort with well-controlled hypertension. METHODS: We completed an observational cohort analysis of the SPRINT-MIND trial (Systolic Blood Pressure Trial Memory and Cognition in Decreased Hypertension), a large randomized controlled trial of participants who completed a baseline and 4-year follow-up brain magnetic resonance image with volumetric WMH data. Antihypertensive medication data were recorded at follow-up visits between the magnetic resonance images. A percentage of follow-up time participants were prescribed each of the 11 classes of antihypertensive was then derived. Progression of CSVD was calculated as the difference in WMH volume between 2 scans and, to address skew, dichotomized into a top tertile of the distribution compared with the remaining. RESULTS: Among 448 individuals, vascular risk profiles were similar across WMH progression subgroups except age (70.1±7.9 versus 65.7±7.3 years; P<0.001) and systolic blood pressure (128.3±11.0 versus 126.2±9.4 mm Hg; P=0.039). Seventy-two (48.3%) of the top tertile cohort and 177 (59.2%) of the remaining cohort were in the intensive blood pressure arm. Those within the top tertile of progression had a mean WMH progression of 4.7±4.3 mL compared with 0.13±1.0 mL (P<0.001). Use of angiotensin-converting enzyme inhibitors (odds ratio, 0.36 [95% CI, 0.16-0.79]; P=0.011) and dihydropyridine calcium channel blockers (odds ratio, 0.39 [95% CI, 0.19-0.80]; P=0.011) was associated with less WMH progression, although dihydropyridine calcium channel blockers lost significance when WMH was treated as a continuous variable. CONCLUSIONS: Among participants of SPRINT-MIND trial, angiotensin-converting enzyme inhibitor was most consistently associated with less WMH progression independent of blood pressure control and age.

Impact of Intracranial Pressure Monitor-Guided Therapy on Neurologic Outcome After Spontaneous Nontraumatic Intracranial Hemorrhage.

OBJECTIVES: Intracranial pressure (ICP) monitors have been used in some patients with spontaneous intracranial hemorrhage (ICH) to provide information to guide treatment without clear evidence for its use in this population. We assessed the impact of ICP monitor placement, including external ventricular drains and intraparenchymal monitors, on neurologic outcome in this population. MATERIALS AND METHODS: In this secondary analysis of the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation III trial, the primary outcome was poor outcome (modified Rankin Scale score 4-6) and the secondary outcome was death, at 1 year from onset. We compared outcomes in patients with or without an ICP monitor using unadjusted and adjusted logistic regression models. The analyses were repeated in a balanced cohort created with propensity score matching. RESULTS: Seventy patients underwent ICP monitor placement and 424 did not. Poor outcome was seen in 77.1% of patients in the ICP-monitor subgroup compared with 53.8% in the no-monitor subgroup (p<0.001). Of patients in the ICP-monitor subgroup, 31.4% died, compared with 21.0% in the no-monitor subgroup (p=0.053). In multivariate models, ICP monitor placement was associated with a >2-fold greater risk of poor outcome (odds ratio 2.76, 95% CI 1.30-5.85, p=0.008), but not with death (p=0.652). Our findings remained consistent in the propensity score-matched cohort. CONCLUSION: These results question whether ICP monitor-guided therapy in patients with spontaneous nontraumatic ICH improves outcome. Further work is required to define the causal pathway and improve identification of patients that might benefit from invasive ICP monitoring.

Black Patients with Ischemic Stroke and Hyperglycemia have Worse outcome than Whites if given Intensive Glucose Control.

