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Background and Purpose: The spectrum of brain infarction in patients with embolic stroke of undetermined source (ESUS) has not been well characterized. Our objective was to define the frequency and pattern of brain infarcts detected by magnetic resonance imaging (MRI) among patients with recent ESUS participating in a clinical trial. Methods: In the NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), an MRI substudy was carried out at 87 sites in 15 countries. Participants underwent an MRI using a specified protocol near randomization. Images were interpreted centrally by those unaware of clinical characteristics. Results: Among the 918 substudy cohort participants, the mean age was 67 years and 60% were men with a median (interquartile range) of 64 (26–115) days between the qualifying ischemic stroke and MRI. On MRI, 855 (93%) had recent or chronic brain infarcts that were multiple in 646 (70%) and involved multiple arterial territories in 62% (401/646). Multiple brain infarcts were present in 68% (510/755) of those without a history of stroke or transient ischemic attack before the qualifying ESUS. Prior stroke/transient ischemic attack ( P 0 ( P P =0.01) were associated with multiple infarcts. Topographically, large and/or cortical infarcts were present in 89% (757/855) of patients with infarcts, while in 11% (98/855) infarcts were exclusively small and subcortical. Among those with multiple large and/or cortical infarcts, 57% (251/437) had one or more involving a different vascular territory from the qualifying ESUS. Conclusions: Most patients with ESUS, including those without prior clinical stroke or transient ischemic attack, had multiple large and/or cortical brain infarcts detected by MRI, reflecting a substantial burden of clinical stroke and covert brain infarction. Infarcts most frequently involved multiple vascular territories. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02313909.

Background Covert brain infarcts are associated with important neurological morbidity. Their incidence in patients with embolic stroke of undetermined source (ESUS) is unknown. Aims To assess the incidence of covert brain infarcts and cerebral microbleeds using MRI in a prospective substudy of the NAVIGATE ESUS randomized trial and to evaluate the effects of antithrombotic therapies. Methods At 87 sites in 15 countries, substudy participants were randomly assigned to receive rivaroxaban 15 mg daily or aspirin 100 mg daily and underwent brain MRI near randomization and after study termination. The primary outcome was incident brain infarct (clinical ischemic stroke or covert brain infarct). Brain infarcts and microbleeds were ascertained centrally by readers unaware of treatment. Treatment effects were estimated using logistic regression. Results Among the 718 substudy participants with interpretable, paired MRIs, the mean age was 67 years and 61% were men with a median of 52 days between the qualifying ischemic stroke and randomization and a median of seven days between randomization and baseline MRI. During the median (IQR) 11 (12) month interval between scans, clinical ischemic strokes occurred in 27 (4%) participants, while 60 (9%) of the remaining participants had an incident covert brain infarct detected by MRI. Assignment to rivaroxaban was not associated with reduction in the incidence of brain infarct (OR 0.77, 95% CI 0.49, 1.2) or of covert brain infarct among those without clinical stroke (OR 0.85, 95% CI 0.50, 1.4). New microbleeds were observed in 7% and did not differ among those assigned rivaroxaban vs. aspirin (HR 0.95, 95% CI 0.52–1.7). Conclusions Incident covert brain infarcts occurred in twice as many ESUS patients as a clinical ischemic stroke. Treatment with rivaroxaban compared with aspirin did not significantly reduce the incidence of covert brain infarcts or increase the incidence of microbleeds, but the confidence intervals for treatment effects were wide. Registration: https://www.clinicaltrials.gov . Unique identifier: NCT 02313909

Background and Purpose: Risks, sites, and predictors of major bleeding during antithrombotic therapies have not been well defined for patients with recent embolic stroke of undetermined source. Methods: Exploratory analysis of major bleeds defined by International Society of Thrombosis and Hemostasis criteria occurring among 7213 participants in international NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial) embolic stroke of undetermined source randomized trial comparing rivaroxaban 15 mg daily with aspirin 100 mg daily. Results: During a median follow-up of 11 months, 85 major bleeds occurred. The most frequent site was gastrointestinal (38%), followed by intracranial (29%). Assignment to rivaroxaban (hazard ratio [HR], 2.7 [95% CI, 1.7–4.3]), East Asia region (HR, 2.5 [95% CI, 1.6–3.9]), systolic blood pressure ≥160 mm Hg (HR, 2.2 [95% CI, 1.2–3.8]), and reduced estimated glomerular filtration rate (HR, 1.2 per 10 mL/min per 1.73 m 2 decrease, [95% CI, 1.0–1.3]) were independently associated with presence of major bleeds. Five (6%) were fatal. Among 15 patients with intracerebral hemorrhage, 2 (13%) were fatal. There was no evidence of an early high-risk period following initiation of rivaroxaban. The annualized rate of intracerebral hemorrhage was 6-fold higher among East Asian participants (0.67%) versus all other regions (0.11%; HR, 6.3 [95% CI, 2.2–18.0]). Distribution of bleeding sites was similar for rivaroxaban and aspirin. Conclusions: Among embolic stroke of undetermined source patients participating in an international randomized trial, independent predictors of major bleeding were assignment to rivaroxaban, East Asia region, increased systolic blood pressure, and impaired renal function. East Asia as a region was strongly associated with risk of intracerebral hemorrhage. Estimated glomerular filtration rate should be a consideration for stratifying bleeding risk. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02313909.

