Severity of Ischemic Stroke After Left Atrial Appendage Closure vs Nonwarfarin Oral Anticoagulants.

BACKGROUND: Strokes after left atrial appendage closure (LAAC) prophylaxis are generally less severe than those after warfarin prophylaxis-thought to be secondary to more hemorrhagic strokes with warfarin. Hemorrhagic strokes are similarly infrequent with direct oral anticoagulant (DOAC) prophylaxis, so the primary subtype after either LAAC or DOAC prophylaxis is ischemic stroke (IS). OBJECTIVES: The purpose of this study was to compare the severity of IS using the modified Rankin Scale in atrial fibrillation patients receiving prophylaxis with DOACs vs LAAC. METHODS: A retrospective analysis was performed of consecutive patients undergoing LAAC at 8 centers who developed an IS (ISLAAC) compared with contemporaneous consecutive patients who developed IS during treatment with DOACs (ISDOAC). The primary outcome was disabling/fatal stroke (modified Rankin Scale 3-5) at discharge and 3 months later. RESULTS: Compared with ISDOAC patients (n = 322), ISLAAC patients (n = 125) were older (age 77.2 ± 13.4 years vs 73.1 ± 11.9 years; P = 0.002), with higher HAS-BLED scores (3.0 vs 2.0; P = 0.004) and more frequent prior bleeding events (54.4% vs 23.6%; P < 0.001), but similar CHA2DS2-VASc scores (5.0 vs 5.0; P = 0.28). Strokes were less frequently disabling/fatal with ISLAAC than ISDOAC at both hospital discharge (38.3% vs 70.3%; P < 0.001) and 3 months later (33.3% vs 56.2%; P < 0.001). Differences in stroke severity persisted after propensity score matching. By multivariate regression analysis, ISLAAC was independently associated with fewer disabling/fatal strokes at discharge (OR: 0.22; 95% CI: 0.13-0.39; P < 0.001) and 3 months (OR: 0.25; 95% CI: 0.12-0.50; P < 0.001), and fewer deaths at 3 months (OR: 0.28; 95% CI: 0.12-0.64; P < 0.001). CONCLUSIONS: Ischemic strokes in patients with atrial fibrillation are less often disabling or fatal with LAAC than DOAC prophylaxis.

Rationale and design of a randomized study comparing the Watchman FLX device to DOACs in patients with atrial fibrillation.

BACKGROUND: Percutaneous left atrial appendage (LAA) closure (LAAC) was developed as a nonpharmacologic alternative to oral anticoagulants (OACs) in patients with atrial fibrillation (AF) who are at an increased risk for stroke or systemic embolism. The Watchman device permanently seals off the LAA to prevent thrombi from escaping into the circulation. Previous randomized trials have established the safety and efficacy of LAAC compared to warfarin. However, direct OACs (DOACs) have become the preferred pharmacologic strategy for stroke prevention in patients with AF, and there is limited data comparing Watchman FLX to DOACs in a broad AF patient population. CHAMPION-AF is designed to prospectively determine whether LAAC with Watchman FLX is a reasonable first-line alternative to DOACs in patients with AF who are indicated for OAC therapy. STUDY DESIGN: A total of 3,000 patients with a CHA2DS2-VASc score ≥2 (men) or ≥3 (women) were randomized to Watchman FLX or DOAC in a 1:1 allocation at 142 global clinical sites. Patients in the device arm were to be treated with DOAC and aspirin, DOAC alone, or DAPT for at least 3 months postimplant followed by aspirin or P2Y12 inhibitor for 1-year. Control patients were required to take an approved DOAC for the duration of the trial. Clinical follow-up visits are scheduled at 3- and 12-months, and then annually through 5 years; LAA imaging is required at 4 months in the device group. Two primary end points will be evaluated at 3 years: (1) composite of stroke (ischemic/hemorrhagic), cardiovascular death, and systemic embolism compared for noninferiority, and (2) nonprocedural bleeding (International Society on Thrombosis and Haemostasis [ISTH] major and clinically relevant nonmajor bleeding) tested for superiority in the device arm against DOACs. The third primary noninferiority end point is the composite of ischemic stroke and systemic embolism at 5 years. Secondary end points include 3- and 5-year rates of (1) ISTH-defined major bleeding and (2) the composite of cardiovascular death, all stroke, systemic embolism, and nonprocedural ISTH bleeding. CONCLUSIONS: This study will prospectively evaluate whether LAAC with the Watchman FLX device is a reasonable alternative to DOACs in patients with AF. CLINICAL TRIAL REGISTRATION: NCT04394546.