BACKGROUND: Hyperglycemia is common after acute ischemic stroke and is associated with worse outcome, but intensive glucose control has not improved outcome. There is also a racial disparity in outcome after stroke, with Black patients more likely to have functional impairment than whites. We aimed to evaluate if there were racial differences in outcomes in acute ischemic stroke patients treated with intensive glucose control. METHODS: We performed a post-hoc analysis of the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial to determine if Black patients had worse functional outcome than whites and if standard versus intensive glucose control modified that association. We included non-Hispanic white and Black patients. The primary outcome was excellent functional outcome (90-day modified Rankin Score of 0-1). To account for patient clustering by study site, we fit mixed-effects logistic regression models to our outcome and tested the interaction of treatment and race. RESULTS: We included 895 patients, of which 304 (34%) were Black and 591 (66%) were white. The rate of excellent outcome was 31.6% in Black patients versus 41.0% in white patients (p=0.006). After adjusting for potential confounders, the odds ratio for excellent outcome in Black patients was 0.54 (95% CI 0.38-0.77). The interaction term between treatment and race was significant (p=0.067). In the intensive treatment arm, Black patients had a predicted probability of excellent outcome of 26.4% (20.1-32.8) versus 42.7% (37.6-47.9) for white patients (p<0.001), while in the standard treatment arm the difference was not significant. CONCLUSIONS: Black patients with acute ischemic stroke and hyperglycemia had worse functional outcome at 90 days than white patients, particularly if given intensive glucose control. These findings are from a post-hoc analysis and may be confounded, thus warrant additional study.

Impact of COVID-19 on Outcomes in Ischemic Stroke Patients in the United States.

BACKGROUND: Studies have shown worse outcomes in patients with comorbid ischemic stroke (IS) and coronavirus disease 2019 (COVID-19), but have had small sample sizes. METHODS: We retrospectively identified patients in the Vizient Clinical Data Base® with IS as a discharge diagnosis. The study outcomes were in-hospital death and favorable discharge (home or acute rehabilitation). In the primary analysis, we compared IS patients with laboratory-confirmed COVID-19 (IS-COVID) discharged April 1-July 31, 2020 to pre-COVID IS patients discharged in 2019 (IS controls). In a secondary analysis, we compared a matched cohort of IS-COVID patients to patients within the IS controls who had pneumonia (IS-PNA), created with inverse-probability-weighting (IPW). RESULTS: In the primary analysis, we included 166,586 IS controls and 2086 IS-COVID from 312 hospitals in 46 states. Compared to IS controls, IS-COVID were less likely to have hypertension, dyslipidemia, or be smokers, but more likely to be male, younger, have diabetes, obesity, acute renal failure, acute coronary syndrome, venous thromboembolism, intubation, and comorbid intracerebral or subarachnoid hemorrhage (all p<0.05). Black and Hispanic patients accounted for 21.7% and 7.4% of IS controls, respectively, but 33.7% and 18.5% of IS-COVID (p<0.001). IS-COVID, versus IS controls, were less likely to receive alteplase (1.8% vs 5.6%, p<0.001), mechanical thrombectomy (4.4% vs. 6.7%, p<0.001), to have favorable discharge (33.9% vs. 66.4%, p<0.001), but more likely to die (30.4% vs. 6.5%, p<0.001). In the matched cohort of patients with IS-COVID and IS-PNA, IS-COVID had a higher risk of death (IPW-weighted OR 1.56, 95% CI 1.33-1.82) and lower odds of favorable discharge (IPW-weighted OR 0.63, 95% CI 0.54-0.73). CONCLUSIONS: Ischemic stroke patients with COVID-19 are more likely to be male, younger, and Black or Hispanic, with significant increases in morbidity and mortality compared to both ischemic stroke controls from 2019 and to patients with ischemic stroke and pneumonia.

End-of-Treatment Intracerebral and Ventricular Hemorrhage Volume Predicts Outcome: A Secondary Analysis of MISTIE III.

Background and Purpose- Trials have shown potential clinical benefit for minimally invasive clot evacuation of intracerebral hemorrhage (ICH). Prior research showing an association between ICH size and functional outcome did not fully address the spectrum of hematoma volumes seen after clot evacuation. Methods- In this secondary analysis of the MISTIE III trial (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation III), we included patients randomized to the surgical arm. The primary outcome was good outcome (modified Rankin Scale score 0-3 at 1 year from study enrollment). The primary predictors were the end-of-treatment (EoT) ICH and intraventricular hemorrhage volumes and an end-of-treatment ICH stratification scale called the EoT ICH volume score. Results- In 246 patients, the end-of-treatment computed tomography was performed an average of 5 days from onset. For patients with good versus poor outcomes, the mean end-of-treatment ICH and intraventricular hemorrhage volumes were 12.9 versus 18.0 mL (P=0.002) and 0.5 versus 2.3 mL (P<0.001), respectively. The probability of a good outcome decreased from 73% for EoT ICH volume 3 (<5 mL) to 28% for EoT ICH volume 0 (>20 mL; P=0.001). Conclusions- After surgical clot evacuation, both ICH and intraventricular hemorrhage volumes have a strong association with good neurological outcome. The EoT ICH volume score needs independent verification, but such an approach could be used for prognostication and therapeutic planning.