Background and Purpose— Emboli in embolic stroke of undetermined source (ESUS) may originate from various potential embolic sources (PES), some of which may respond better to anticoagulation, whereas others to antiplatelets. We analyzed whether rivaroxaban is associated with reduction of recurrent stroke compared with aspirin in patients with ESUS across different PES and by number of PES. Methods— We assessed the presence/absence of each PES (atrial cardiopathy, atrial fibrillation, arterial atherosclerosis, left ventricular dysfunction, cardiac valvulopathy, patent foramen ovale, cancer) in NAVIGATE-ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) participants. Prevalence of each PES, as well as treatment effect and risk of event for each PES were determined. Results by number of PES were also determined. The outcomes were ischemic stroke, all-cause mortality, cardiovascular mortality, and myocardial infarction. Results— In 7213 patients (38% women, mean age 67years) followed for a median of 11 months, the 3 most prevalent PES were atrial cardiopathy (37%), left ventricular disease (36%), and arterial atherosclerosis (29%). Forty-one percent of all patients had multiple PES, with 15% having ≥3 PES. None or a single PES was present in 23% and 36%, respectively. Recurrent ischemic stroke risk was similar for rivaroxaban- and aspirin-assigned patients for each PES, except for those with cardiac valvular disease which was marginally higher in rivaroxaban-assigned patients (hazard ratio, 1.8 [95% CI, 1.0–3.0]). All-cause mortality risks were similar across treatment groups for each PES while too few myocardial infarctions and cardiovascular deaths occurred for meaningful assessment. Increasing number of PES was not associated with increased stroke recurrence nor all-cause mortality, and outcomes did not vary between rivaroxaban- and aspirin-assigned patients by number of PES. Conclusions— A large proportion of patients with ESUS had multiple PES which could explain the neutral results of NAVIGATE-ESUS. Recurrence rates between rivaroxaban- and aspirin-assigned patients were similar across the spectrum of PES. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02313909.

Function is an important outcome after stroke; traditional assessments may not capture functional deficits important to patients. We examined the validity of the Standard Assessment of Global Everyday Activities (SAGEA), a patient-reported outcome that assesses activities important to patients and for use in international clinical trials.The NAVIGATE-ESUS trial evaluated rivaroxaban compared to aspirin in preventing recurrent stroke in 7213 participants. The Modified Rankin Scale (mRS), the National Institutes of Health Stroke Scale (NIHSS), and the SAGEA were collected at entry. Chi square tests were used to compare proportions and Spearman rank correlations were used to compare between measures. SAGEA was compared to the Modified Frailty Index (MFI) and the occurrence of infarct to examine criterion validity RESULTS: Participants were 67 years, 2/3 were male, and at baseline 30% had no disability and 58% had slight disability according to mRS scores. SAGEA was weakly correlated with the mRS (r=0.37), the NIHSS (r=0.29) and the MFI (r=0.30). Of the 2154 with an mRS score of 0, 61% reported difficulty on the SAGEA. The largest discrepancies between SAGEA and other measures were because of cognitive functional deficits detected by the SAGEA that were not identified on other assessments. A larger number of MRI identified infarcts (acute and covert) were associated with a higher SAGEA score (p=0.007).The SAGEA is a simple, globally applicable measure of cognitive and functional abilities that identifies issues that other commonly used assessments of disability and function do not capture.

WOS: 000492999300054, PubMed: 31526123, Background and Purpose- Aortic arch atherosclerosis (AAA) is a possible source of embolism in patients with embolic stroke of undetermined source. Previous studies reported high rates of embolic events in patients with AAA, especially those with high-risk AAA. This exploratory analysis of NAVIGATE ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) focused on patients with AAA and assessed their characteristics, stroke recurrence rates, and response to treatment. Methods- The detection of AAA and the assessment of its features were based on transesophageal echocardiography that was done in 19% of participants. AAA plaques were considered to have complex features when reported as complex or ulcerated or were >= 4 mm in thickness or had a mobile thrombus present. Results- Among 1382 participants who had transesophageal echocardiography, 397 (29%) had AAA and 112 (8%) had complex AAA. Mean (SD) age (63 [10] versus 67 [9] versus 69 [9]; P, BayerBayer AG; Janssen Research and Development, This study was supported by Bayer and Janssen Research and Development.

Background and aim The diagnosis of embolic stroke of undetermined source (ESUS) is based on excluding other more likely stroke etiologies, and therefore diagnostic testing plays an especially crucial role. Our objective was to compare the diagnostic testing by region, sex, and age among the participants of NAVIGATE-ESUS trial. Methods Participants were grouped according to five global regions (North America, Latin America, Western Europe, Eastern Europe and East Asia), age (75 years), and sex. Frequencies of each diagnostic test within areas of echocardiography, cardiac rhythm monitoring, and arterial imaging were described and compared across groups. A multivariable logistic regression model for each diagnostic test was fit to assess the independent influence of each of region, age, and sex and likelihood of testing. Results We included 6985 patients in the analysis (918 from North America; 746 from Latin America; 2853 from Western Europe; 1118 from Eastern Europe; 1350 from East Asia). Average age (highest in Western Europe (69 years), lowest in Eastern Europe (65 years)), % females (highest in Latin America (44%) and lowest in East Asia (31%)), and use of each diagnostic test varied significantly across regions. Region, but not sex, was independently associated with use of each diagnostic test examined. Transesophageal echocardiography and either CT or MR angiogram were more often used in younger patients. Conclusion Diagnostic testing differed by region, and less frequently by age, but not by sex. Our findings reflect the existing variations in global practice in diagnostic testing in ESUS patients.