New and expanding ventricular hemorrhage predicts poor outcome in acute intracerebral hemorrhage.

OBJECTIVE: To describe the relationship between intraventricular hemorrhage (IVH) expansion and long-term outcome and to use this relationship to select and validate clinically relevant thresholds of IVH expansion in 2 separate intracerebral hemorrhage (ICH) populations. METHODS: We used fractional polynomial analysis to test linear and nonlinear models of 24-hour IVH volume change and clinical outcome with data from the Predicting Hematoma Growth and Outcome in Intracerebral Hemorrhage Using Contrast Bolus CT (PREDICT)-ICH study. The primary outcome was poor clinical outcome (modified Rankin Scale [mRS] score 4-6) at 90 days. We derived dichotomous thresholds from the selected model and calculated diagnostic accuracy measures. We validated all thresholds in an independent single-center ICH cohort (Massachusetts General Hospital). RESULTS: Of the 256 patients from PREDICT, 127 (49.6%) had an mRS score of 4 to 6. Twenty-four-hour IVH volume change and poor outcome fit a nonlinear relationship, in which minimal increases in IVH were associated with a high probability of an mRS score of 4 to 6. IVH expansion ≥1 mL (n = 53, sensitivity 33%, specificity 92%, adjusted odds ratio [aOR] 2.68, 95% confidence interval [CI] 1.11-6.46) and development of any new IVH (n = 74, sensitivity 43%, specificity 85%, aOR 2.53, 95% CI 1.22-5.26) strongly predicted poor outcome at 90 days. The dichotomous thresholds reproduced well in a validation cohort of 169 patients. CONCLUSION: IVH expansion as small as 1 mL or any new IVH is strongly predictive of poor outcome. These findings may assist clinicians with bedside prognostication and could be incorporated into definitions of hematoma expansion to inform future ICH treatment trials.

Prospective Study of Fasting Blood Glucose and Intracerebral Hemorrhagic Risk.

BACKGROUND AND PURPOSE: Although diabetes mellitus is an established independent risk factor for ischemic stroke, the association between fasting blood glucose and intracerebral hemorrhage (ICH) is limited and inconsistent. The objective of the current study was to examine the potential impact of long-term fasting blood glucose concentration on subsequent risk of ICH. METHODS: This prospective study included 96 110 participants of the Kailuan study, living in Kailuan community, Tangshan city, China, who were free of cardiovascular diseases and cancer at baseline (2006). Fasting blood glucose concentration was measured in 2006, 2008, 2010, and 2012. Updated cumulative average fasting blood glucose concentration was used as primary exposure of the current study. Incident ICH from 2006 to 2015 was confirmed by review of medical records. RESULTS: During 817 531 person-years of follow-up, we identified 755 incident ICH cases. The nadir risk of ICH was observed at fasting blood glucose concentration of 5.3 mmol/L. The adjusted hazard ratios and their 95% confidence intervals (CIs) of ICH were 1.59 (95% CI, 1.26-2.02) for diabetes mellitus or fasting blood glucose ≥7.00 mmol/L, 1.31 (95% CI, 1.02-1.69) for impaired fasting blood glucose (fasting blood glucose, 6.10-6.99 mmol/L), 0.98 (95% CI, 0.78-1.22) for fasting blood glucose 5.60 to 6.09 mmol/L, and 2.04 (95% CI, 1.23-3.38) for hypoglycemia (fasting blood glucose, <4.00 mmol/L), comparing with normal fasting blood glucose 4.00 to 5.59 mmol/L. The results persisted after excluding individuals who used hypoglycemic, aspirin, antihypertensive agents, or anticoagulants, and those with intracerebral hemorrhagic cases occurred in the first 2 years of follow-up. CONCLUSIONS: In this large community-based cohort, low (<4.0 mmol/L) and high (≥6.1 mmol/L) fasting blood glucose concentrations were associated with higher risk of incident ICH, relative to fasting blood glucose concentrations of 4.00 to 6.09 mmol/L.