Vasculitis in the Central Nervous System: Etiology, Characteristics, and Outcomes in a Large Single-Center Cohort.

Background and Purpose: For the management of central nervous system (CNS) vasculitis, it is crucial to differentiate between primary and secondary CNS vasculitis and to understand the respective etiologies. We assessed the etiology, characteristics, and outcomes of patients with CNS vasculitis. Methods: A single-center retrospective chart review was conducted at the University of Utah, Department of Neurology, between February 2011 and October 2022. Results: The median age of the 44 included patients at diagnosis was 54 years; 25.0% were men. Compared to primary CNS vasculitis, secondary CNS vasculitis exhibits higher fever incidence (observed in infectious and connective tissue disorder [CTD]-associated vasculitis), low glucose levels (mostly in infectious vasculitis) and unique cerebrospinal fluid oligoclonal bands (observed in infectious and CTD-associated vasculitis). Patients with inflammatory cerebral amyloid angiopathy (CAA) were older and more commonly had microhemorrhage than primary angiitis of the CNS (PACNS). All patients with CTD-associated vasculitis had a known history of CTD at presentation. Brain biopsies were performed on 10 of 17 PACNS patients and 4 of 8 inflammatory CAA patients, confirming vasculitis in 7 and 4 patients, respectively. Intravenous methylprednisolone was the predominant induction therapy (63.6%), and cyclophosphamide was the most used adjunctive therapy. Cyclophosphamide, rituximab, azathioprine, and mycophenolate mofetil were utilized as maintenance therapy, often with concurrent prednisone. Patients with inflammatory CAA had a higher tendency for relapse rates than PACNS. Conclusions: This study highlights the variations in patients' characteristics, symptoms, and treatment for CNS vasculitis. Understanding these differences can lead to more efficient diagnostic and management strategies.

Direct cost analysis of rapid MRI in the emergency department evaluation of patients suspected of having acute ischemic stroke*.

BACKGROUND: Abbreviated "rapid MRI" protocols have become more common for the evaluation of acute ischemic stroke (AIS). Prior research has not evaluated the effect of rapid MRIs on cost or hospital length of stay in AIS patients. METHODS: We retrospectively identified AIS patients who presented within 6 h of acute neurologic symptom onset to an emergency department (ED) and activated a "brain attack" code. We included sequential patients from January 2012 to September 2015, before rapid MRI was available, who had CT perfusion (CTP) and compared them to patients from October 2015 to May 2018 who had a rapid MRI. We used inverse-probability-weighting (IPW) to balance the cohorts. The primary outcomes were direct cost to our healthcare system and total hospital length of stay (LOS). RESULTS: We included 408 brain attack activations (mean ± SD age 62.1 ± 17.6 years, 47.8% male): 257 in the CTP cohort and 151 in the MRI cohort. Discharge diagnosis was ischemic stroke in 193/408 (47.3%). After patient matching, we found significant reductions for the MRI cohort in total cost (-18.7%, 95% CI -35.0, -2.4, p = 0.02) and hospital LOS (-17.0%, 95% CI -31.2, -2.8, p = 0.02), with no difference in ED LOS (p = 0.74) as compared to the CTP cohort. CONCLUSION: Although these results are preliminary and hypothesis-generating, we found that the use of a rapid MRI protocol in emergency department brain attacks was associated with a 18.7% reduction in total direct cost and 17% reduction in hospital length of stay.

Association of Blood Pressure Variability With Death and Discharge Destination Among Critically Ill Patients With and Without Stroke.