Background and Purpose Subdural hematomas are an uncommon, but a serious, bleeding complication of antithrombotic therapies. We update our previous inconclusive meta-analysis to better estimate the risk of subdural hematoma associated with aspirin use. Methods For the initial meta-analysis, nine randomized trials published between1980 and 2012 comparing aspirin with placebo/control were considered. Additional data from four large primary prevention trials were added. Two reviewers independently extracted data on subdural hematomas, with differences resolved by joint review and consensus. Results Numbers of subdural hematoma were available from thirteen randomized trials involving 155,554 participants comparing aspirin (dosage range 25 mg twice daily to 325 mg daily) to placebo (ten double-blind trials) or no aspirin (three trials). Participants included healthy healthcare providers, older people with vascular risk factors without manifest vascular disease, and those with atrial fibrillation or chronic angina. Pooling all trials, subdural hematomas were identified in 93 of 77,698 participants assigned to aspirin versus 62 of 77,856 participants assigned to placebo/no aspirin. By meta-analysis, the relative risk ratiometa of subdural hematoma associated with assignment to aspirin was 1.5 (95%CI 1.1, 2.0, p = 0.01; p = 0.9 for heterogeneity, I2 index = 0%). Based on recent primary prevention trials, subdural hematoma diagnosis averaged 1 per 3,125 people per year without aspirin use; the absolute increase associated with aspirin use was estimated as one additional subdural hematoma per 6,500 patients annually. Conclusions This meta-analysis confirms that aspirin use increases the relative risk of subdural hematoma, but the absolute increased rate associated with aspirin therapy is very low for most people.

The effect of interventions on functional impairment is an important outcome in stroke prevention trials and should be considered as an adjunct to counting discrete events. In the NAVIGATE-ESUS trial, 7213 patients with recent embolic strokes of undetermined source were randomized to rivaroxaban (15 mg once daily) or aspirin (100 mg daily). After 11 months there was no effect on the prevention of recurrent stroke.To determine the effect of rivaroxaban compared to aspirin on functional and cognitive outcomes.Function and cognition were measured at baseline, 1 year, and study end using the Standard Assessment of Global Everyday Activities (SAGEA), a 15-item scale assessing cognitive, instrumental, and basic activities of daily living as well as mobility, and the Montreal Cognitive Assessment (MoCA). Changes in scores were calculated by subtracting either study end or 1-year scores from baseline, and differences in distributions were compared using the Mann-Whitney U test. SAGEA and MoCA scores were also correlated with recurrent stroke.Follow-up SAGEA scores were available in 6378 (88%) participants. There was no difference in change in function for those allocated to rivaroxaban compared to aspirin (Mann-Whitney U test, p = 0.8), with both distributions having a median (25p,75p) change of 0 (-2,1). Overall, more of those who experienced a recurrent stroke (n=247; mostly minor ischemic), reported functional difficulty at study end versus entry, compared with those who did not (51% versus 30%, chi-square test, p0.001), and this was consistent across global regions. There was no difference in the change in cognition by treatment group, nor were recurrent strokes associated with a change in cognition.Rivaroxaban, compared to aspirin, was not associated with changes in functional or cognitive status in patients with recent ESUS. The SAGEA scale detected changes in functional status associated with recurrent strokes in an international stroke population.

Importance It is uncertain whether anticoagulation is superior to aspirin at reducing recurrent stroke in patients with recent embolic strokes of undetermined source (ESUS) and left ventricular (LV) dysfunction. Objective To determine whether anticoagulation is superior to aspirin in reducing recurrent stroke in patients with ESUS and LV dysfunction. Design, Setting, and Participants Post hoc exploratory analysis of data from the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs Aspirin to Prevent Embolism in ESUS (NAVIGATE ESUS) trial, a randomized, phase 3 clinical trial with enrollment from December 2014 to September 2017. The study setting included 459 stroke recruitment centers in 31 countries. Patients 50 years or older who had neuroimaging-confirmed ESUS between 7 days and 6 months before screening were eligible. Of the 7213 NAVIGATE ESUS participants, 7107 (98.5%) had a documented assessment of LV function at study entry and were included in the present analysis. Data were analyzed in January 2021. Interventions Participants were randomized to receive either 15 mg of rivaroxaban or 100 mg of aspirin once daily. Main Outcomes and Measures The study examined whether rivaroxaban was superior to aspirin at reducing the risk of (1) the trial primary outcome of recurrent stroke or systemic embolism and (2) the trial secondary outcome of recurrent stroke, systemic embolism, myocardial infarction, or cardiovascular mortality during a median follow-up of 10.4 months. LV dysfunction was identified locally through echocardiography and defined as moderate to severe global impairment in LV contractility and/or a regional wall motion abnormality. A Cox proportional hazards model was used to assess for treatment interaction and to estimate the hazard ratios for those randomized to rivaroxaban vs aspirin by LV dysfunction status. Results LV dysfunction was present in 502 participants (7.1%). Of participants with LV dysfunction, the mean (SD) age was 67 (10) years, and 130 (26%) were women. Among participants with LV dysfunction, annualized primary event rates were 2.4% (95% CI, 1.1-5.4) in those assigned to rivaroxaban vs 6.5% (95% CI, 4.0-11.0) in those assigned aspirin. Among the 6605 participants without LV dysfunction, rates were similar between those assigned to rivaroxaban (5.3%; 95% CI, 4.5-6.2) vs aspirin (4.5%; 95% CI, 3.8-5.3). Participants with LV dysfunction assigned to rivaroxaban vs aspirin had a lower risk of the primary outcome (hazard ratio, 0.36; 95% CI, 0.14-0.93), unlike those without LV dysfunction (hazard ratio, 1.16; 95% CI, 0.93-1.46) (Pfor treatment interaction = .03). Results were similar for the secondary outcome. Conclusions and Relevance In this post hoc exploratory analysis, rivaroxaban was superior to aspirin in reducing the risk of recurrent stroke or systemic embolism among NAVIGATE ESUS participants with LV dysfunction. Trial Registration ClinicalTrials.gov Identifier:NCT02313909