Blood Pressure Trajectories and the Risk of Intracerebral Hemorrhage and Cerebral Infarction: A Prospective Study.

The association between long-term blood pressure (BP) patterns in community-dwelling adults and risk of intracerebral hemorrhage and cerebral infarction is not well characterized. This prospective study included 79 385 participants, free of stroke, myocardial infarction, and cancer in or before 2010 (baseline). Systolic BP trajectories were identified using latent mixture modeling with data from 2006, 2008, and 2010. Incident cases of intracerebral hemorrhage and cerebral infarction occurred during 2010 to 2014, confirmed by review of medical records, by 3 physicians. We identified 5 distinct systolic BP trajectories during 2006 to 2010. Each of the trajectories was labeled according to their BP range and pattern over time: normotensive-stable (n=26 740), prehypertension-stable (n=35 674), stage 1 hypertension-increasing (n=8215), stage 1 hypertension-decreasing (n=6422), and stage 2 hypertension-stable (n=2334). We documented 1034 incident cases of cerebral infarction and 187 cases of intracerebral hemorrhage. Although the prehypertension-stable trajectory exhibited systolic BP range within the normal range (120-140 mm Hg) during 2006 to 2010, this group had higher stroke risk relative to the normotensive-stable group (<120 mm Hg) (adjusted hazard ratio was 3.11 for intracerebral hemorrhage and 1.99 for cerebral infarction; P<0.001 for both), after adjusting for possible confounders. Individuals in the stage 2 hypertension-stable systolic BP trajectory (175-179 mm Hg) had the highest risk of intracerebral hemorrhage (adjusted hazard ratio was 12.4) and cerebral infarction (adjusted hazard ratio was 5.07), relative to the normotensive-stable group (P<0.001 for both). BP trajectories were associated with the risk of stroke and increasing BP trajectories within the currently designated normal range may still increase the risk for stroke.

Noncontrast Computed Tomography Hypodensities Predict Poor Outcome in Intracerebral Hemorrhage Patients.

BACKGROUND AND PURPOSE: Noncontrast computed tomographic (CT) hypodensities have been shown to be associated with hematoma expansion in intracerebral hemorrhage (ICH), but their impact on functional outcome is yet to be determined. We evaluated whether baseline noncontrast CT hypodensities are associated with poor clinical outcome. METHODS: We performed a retrospective review of a prospectively collected cohort of consecutive patients with primary ICH presenting to a single academic medical center between 1994 and 2016. The presence of CT hypodensities was assessed by 2 independent raters on the baseline CT. Unfavorable outcome was defined as a modified Rankin score >3 at 90 days. The associations between CT hypodensities and unfavorable outcome were investigated using uni- and multivariable logistic regression models. RESULTS: During the study period, 1342 patients presented with ICH and 800 met restrictive inclusion criteria (baseline CT available for review, and 90-day outcome available). Three hundred and four (38%) patients showed hypodensities on CT, and 520 (65%) patients experienced unfavorable outcome. In univariate analysis, patients with unfavorable outcome were more likely to demonstrate hypodensities (48% versus 20%; P<0.0001). After adjustment for age, admission Glasgow coma scale, warfarin use, intraventricular hemorrhage, baseline ICH volume, and location, CT hypodensities were found to be independently associated with an increase in the odds of unfavorable outcome (odds ratio 1.70, 95% confidence interval [1.10-2.65]; P=0.018). CONCLUSIONS: The presence of noncontract CT hypodensities at baseline independently predicts poor outcome and comes as a useful and widely available addition to our ability to predict ICH patients' clinical evolution.