BACKGROUND AND OBJECTIVES: It is unclear whether blood pressure variability's (BPV) association with worse outcomes is unique to patients with stroke or a risk factor among all critically ill patients. We (1) determined whether BPV differed between patients with stroke and nonstroke patients, (2) examined BPV's associations with in-hospital death and favorable discharge destination in patients with stroke and nonstroke patients, and (3) assessed how minimum mean arterial pressure (MAP)-a correlate of illness severity and cerebral perfusion-affects these associations. METHODS: This is a retrospective analysis of adult intensive care unit patients hospitalized between 2001 and 2012 from the Medical Information Mart for Intensive Care III database. Confounder-adjusted logistic regressions determined associations between BPV, measured as SD and average real variability (ARV), and (1) in-hospital death and (2) favorable discharge, with testing of minimum MAP for effect modification. RESULTS: BPV was higher in patients with stroke (N = 2,248) compared with nonstroke patients (N = 9,085) (SD mean difference 2.3, 95% CI 2.1-2.6, p < 0.01). After adjusting for minimum tertile of MAP and other confounders, higher SD remained significantly associated (p < 0.05) with higher odds of in-hospital death for patients with acute ischemic strokes (AISs, odds ratio [OR] 2.7, 95% CI 1.5-4.8), intracerebral hemorrhage (ICH, OR 2.6, 95% CI 1.6-4.3), subarachnoid hemorrhage (SAH, OR 3.4, 95% CI 1.2-9.3), and pneumonia (OR 1.9, 95% CI 1.1-3.3) and lower odds of favorable discharge destination in patients with ischemic stroke (OR 0.3, 95% CI 0.2-0.6) and ICH (OR 0.4, 95% CI 0.3-0.6). No interaction was found between minimum MAP tertile with SD (p > 0.05). Higher ARV was not significantly associated with increased risk of death in any condition when adjusting for illness severity but portended worse discharge destination in those with AIS (OR favorable discharge 0.4, 95% CI 0.3-0.7), ICH (OR favorable discharge 0.5, 95% CI 0.3-0.7), sepsis (OR favorable discharge 0.8, 95% CI 0.6-1.0), and pneumonia (OR favorable discharge 0.5, 95% CI 0.4-0.8). DISCUSSION: BPV is higher and generally associated with worse outcomes among patients with stroke compared with nonstroke patients. BPV in patients with AIS and patients with ICH may be a marker of central autonomic network injury, although clinician-driven blood pressure goals likely contribute to the association between BPV and outcomes.

Modelling anticoagulation and health-related quality of life in those with atrial fibrillation: a secondary analysis of AFFIRM.

Associations of anticoagulation with primary endpoints in longitudinal studies are impacted by selection bias and time-varying covariates (e.g. comorbidities). We demonstrate how time-varying covariates and selection bias influence association estimates between anticoagulation and health-related quality of life (HRQoL) in patients with atrial fibrillation. We performed a secondary analysis of the Atrial Fibrillation Follow-up Investigation of Rhythm Management trial quality of life substudy. Dichotomized warfarin use was ascertained at the study baseline, 2 months later, and annually for up to 6 years. HRQoL was measured at every time point using a self-reported ordinal 5-point Likert-scale (lower score and lower odds ratio represents better health-related quality of life). Static and time-varying covariates were ascertained throughout the study period. Confounder-adjusted generalized mixed model and generalized estimating equation regressions were used to demonstrate traditional association estimates between anticoagulation and HRQoL. Inverse probability of treatment and censorship weights were used to ascertain the influence of time-varying confounding and selection bias. Age-stratified analysis (age ≥ 70 years) evaluated for effect modification. 656 individuals were included in the analysis, 601 on warfarin at baseline. The association of warfarin use with better HRQoL over time strengthened when accounting for time-varying confounding and selection bias (OR 0.30, 95% CI 0.14-0.55) compared to traditional analyses (OR 0.61, 95% CI 0.38-0.97), and was most pronounced in those ≥ 70 years upon stratified analysis. Anticoagulation is associated with higher HRQoL in patients with atrial fibrillation, with time-varying confounding and selection bias likely influencing longitudinal estimates in anticoagulation-HRQoL research.

Twenty-Year Disparity Trends in United States Stroke Death Rate by Age, Race/Ethnicity, Geography, and Socioeconomic Status.