OBJECTIVE To characterize cerebral microbleeds (CMBs) in lacunar stroke patients in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial and to assess their relationship with recurrent stroke and death, and response to assigned treatment. METHODS SPS3 is a randomized, clinical trial conducted between 2003 and 2011. Patients with recent magnetic resonance imaging (MRI)-documented lacunar infarcts were randomly assigned in a factorial design to target levels of systolic blood pressure (130-149mmHg vs

Background and Purpose— Atrial cardiopathy and atherosclerotic plaque are two potential mechanisms underlying embolic strokes of undetermined source (ESUS). The relationship between these two mechanisms among ESUS patients remains unclear. A better understanding of their association may inform targeted secondary prevention strategies. Methods— We examined the association between atrial cardiopathy and atherosclerotic plaque in the NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), which enrolled 7213 patients with recent ESUS during 2014 to 2017. For this analysis, we included patients with data on left atrial dimension, location of brain infarction, and cervical large artery plaque. The variables of primary interest were left atrial diameter and cervical plaque ipsilateral to brain infarction. Secondary markers of atrial cardiopathy were premature atrial contractions on Holter monitoring and newly diagnosed atrial fibrillation. For descriptive purposes, left atrial enlargement was defined as ≥4.7 cm. Multivariable logistic regression was used to examine the association between atrial cardiopathy markers and ipsilateral plaque after adjustment for age, sex, body mass index, hypertension, diabetes mellitus, current smoking, and hyperlipidemia. Results— Among 3983 eligible patients, 235 (5.9%) had left atrial enlargement, 939 (23.6%) had ipsilateral plaque, and 94 (2.4%) had both. Shared risk factors for left atrial enlargement and ipsilateral plaque were male sex, white race, hypertension, tobacco use, and coronary artery disease. Despite shared risk factors, increasing left atrial dimension was not associated with ipsilateral plaque after adjustment for covariates (odds ratio per cm, 1.1 [95% CI, 1.0–1.2]; P =0.08). We found no consistent associations between secondary markers of atrial cardiopathy and ipsilateral plaque. Conclusions— In a large population of patients with ESUS, we did not observe a notable association between atrial cardiopathy and atherosclerotic plaque, and few patients had both conditions. These findings suggest that atrial cardiopathy and atherosclerotic plaque may be distinct, nonoverlapping risk factors for stroke among ESUS patients.

Importance The concept of embolic stroke of undetermined source (ESUS) unifies a subgroup of cryptogenic strokes based on neuroimaging, a defined minimum set of diagnostic tests, and exclusion of certain causes. Despite an annual stroke recurrence rate of 5%, little is known about the etiology underlying recurrent stroke after ESUS. Objective To identify the stroke subtype of recurrent ischemic strokes after ESUS, to explore the interaction with treatment assignment in each category, and to examine the consistency of cerebral location of qualifying ESUS and recurrent ischemic stroke. Design, Setting, and Participants The NAVIGATE-ESUS trial was a randomized clinical trial conducted from December 23, 2014, to October 5, 2017. The trial compared the efficacy and safety of rivaroxaban and aspirin in patients with recent ESUS (n = 7213). Ischemic stroke was validated in 309 of the 7213 patients by adjudicators blinded to treatment assignment and classified by local investigators into the categories ESUS or non-ESUS (ie, cardioembolic, atherosclerotic, lacunar, other determined cause, or insufficient testing). Five patients with recurrent strokes that could not be defined as ischemic or hemorrhagic in absence of neuroimaging or autopsy were excluded. Data for this secondary post hoc analysis were analyzed from March to June 2019. Interventions Patients were randomly assigned to receive rivaroxaban, 15 mg/d, or aspirin, 100 mg/d. Main Outcomes and Measures Association of recurrent ESUS with stroke characteristics. Results A total of 309 patients (205 men [66%]; mean [SD] age, 68 [10] years) had ischemic stroke identified during the median follow-up of 11 (interquartile range [IQR], 12) months (annualized rate, 4.6%). Diagnostic testing was insufficient for etiological classification in 39 patients (13%). Of 270 classifiable ischemic strokes, 156 (58%) were ESUS and 114 (42%) were non-ESUS (37 [32%] cardioembolic, 26 [23%] atherosclerotic, 35 [31%] lacunar, and 16 [14%] other determined cause). Atrial fibrillation was found in 27 patients (9%) with recurrent ischemic stroke and was associated with higher morbidity (median change in modified Rankin scale score 2 [IQR, 3] vs 0 (IQR, 1]) and mortality (15% vs 1%) than other causes. Risk of recurrence did not differ significantly by subtype between treatment groups. For both the qualifying and recurrent strokes, location of infarct was more often in the left (46% and 54%, respectively) than right hemisphere (40% and 37%, respectively) or brainstem or cerebellum (14% and 9%, respectively). Conclusions and Relevance In this secondary analysis of randomized clinical trial data, most recurrent strokes after ESUS were embolic and of undetermined source. Recurrences associated with atrial fibrillation were a minority but were more often disabling and fatal. More extensive investigation to identify the embolic source is important toward an effective antithrombotic strategy. Trial Registration ClinicalTrials.gov Identifier:NCT02313909.