Association Between Hypodensities Detected by Computed Tomography and Hematoma Expansion in Patients With Intracerebral Hemorrhage.

IMPORTANCE: Hematoma expansion is a potentially modifiable predictor of poor outcome following an acute intracerebral hemorrhage (ICH). The ability to identify patients with ICH who are likeliest to experience hematoma expansion and therefore likeliest to benefit from expansion-targeted treatments remains an unmet need. Hypodensities within an ICH detected by noncontrast computed tomography (NCCT) have been suggested as a predictor of hematoma expansion. OBJECTIVE: To determine whether hypodense regions, irrespective of their specific patterns, are associated with hematoma expansion in patients with ICH. DESIGN, SETTING, AND PARTICIPANTS: We analyzed a large cohort of 784 patients with ICH (the development cohort; 55.6% female), examined NCCT findings for any hypodensity, and replicated our findings on a different cohort of patients (the replication cohort; 52.7% female). Baseline and follow-up NCCT data from consecutive patients with ICH presenting to a tertiary care hospital between 1994 and 2015 were retrospectively analyzed. Data analyses were performed between December 2015 and January 2016. MAIN OUTCOMES AND MEASURES: Hypodensities were analyzed by 2 independent blinded raters. The association between hypodensities and hematoma expansion (>6 cm3 or 33% of baseline volume) was determined by multivariable logistic regression after controlling for other variables associated with hematoma expansion in univariate analyses with P ≤ .10. RESULTS: A total of 1029 patients were included in the analysis. In the development and replication cohorts, 222 of 784 patients (28.3%) and 99 of 245 patients (40.4%; 321 of 1029 patients [31.2%]), respectively, had NCCT scans that demonstrated hypodensities at baseline (κ = 0.87 for interrater reliability). In univariate analyses, hypodensities were associated with hematoma expansion (86 of 163 patients with hematoma expansion had hypodensities [52.8%], whereas 136 of 621 patients without hematoma expansion had hypodensities [21.9%]; P < .001). The association between hypodensities and hematoma expansion remained significant (odds ratio, 3.42 [95% CI, 2.21-5.31]; P < .001) in a multivariable model; other independent predictors of hematoma expansion were a CT angiography spot sign, a shorter time to CT, warfarin use, and older age. The independent predictive value of hypodensities was again demonstrated in the replication cohort (odds ratio, 4.37 [95% CI, 2.05-9.62]; P < .001). CONCLUSION AND RELEVANCE: Hypodensities within an acute ICH detected on an NCCT scan may predict hematoma expansion, independent of other clinical and imaging predictors. This novel marker may help clarify the mechanism of hematoma expansion and serve as a useful addition to clinical algorithms for determining the risk of and treatment stratification for hematoma expansion.

Small vessel disease and cognitive impairment: The relevance of central network connections.

Central brain network connections greatly contribute to overall network efficiency. Here we examined whether small vessel disease (SVD) related white matter alterations in central brain network connections have a greater impact on executive functioning than alterations in non-central brain network connections. Brain networks were reconstructed from diffusion-weighted MRI scans in 72 individuals (75 ± 8 years) with cognitive impairment and SVD on MRI. The centrality of white matter connections in the network was defined using graph theory. The association between the fractional anisotropy (FA) of central versus non-central connections, executive functioning, and markers of SVD was evaluated with linear regression and mediation analysis. Lower FA in central network connections was more strongly associated with impairment in executive functioning than FA in non-central network connections (r = 0.41 vs. r = 0.27; P < 0.05). Results were consistent across varying thresholds to define the central subnetwork (>50%-10% connections). Higher SVD burden was associated with lower FA in central as well as non-central network connections. However, only central network FA mediated the relationship between white matter hyperintensity volume and executive functioning [change in regression coefficient after mediation (95% CI): -0.15 (-0.35 to -0.02)]. The mediation effect was not observed for FA alterations in non-central network connections [-0.03 (-0.19 to 0.04)]. These findings suggest that the centrality of network connections, and thus their contribution to global network efficiency, appears to be relevant for understanding the relationship between SVD and cognitive impairment. Hum Brain Mapp 37:2446-2454, 2016. © 2016 Wiley Periodicals, Inc.