BACKGROUND AND OBJECTIVES: In 2017, the Centers for Disease Control and Prevention (CDC) issued an alert that, after decades of consistent decline, the stroke death rate levelled off in 2013, particularly in younger individuals and without clear origin. The objective of this analysis was to understand whether social determinants of health have influenced trends in stroke mortality. METHODS: We performed a longitudinal analysis of county-level ischemic and hemorrhagic stroke death rate per 100,000 adults from 1999 to 2018 using a Bayesian spatiotemporally smoothed CDC dataset stratified by age (35-64 years [younger] and 65 years or older [older]) and then by county-level social determinants of health. We reported stroke death rate by county and the percentage change in stroke death rate during 2014-2018 compared with that during 2009-2013. RESULTS: We included data from 3,082 counties for younger individuals and 3,019 counties for older individuals. The stroke death rate began to increase for younger individuals in 2013 (p < 0.001), and the slope of the decrease in stroke death rate tapered for older individuals (p < 0.001). During the 20-year period of our study, counties with a high social deprivation index and ≥10% Black residents consistently had the highest rates of stroke death in both age groups. Comparing stroke death rate during 2014-2018 with that during 2009-2013, larger increases in younger individuals' stroke death rate were seen in counties with ≥90% (vs <90%) non-Hispanic White individuals (3.2% mean death rate change vs 1.7%, p < 0.001), rural (vs urban) populations (2.6% vs 2.0%, p = 0.019), low (vs high) proportion of medical insurance coverage (2.9% vs 1.9%, p = 0.002), and high (vs low) substance abuse and suicide mortality (2.8 vs 1.9%, p = 0.008; 3.3% vs 1.5%, p < 0.001). In contrast to the younger individuals, in older individuals, the associations with increased death rates were with more traditional social determinants of health such as the social deprivation index, urban location, unemployment rate, and proportion of Black race and Hispanic ethnicity residents. DISCUSSION: Improvements in the stroke death rate in the United States are slowing and even reversing in younger individuals and many US counties. County-level increases in stroke death rate were associated with distinct social determinants of health for younger vs older individuals. These findings may inform targeted public health strategies.

Neurologic Manifestations of Common Variable Immunodeficiency: Impact on Quality of Life.

BACKGROUND AND OBJECTIVES: Common variable immunodeficiency is a systemic disease and not solely a disease of humoral immunity. Neurologic symptoms associated with common variable immunodeficiency are underrecognized and warrant further study. This work aimed to characterize the neurologic symptoms reported by people living with common variable immunodeficiency. METHODS: We conducted a single academic medical center study of neurologic symptoms reported by adults previously diagnosed with common variable immunodeficiency. We used a survey of common neurologic symptoms to determine the prevalence of these symptoms in a population with common variable immunodeficiency and further assessed these patient-reported symptoms with validated questionnaires and compared symptom burden with other neurologic conditions. RESULTS: A volunteer sample of adults (aged 18 years or older) previously diagnosed with common variable immunodeficiency at the University of Utah Clinical Immunology/Immune Deficiency Clinic who were able to read and comprehend English and willing and able to answer survey-based questions were recruited. Of 148 eligible participants identified, 80 responded and 78 completed the surveys. The mean age of respondents was 51.3 years (range 20-78 years); 73.1% female and 94.8% White. Patients with common variable immunodeficiency reported many common neurologic symptoms (mean 14.6, SD 5.9, range 1-25), with sleep issues, fatigue, and headache reported by more than 85%. Validated questionnaires addressing specific neurologic symptoms supported these results. T-scores on Neuro QoL questionnaires for sleep (mean 56.4, SD 10.4) and fatigue (mean 54.1, SD 11) were higher, indicating more dysfunction, than in the reference clinical population (p < 0.005). The Neuro QoL questionnaire for cognitive function showed a lower T-score (mean 44.8, SD 11.1) than that in the reference general population (p < 0.005), indicating worse function in this domain. DISCUSSION: Among survey respondents, there is a marked burden of neurologic symptoms. Given the impact of neurologic symptoms on health-related quality-of-life measures, clinicians should screen patients with common variable immunodeficiency for the presence of these symptoms and offer referral to neurologists and/or symptomatic treatment when indicated. Frequently prescribed neurologic medications may also affect the immune system, and neurologists should consider screening patients for immune deficiency before prescribing them.