Background and Purpose: Optimal secondary prevention for patients with embolic stroke of undetermined source (ESUS) remains unknown. We aimed to assess whether high-sensitivity cardiac troponin T (hs-cTnT) levels are associated with major vascular events and whether hs-cTnT may identify patients who benefit from anticoagulation following ESUS. Methods: Data were obtained from the biomarker substudy of the NAVIGATE ESUS trial, a randomized controlled trial testing the efficacy of rivaroxaban versus aspirin for secondary stroke prevention in ESUS. Patients were dichotomized at the hs-cTnT upper reference limit (14 ng/L, Gen V, Roche Diagnostics). Cox proportional hazard models were computed to explore the association between hs-cTnT, the combined cardiovascular end point (recurrent stroke, myocardial infarction, systemic embolism, cardiovascular death), and recurrent ischemic stroke. Results: Among 1337 patients enrolled at 111 participating centers in 18 countries (mean age 67±9 years, 61% male), hs-cTnT was detectable in 95% and at/above the upper reference limit in 21%. During a median follow-up of 11 months, the combined cardiovascular end point occurred in 68 patients (5.0%/y, rivaroxaban 28 events, aspirin 40 events; hazard ratio, 0.67 [95% CI, 0.41–1.1]), and recurrent ischemic stroke occurred in 50 patients (4.0%/y, rivaroxaban 16 events, aspirin 34 events, hazard ratio 0.45 [95% CI, 0.25–0.81]). Annualized combined cardiovascular end point rates were 8.2% (9.5% rivaroxaban, 7.0% aspirin) for those above hs-cTnT upper reference limit and 4.8% (3.1% rivaroxaban, 6.6% aspirin) below with a significant treatment modification ( P =0.04). Annualized ischemic stroke rates were 4.7% above hs-cTnT upper reference limit and 3.9% below, with no suggestion of an interaction between hs-cTnT and treatment ( P =0.3). Conclusions: In patients with ESUS, hs-cTnT was associated with increased cardiovascular event rates. While fewer recurrent strokes occurred in patients receiving rivaroxaban, outcomes were not stratified by hs-cTn results. Our findings support using hs-cTnT for cardiovascular risk stratification but not for decision-making regarding anticoagulation therapy in patients with ESUS. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02313909.

ObjectiveTo compare the efficacy and safety of oral anticoagulants vs antiplatelets in patients with stroke and atherosclerotic plaques in the aortic arch or cervical or intracranial arteries, collectively described as supracardiac atherosclerosis.MethodsWe searched PubMed and Scopus until August 28, 2019, for randomized trials comparing oral anticoagulants vs antiplatelets in patients with stroke and supracardiac atherosclerosis using the terms “anticoagulant or anticoagulation” and “antiplatelet or aspirin” and “randomized controlled trial or RCT” and “stroke or cerebral ischemia” and “aortic or carotid or vertebrobasilar or intracranial or atherosclerosis or stenosis or arterial.” Four outcomes were assessed: recurrent ischemic stroke, major ischemic event or death, major bleeding, and intracranial bleeding. Treatment effects (relative risk [RR] and 95% confidence interval [CI]) were estimated by meta-analysis using random-effects models.ResultsAmong 1,117 articles identified in the literature search, results from 10 randomized controlled trials involving 6,068 patients with stroke/TIA with supracardiac atherosclerosis were included in the meta-analysis. Recurrent ischemic stroke rates were 2.94 per 100 patient-years in the anticoagulant-assigned patients vs 3.30 per 100 patient-years in the antiplatelet-assigned patients (RR, 0.91; 95% CI, 0.70–1.18 for the SJ estimator, I2 = 26%). Major ischemic event or death rates were 4.39 per 100 patient-years in anticoagulant-assigned patients vs 4.32 in antiplatelet-assigned patients (RR, 1.03; 95% CI, 0.79–1.35; I2 = 54.5%). Major bleeding rates were 2.88 per 100 patient-years in anticoagulant-assigned patients vs 0.82 in antiplatelet-assigned patients (RR, 3.21; 95% CI, 1.96–5.24; I2 = 46%).ConclusionThis systematic review and meta-analysis showed that anticoagulant-assigned patients with stroke and supracardiac atherosclerosis were not at different risk of ischemic stroke recurrence and increased risk of major bleeding compared to antiplatelet-assigned patients.

Background Pontine infarcts are common and often attributed to small vessel disease (“small deep infarcts”) or basilar branch atherosclerosis (“wedge shaped”). A well-described morphological differentiation using magnetic resonance images has not been reported. Furthermore, whether risk factors and outcomes differ by morphology, or whether infarct morphology should guide secondary prevention strategy, is not well characterized. Methods All participants in the Secondary Prevention of Small Subcortical Strokes Study with magnetic resonance imaging -proven pontine infarcts were included. Infarcts were classified as well-circumscribed small deep (small deep infarct, i.e. lacunar), paramedian, atypical paramedian, or other based on diffusion-weighted imaging, T2/fluid-attenuated inversion recovery, and T1-magnetic resonance images. Inter-rater reliability was high (90% agreement, Cohen’s kappa = 0.84). Clinical and radiologic features independently associated with small deep infarct versus paramedian infarcts were identified (multivariable logistic regression). Differences in stroke risk and death were assessed using Cox proportional hazards. Results Of the 3020 patients enrolled, 644 had pontine infarcts; 619 images were available: 302(49%) small deep infarct, 245 (40%) paramedian wedge, 35 (6%) atypical paramedian, and 37 (6%) other. Among vascular risk factors, only smoking (OR 2.1, 95% CI 1.3–3.3) was independently associated with small deep infarct versus paramedian infarcts; on neuroimaging, old lacunes on T1/fluid-attenuated inversion recovery (OR 1.8, 1.3–2.6) and intracranial stenosis (any location) ≥50% (OR 0.62, 0.41–0.96). Small deep infarct versus paramedian was not predictive of either recurrent stroke or death, and there was no interaction with assigned treatment. Conclusions Pontine infarcts can be reliably classified based on morphology using clinical magnetic resonance images. Few risk factors differed between small deep infarct and paramedian infarcts with no differences in recurrent stroke or mortality. There was no difference in response to different antiplatelet or blood pressure treatment strategies between these two groups. Registration http://www.clinicaltrials.gov/NCT00059306 .