Stroke prevention in atrial fibrillation in older adults: existing knowledge gaps and areas for innovation: a summary of an American Federation for Aging research seminar.

Atrial fibrillation (AF) is a common and morbid cardiac arrhythmia that increases in prevalence with advancing age. The risk of ischemic stroke, a primary and disabling hazard of AF, also increases with advancing age. The aging of the population is anticipated to contribute to a rising burden of AF-related morbidity and economic costs, given the close association between the arrhythmia and aging. Recent biological, diagnostic, and therapeutic developments raise hope that AF-related stroke can be largely prevented, yet despite advances in stroke prevention for individuals with AF, numerous scientific and clinical knowledge gaps remain, particularly as these developments are applied to older adults. Given the public health importance of AF-related stroke in elderly adults, a group of clinician-investigators convened on April 5, 2012, to identify promising areas for investigation that may ultimately reduce stroke-related morbidity. This article summarizes the meeting discussion and emphasizes innovative topic areas that may ultimately facilitate the application of novel preventive, diagnostic, and therapeutic insights into the management of older adults with AF. The opinions of those that participated in the meeting limit this report, which may not represent all of the questions that other experts in this field might raise.

Early edema in warfarin-related intracerebral hemorrhage.

BACKGROUND AND PURPOSE: The pathophysiology and clinical significance of perihematomal edema (PHE), a cause of secondary neuronal injury after intracerebral hemorrhage (ICH), is poorly understood. A leading theory proposes that early PHE results from activation of the clotting cascade. We sought to test this theory by examining the relationship between early PHE and warfarin use in ICH patients. METHODS: ICH and PHE volumes were measured in consecutive patients with warfarin-related ICH and compared to those of controls with non-coagulopathic ICH. Subjects were identified from a prospective database of ICH patients. Clinical and radiological predictors of PHE volume and relative PHE (PHE volume/ICH volume) were identified. The relationship between PHE volume and 90-day mortality was determined. RESULTS: For the 49 consecutive warfarin-related ICH patients and 49 matched controls: median INRs (interquartile ranges) were 3.2 (2.3, 4.1) and 1.1 (1.08, 1.2); median hematoma volumes were 37.8 cm(3) (6.7, 102.9) and 18.1 cm(3) (9, 51) (P = 0.18); median PHE volumes were 12 cm(3) (3.7, 36.7), and 11 cm(3) (4.1, 24) (P = 0.87); and median relative PHE was 0.38 (0.28, 0.52) and 2 (1.37, 3.06), respectively. In multivariable analysis, ICH volume and warfarin use independently predicted PHE volume. There was an association between higher PHE volume and decreased 90-day mortality. CONCLUSIONS: Warfarin-related ICH is associated with less early relative edema than non-coagulopathic ICH. This is consistent with the theory that coagulation contributes to early edema. Early edema may be associated with improved functional outcome.

Validation of intracranial area as a surrogate measure of intracranial volume when using clinical MRI.

BACKGROUND AND PURPOSE: We sought to determine whether mid-sagittal intracranial area (ICA) is a valid surrogate of intracranial volume (ICV) when using retrospective data with relatively thick (6-7 mm) sagittal slices. METHODS: Data were retrospectively analyzed from 47 subjects who had two MRI scans taken at least nine months apart. Twenty-three subjects had manual segmentation of ICV on the T2-weighted sequence for comparison. RESULTS: Intraclass correlation coefficient (ICC) for intraobserver, interobserver, and intraobserver scan-rescan comparisons were 0.96, 0.97 and 0.95. Pearson correlation coefficients between ICV and ICA, averaging the cumulative 1, 2, 3, and 4 most midline slices, were 0.89, 0.94, 0.93, and 0.95. There was a significant marginal increase in explained variance of ICV by measuring two, rather than one, slices (P= 0.001). CONCLUSIONS: These data suggest that ICA, even measured without high-resolution imaging, is a reasonable substitute for ICV.