Effect of dihydropyridine calcium channel blockers on blood pressure variability in the SPRINT trial: a treatment effects approach.

OBJECTIVE: Increased visit-to-visit blood pressure variability (vvBPV) has negative effects on multiple organ systems. Prior research has suggested that dihydropyridine calcium channel blockers (CCB) may reduce vvBPV, which we attempted to verify in a high-quality dataset with robust statistical methodology. METHODS: We performed a post hoc analysis of the SPRINT trial and included participants who were on a dihydropyridine CCB either 0 or 100% of follow-up study visits. The primary outcome was vvBPV, defined as residual standard deviation (rSD) of SBP from month 6 until study completion. We estimated the average treatment effect of the treated (ATET) after augmented inverse-probability-weighting (AIPW) matching. RESULTS: Of the 9361 participants enrolled in SPRINT, we included 5020, of whom 1959 were on a dihydropyridine CCB and 3061 were not; mean age was 67.4 ±â€Š9.2 years, 34.5% were men, 65.9% were white, 49.4% were randomized to intensive blood pressure control, and the rSD was 10.1 ±â€Š4.0 mmHg. Amlodipine represented greater than 95% of dihydropyridine CCB use. After AIPW matching of demographics and other antihypertensive medications, the ATET estimation for participants on a dihydropyridine CCB was an rSD that was 2.05 mmHg lower (95% CI -3.19 to -0.91). We did not find that other antihypertensive medications classes decreased vvBPV, and several increased it. CONCLUSION: In the SPRINT trial, consistent use of a dihydropyridine CCB was associated with a 2 mmHg reduction in vvBPV. The implication of this hypothesis-generating finding in a high-quality dataset is that future trials to reduce vvBPV could consider using dihydropyridine CCBs.

Association of Preeclampsia With Incident Stroke in Later Life Among Women in the Framingham Heart Study.

Importance: Contemporary research suggests an association between preeclampsia and later-life stroke among women. To our knowledge, no research to date has accounted for the time-varying nature of shared risk factors for preeclampsia and later-life stroke incidence. Objective: To assess the relative risk of incident stroke in later life among women with and without a history of preeclampsia after accounting for time-varying covariates. Design, Setting, and Participants: This population-based cohort study was a secondary analysis of data from the Framingham Heart Study, which was conducted from 1948 to 2016. Women were included in the analysis if they were stroke free at enrollment and had a minimum of 3 study visits and 1 pregnancy before menopause, hysterectomy, or age 45 years. Data on vascular risk factors, history of preeclampsia, and stroke incidence were collected biannually. Participants were followed up until incident stroke or censorship from the study. Marginal structural models were used to evaluate the relative risk of incident stroke among participants with and without a history of preeclampsia after accounting for time-varying covariates. Data were analyzed from May 2019 to December 2020. Exposures: Presence or absence of preeclampsia among women with 1 or more pregnancies. Main Outcomes and Measures: Incident stroke in later life. Results: A total of 1435 women (mean [SD] age, 44.4 [7.7] years at the beginning of the study; 100% White) with 41 422 person-years of follow-up were included in the analytic sample. Of those, 169 women had a history of preeclampsia, and 231 women experienced strokes during follow-up. At baseline, women with preeclampsia were more likely to be younger, to be receiving cholesterol-lowering medications, to have lower cholesterol and higher diastolic blood pressure, and to currently smoke. The association between preeclampsia and stroke in the marginal structural model was only evident when adjustment was made for all vascular risk factors over the life course, which indicated that women with a history of preeclampsia had a higher risk of stroke in later life compared with women without a history of preeclampsia (relative risk, 3.79; 95% CI, 1.24-11.60). Conclusions and Relevance: The findings of this cohort study suggest that preeclampsia may be a risk factor for later-life stroke among women after adjustment for time-varying vascular and demographic factors. Future research is warranted to fully explore the mediation of this association by midlife vascular risk factors.

Acute Ischemic Stroke Interventions in the United States and Racial, Socioeconomic, and Geographic Disparities.