Background Non-stenotic intracranial and systemic atherosclerosis are associated with ischemic stroke. We report frequency and response to anticoagulant vs. antiplatelet prophylaxis of patients with embolic stroke of undetermined source (ESUS) who have non-stenotic intracranial atherosclerosis and/or systemic atherosclerosis. Methods Exploratory analysis of the international NAVIGATE ESUS randomized trial comparing rivaroxaban 15mg daily with aspirin 100mg daily in 7213 patients with recent ESUS. Among participants with results of intracranial arterial imaging with either computed tomographic angiography (CTA) or magnetic resonance angiography (MRA), the frequency and predictors of non-stenotic intracranial and systemic atherosclerosis and responses to antithrombotic therapy were assessed. Results Among 4723 participants with available intracranial CTA or MRA results (65% of the trial cohort), the prevalence of intracranial atherosclerosis was 16% (n=739). Patient features independently associated with intracranial atherosclerosis included East Asian region (odds ratio 2.7, 95%CI 2.2,3.3) and cervical carotid plaque (odds ratio 2.3, 95%CI 1.9,2.7), among others. The rate of recurrent ischemic stroke averaged 4.8%/year among those with intracranial atherosclerosis vs. 5.0.%/year for those without (HR 0.95, 95%CI 0.65, 1.4). Among those with intracranial atherosclerosis, the recurrent ischemic stroke rate was higher if assigned to rivaroxaban (5.8%/year) vs. aspirin (3.7%/year), but the difference was not statistically significant (HR 1.6, 95%CI 0.78, 3.3). There was trend for the effect of antithrombotic treatments to be different according to the presence or absence of intracranial atherosclerosis (pinteraction=0.09). Among participants with evidence of systemic atherosclerosis by either history or imaging (n=3820), recurrent ischemic stroke rates were similar among those assigned to rivaroxaban (5.5%/year) vs. aspirin (4.9%/year)(HR 1.1, 95%CI 0.84, 1.5). Conclusions East Asia region was the strongest factor associated with intracranial atherosclerosis. There were no statistically significant differences between rivaroxaban and aspirin prophylaxis for recurrent ischemic stroke in patients with non-stenotic intracranial atherosclerosis and/or systemic atherosclerosis.

Background: The spectrum, prevalence, and prognosticimplications of abnormal left ventricular geometry (LVG) in patients with lacunar stroke are unknown. We examined the spectrum of LVG and its relationship with vascular risk factors and outcomes after lacunar stroke. Methods: LVG was determined with transthoracic echocardiography for 1961 patients with magnetic resonance imaging–verified recent lacunar stroke participating in the Secondary Prevention of Small Subcortical Strokes trial. Multivariable logistic regression and Cox proportional hazards models were used to identify characteristics independently associated with LVG and to estimate risk from abnormal LVG for recurrent stroke and death. Results: Abnormal LVG was present in 77%. Hispanic (odds ratio [OR], 1.4; 95% confidence interval, 1.1-1.8) or black (OR, 2.0; 1.3-2.9) race-ethnicity, diabetes (OR, 1.3; 1.0-1.7), hypertension, impaired renalfunction (OR, 1.8; 1.2-2.5), intracranial stenosis (OR, 1.5;1.1-2.1), and abnormal left ventricular function (OR, 2.0; 1.4-3.0) were independently associated with abnormal LVG. Subjects with abnormal LVG also more frequently had advanced manifestations of small-vessel disease specifically previous subcortical infarcts and white matter hyperintensities. After adjusting for assigned treatments, clinical risk factors, and advanced manifestations of small-vessel disease, subjects with abnormal LVG remained at increased risk of stroke recurrence (hazard ratio, 1.5; confidence interval, 1.0-2.4). There was no interaction between LVG and assigned antiplatelet or blood pressure target. Abnormal LVG was not associated with mortality. Conclusions: LVG consistent with chronic hypertensive changes was highly prevalent and correlated with neuroradiologic manifestations of small-vessel disease in lacunar stroke patients. These results support the constructs that both cerebral small-vessel disease and LVG represent end-organ conse

Background: Cerebral microbleeds (CMBs) have been associated with cognitive dysfunction. However, characterization of CMBs and cognitive dysfunction in a large population of stroke patients is lacking. We aimed to characterize the association of CMBs with cognitive function in lacunar stroke patients and the response to assigned treatments in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial. Methods: SPS3 was a randomized trial comparing two systolic blood pressure targets and two antiplatelet regimens in 3020 dementia-free patients with symptomatic, MRI-confirmed lacunar stroke. Participants underwent detailed neuropsychological testing covering multiple domains, including short delay recall, long delay recall, discriminability, block design, symbol search, grooved pegboard, controlled oral word association and clock drawing, at baseline and then annually for 5 years. Participants with axial MRI T2*- GRE sequences allowing for CMB detection and Cognitive Abilities Screening Instrument (CASI) Z scores available at baseline were included in the current analysis. Results: CMBs were present in 30% of 1225 eligible patients (mean age 63 years, 35% women) with median follow up of 3 years. Patients with CMBs had greater proportion of mild cognitive impairment (MCI; 56% vs. 42%, p Conclusions: In this largest reported cohort assessing the association between CMBs and post-stroke cognitive impairment, CMBs were associated with lower cognitive scores and greater rates of MCI at baseline. However, changes over time in cognition were similar in lacunar stroke patients with and without CMBs who receive adequate vascular risk management.

The mortality rate of most patients with atrial fibrillation (AF) exceeds the stroke rate, but predictors of mortality have not been well defined. The Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE A) recruited patients with AF who were unsuitable to receive vitamin K-antagonists and were randomized to aspirin alone versus aspirin plus clopidogrel. We investigated independent predictors of all-cause mortality by multivariable Cox regression analysis and explored interactions with assigned antiplatelet therapy. Of the 7,554 patients enrolled with a mean age of 71 years, 1,687 (22%) patients died during the median follow-up of 3.7 years (annualized mortality rate 6.4%/year). Assignment to dual antiplatelet therapy had no effect on mortality (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.90 to 1.1) or on vascular and nonvascular death. Independent predictors of all-cause mortality were advancing age, lower body mass index (HR 1.4

Background Clopidogrel combined with aspirin is routinely prescribed after coronary artery stenting, in patients with acute coronary syndromes, and recently to prevent stroke in patients with acute minor ischemic stroke and TIA. Subdural hematomas are an important complication of antithrombotic treatment, but the risk associated with clopidogrel plus aspirin has not been previously defined. Purpose To quantify the risk of subdural hematoma associated with dual antiplatelet therapy with clopidogrel plus aspirin. Methods Randomized clinical trials comparing clopidogrel plus aspirin with aspirin alone were identified by searching the Cochrane Central Register of Controlled Trials from 1990 to 2014, and restricted to those with more than 7 days of treatment. Two reviewers independently extracted data about subdural hematomas. Results Of 24 randomized trials testing clopidogrel added to aspirin, results for subdural hematoma were available for 11 trials, of which eight did not identify any subdural hematomas. The three trials reporting subdural hematomas were double-blind and included patients with recent lacunar stroke, acute coronary syndromes or atrial fibrillation with a total of 23,136 patients (mean age 66 years) and reported 39 subdural hematomas during a mean follow-up 2·1 years per patient. Clopidogrel plus aspirin was associated with a significantly increased risk of subdural hematoma compared with aspirin alone (risk ratio 2·0, 95% CI 1·0, 3·8; P = 0·04; fixed effects model; I2 for heterogeneity of 0%, P = 0·51). The average absolute incidence of subdural hematoma averaged 1·1 (95%CI 0·7,1·6) per 1000 patient – years among those assigned clopidogrel plus aspirin in 11 randomized trials. Conclusions The absolute rate of subdural hematoma during dual antiplatelet therapy is low, averaging 1·1 per 1000 patient-years. Chronic treatment with clopidogrel plus aspirin significantly increases the risk of subdural hematoma compared with aspirin alone.

Background and Purpose— The Secondary Prevention of Small Subcortical Stroke trial (SPS3) recruited participants meeting clinical and radiological criteria for symptomatic lacunes. Individuals randomized to dual antiplatelet therapy with clopidogrel and aspirin had an unanticipated increase in all-cause mortality compared with those assigned to aspirin. We investigated the factors associated with mortality in this well-characterized population. Methods— We identified independent predictors of mortality among baseline demographic and clinical factors by Cox regression analysis in participants of the SPS3 trial. Separately, we examined the effect on mortality of nonfatal bleeding during the trial. Results— During a mean follow-up of 3.6 years, the mortality rate was 1.78% per year for the 3020 participants (mean age, 63 years). Significant independent predictors of mortality at study entry were age, diabetes mellitus, history of hypertension, systolic blood pressure (hazard ratio [HR], 1.3 per 20 mm Hg increase), serum hemoglobin 2 decrease). Participants with ischemic heart disease ( P =0.01 for interaction) and normotensive/prehypertensive participants ( P =0.03 for interaction) were at increased risk if assigned to dual antiplatelet therapy. Nonfatal major hemorrhage increased mortality in both treatment arms (HR, 4.5; 95% confidence interval, 3.1–6.6; P Conclusions— Unexpected interactions between assigned antiplatelet therapy and each of ischemic heart disease and normal/prehypertensive status accounted for increased mortality among patients with recent lacunar stroke given dual antiplatelet therapy. Despite extensive exploratory analyses, the mechanisms underlying these interactions are uncertain. Clinical Trial Registration— URL: http://www.SPS3ClinicalTrials.gov . Unique identifier: NCT00059306.