BACKGROUND AND OBJECTIVES: In patients with ischemic stroke (IS), IV alteplase (tissue plasminogen activator [tPA]) and endovascular thrombectomy (EVT) reduce long-term disability, but their utilization has not been fully optimized. Prior research has also demonstrated disparities in the use of tPA and EVT specific to sex, race/ethnicity, socioeconomic status, and geographic location. We sought to determine the utilization of tPA and EVT in the United States from 2016-2018 and if disparities in utilization persist. METHODS: This is a retrospective, longitudinal analysis of the 2016-2018 National Inpatient Sample. We included adult patients who had a primary discharge diagnosis of IS. The primary study outcomes were the proportions who received tPA or EVT. We fit a multivariate logistic regression model to our outcomes in the full cohort and also in the subset of patients who had an available baseline National Institutes of Health Stroke Scale (NIHSS) score. RESULTS: The full cohort after weighting included 1,439,295 patients with IS. The proportion who received tPA increased from 8.8% in 2016 to 10.2% in 2018 (p < 0.001) and who had EVT from 2.8% in 2016 to 4.9% in 2018 (p < 0.001). Comparing Black to White patients, the odds ratio (OR) of receiving tPA was 0.82 (95% confidence interval [CI] 0.79-0.86) and for having EVT was 0.75 (95% CI 0.70-0.81). Comparing patients with a median income in their zip code of ≤$37,999 to >$64,000, the OR of receiving tPA was 0.81 (95% CI 0.78-0.85) and for having EVT was 0.84 (95% CI 0.77-0.91). Comparing patients living in a rural area to a large metro area, the OR of receiving tPA was 0.48 (95% CI 0.44-0.52) and for having EVT was 0.92 (95% CI 0.81-1.05). These associations were largely maintained after adjustment for NIHSS, although the effect size changed for many of them. Contrary to prior reports with older datasets, sex was not consistently associated with tPA or EVT. DISCUSSION: Utilization of tPA and EVT for IS in the United States increased from 2016 to 2018. There are racial, socioeconomic, and geographic disparities in the accessibility of tPA and EVT for patients with IS, with important public health implications that require further study.

Carotid Compliance and Parahippocampal and Hippocampal Volume over a 20-Year Period.

INTRODUCTION: We evaluated the association between carotid compliance, a measure of arterial stiffness, to parahippocampal volume (PHV) and hippocampal volume (HV) over 20 years later in the Atherosclerosis Risk in the Community study. METHODS: We included participants with common carotid compliance measurements at visit 1 (1987-1989) and volumetric brain MRI at visit 5 (2011-2013). The primary outcomes are pooled bilateral PHV and HV. We performed linear regression models adjusting for age, sex, vascular risk factors, and total brain volume. RESULTS: Of the 614 participants, higher compliance was correlated with higher PHV (R = 0.218[0.144-0.291], p < 0.001) and HV (R = 0.181 [0.105-0.255, p < 0.001]). The association was linear and significant after adjusting for confounders. At follow-up MRI, 30 patients with dementia had lower PHV and HV than patients without dementia (p < 0.001 and p < 0.001, respectively). CONCLUSION: Carotid compliance is associated with higher PHV and HV when measured 20 years later, further supporting the link between arterial stiffness and cognitive decline.

Midlife Blood Pressure Variability and Risk of All-Cause Mortality and Cardiovascular Events During Extended Follow-up.

BACKGROUND: Studies demonstrate an association between visit-to-visit blood pressure variability (BPV) and cardiovascular events and death. We aimed to determine the long-term cardiovascular and mortality effects of BPV in midlife in participants with and without cardiovascular risk factors. METHODS: This is a post-hoc analysis of the Atherosclerosis Risk in the Community study. Long-term BPV was derived utilizing mean systolic blood pressure at Visits 1-4 (Visit 1: 1987-1989, Visit 2: 1990-1992, Visit 3: 1993-1995, Visit 4: 1996-1998). The primary outcome was mortality from Visit 4 to 2016 and secondary outcome was cardiovascular events (fatal coronary heart disease, myocardial infarction, cardiac procedure, or stroke). We fit Cox proportional hazards models and also performed the analysis in a subgroup of cardiovascular disease-free patients without prior stroke, myocardial infarction, congestive heart failure, hypertension, or diabetes. RESULTS: We included 9,578 participants. The mean age at the beginning of follow-up was 62.9 ± 5.7 years, and mean follow-up was 14.2 ± 4.5 years. During follow-up, 3,712 (38.8%) participants died and 1,721 (n = 8,771, 19.6%) had cardiovascular events. For every SD higher in systolic residual SD (range 0-60.5 mm Hg, SD = 5.6 mm Hg), the hazard ratio for death was 1.09 (95% confidence interval [CI] 1.05-1.12) and for cardiovascular events was 1.00 (95% CI 0.95-1.05). In cardiovascular disease-free participants (n = 4,452), the corresponding hazard ratio for death was 1.12 (95% CI 1.03-1.21) and for cardiovascular events was 1.01 (95% CI 0.89-1.14). CONCLUSION: Long-term BPV during midlife is an independent predictor of later life mortality but not cardiovascular events.

Using Ultrasound and Inflammation to Improve Prediction of Ischemic Stroke: A Secondary Analysis of the Multi-Ethnic Study of Atherosclerosis.

INTRODUCTION: Current ischemic stroke risk prediction is primarily based on clinical factors, rather than imaging or laboratory markers. We examined the relationship between baseline ultrasound and inflammation measurements and subsequent primary ischemic stroke risk. METHODS: In this secondary analysis of the Multi-Ethnic Study of Atherosclerosis (MESA), the primary outcome is the incident ischemic stroke during follow-up. The predictor variables are 9 carotid ultrasound-derived measurements and 6 serum inflammation measurements from the baseline study visit. We fit Cox regression models to the outcome of ischemic stroke. The baseline model included patient age, hypertension, diabetes, total cholesterol, smoking, and systolic blood pressure. Goodness-of-fit statistics were assessed to compare the baseline model to a model with ultrasound and inflammation predictor variables that remained significant when added to the baseline model. RESULTS: We included 5,918 participants. The primary outcome of ischemic stroke was seen in 105 patients with a mean follow-up time of 7.7 years. In the Cox models, we found that carotid distensibility (CD), carotid stenosis (CS), and serum interleukin-6 (IL-6) were associated with incident stroke. Adding tertiles of CD, IL-6, and categories of CS to a baseline model that included traditional clinical vascular risk factors resulted in a better model fit than traditional risk factors alone as indicated by goodness-of-fit statistics. CONCLUSIONS: In a multiethnic cohort of patients without cerebrovascular disease at baseline, we found that CD, CS, and IL-6 helped predict the occurrence of primary ischemic stroke. Future research could evaluate if these basic ultrasound and serum measurements have implications for primary prevention efforts or clinical trial inclusion criteria.

Five-Year Trends in Payments for Neurologist-Prescribed Drugs in Medicare Part D.

OBJECTIVE: To determine whether there was an increase in payments for neurologist-prescribed drugs, we performed a retrospective analysis of prescription claims in the Medicare Part D Prescriber Public Use Files from 2013 to 2017. METHODS: We included claims prescribed by providers with the taxonomy "neurology" and included drugs present in all 5 years. Drugs were designated in 2013 as generic (GEN), brand name only (BNO), and brand name prescribed even though a generic equivalent is available (BNGE). To observe payment trends, the percentage change in the per claim payment was compared between drug classes. RESULTS: We included 520 drugs, of which 322 were GEN, 61 were BNO, and 137 were BNGE, representing 90,716,536 claims and generating payments of $26,654,750,720. While the number of claims from 2013 to 2017 increased only 7.6%, the total payment increased 50.4%. Adjusted for inflation, claim payments for GEN drug increased 0.6%, compared to significant increases in BNO and BNGE drugs of 42.4% and 45.0% (p trend < 0.001). The percentage of overall GEN claims increased from 81.9% to 88.0%, BNO increased from 4.9% to 6.2%, and BNGE decreased from 13.3% to 5.8%. Neuroimmunology/multiple sclerosis drugs represented >50% of the total payments despite being only 4.3% of claims. CONCLUSIONS: Payments for neurologist-prescribed brand name, but not generic, drugs in Medicare Part D increased consistently and well above inflation from 2013 to 2017. Unless the overall trend stabilizes or is reversed or high cost-to-claim drugs are addressed, this trend will place an increasing burden on the neurologic Medicare budget.