To determine the ability of serial cardiac troponin (cTnI) changes (delta) to distinguish type 1 and type 2 myocardial infarction (MI) (excluding all ST-segment elevation MIs (STEMIs)) and describe the diagnostic accuracy and 180-day mortality in MI versus no-MI patients.Serial cTnIs were measured in 1112 consecutive patients without STEMI and within 6h of presentation to a United States emergency department: 856 (77%) with no MI, 66 (6%) type 1 MI, and 190 (17%) type 2 MI. Of the 0 to 3h and 0 to 6h absolute and relative cTnI changes, only the distribution of absolute change from 0 to 6h was significantly different between type 1 and type 2 MI: median (interquartile range) 311 (1430) ng/l vs. 80 (330) ng/l, p=0.03. Neither the absolute concentration change nor the absolute percent change from either 0 h to 3h (areas under the curves (AUCs) 0.57 and 0.54 respectively) or 0 h to 6h (AUCs 0.60 and 0.51) improved on the performance of the individual cTnI results at 3h (AUC 0.60) or 6h (AUC 0.62), respectively. After adjusting for age, and histories of heart failure and renal insufficiency, those with type 2 MI (hazard ratio 2.9, 95% confidence interval (CI) 1.4-5.9, p=0.004) and those with no index MI and cTnI(max0-6h)34 ng/l (2.5, CI 1.1-6.0, p=0.04) had increased risk of death within 180 days compared with those with no MI and cTnI(max 0-6h) ≤ 34 ng/l.Delta cTnI did not aid in distinguishing type 1 MI from the more common type 2 MI. Patients diagnosed with type 2 MIs, which represented more than half of all index MIs, had increased risk of death after discharge.

Background and Purpose— Subdural hematomas are an important bleeding complication of anticoagulation. We quantify the risk of subdural hematoma associated with anticoagulation with vitamin K antagonists (VKAs) compared with other oral antithrombotic therapies. Methods— Randomized trials were identified from the Cochrane Central Register of Controlled Trials and were included if published since 1980 and compared oral VKAs with antiplatelet therapy or with direct-acting oral anticoagulants. Two reviewers independently extracted data with differences resolved by joint review. Results— Nineteen randomized trials were included that involved 92 156 patients and 275 subdural hematomas. By meta-analysis, VKAs were associated with a significantly increased risk of subdural hematoma (odds ratios, 3.0; 95% confidence interval, 1.5–6.1) compared with antiplatelet therapy (9 trials, 11 603 participants). The risk of subdural hematoma was also significantly higher with VKAs versus factor Xa inhibitors (meta-analysis odds ratios, 2.9; 95% confidence interval, 2.1–4.1; 5 trials, 49 687 patients) and direct thrombin inhibitors (meta-analysis odds ratios, 1.8; 95% confidence interval, 1.2–2.7; 5 trials, 30 866 patients) versus VKAs. The absolute rate of subdural hematoma among 24 485 patients with atrial fibrillation treated with VKAs pooled from 6 trials testing direct-acting oral anticoagulants was 2.9 (95% confidence interval, 2.5–3.5) per 1000 patient-years. Conclusions— VKA use significantly increases the risk of subdural hematoma by ≈3-fold relative to antiplatelet therapy. Direct-acting oral anticoagulants are associated with a significantly reduced risk of subdural hematomas versus VKAs. Based on indirect comparisons to VKAs, the risks of subdural hematoma are similar with antiplatelet monotherapies and factor Xa inhibitors.

Background: Among participants in the Secondary Prevention of Small Subcortical Strokes randomized trial, we sought to identify patients with high versus low rates of recurrent ischemic stroke and to assess effects of aggressive blood pressure control and dual antiplatelet therapy according to risk status. Methods: Multivariable analyses of 3020 participants with recent magnetic resonance imaging–defined lacunar strokes followed for a mean of 3.7 years with 243 recurrent ischemic strokes. Results: Prior symptomatic lacunar stroke or transient ischemic attack (TIA) (hazard ratio [HR] 2.2, 95% confidence interval [CI] 1.6, 2.9), diabetes (HR 2.0, 95% CI 1.5, 2.5), black race (HR 1.7, 95% CI 1.3, 2.3), and male sex (HR 1.5, 95% CI 1.1, 1.9) were each independently predictive of recurrent ischemic stroke. Recurrent ischemic stroke occurred at a rate of 4.3% per year (95% CI 3.4, 5.5) in patients with prior symptomatic lacunar stroke or TIA (15% of the cohort), 3.1% per year (95% CI 2.6, 3.9) in those with more than 1 of the other 3 risk factors (27% of the cohort), and 1.3% per year (95% CI 1.0, 1.7) in those with 0-1 risk factors (58% of the cohort). There were nosignificantinteractions between treatmenteffects andstroke risk status. Conclusions: In this large, carefully followed cohort of patients with recent lacunar stroke and aggressive blood pressure management, prior symptomatic lacunar ischemia, diabetes, black race, and male sex independently predicted ischemic stroke recurrence. The effects of blood pressure targets and dual antiplatelet therapy were similar across the spectrum of independent risk fac

Background While living with others has been associated with improved functional outcome after acute stroke, it is unclear if this affects adherence to stroke prevention measures. Aims We examined the relationship between living arrangements and adherence to antiplatelet therapy assignment and participation status in an international randomized trial for secondary stroke prevention. Method Antiplatelet therapy adherence, trial retention outcomes, and baseline characteristics for participants enrolled in the Secondary Prevention of Small Subcortical Strokes study were compared between those who lived alone vs. with others ( n = 2374). Participant status at end-of-trial was categorized into ( 1 ) on assigned antiplatelet, ( 2 ) off assigned anti-platelet by participant request, or ( 3 ) participant withdrew consent/lost to follow-up. Multivariable multivariate logistic regression was used to identify patient features at entry predictive of participant status at trial end. Results Living arrangement, alone vs. with other(s), was not significantly associated with participant status. Participants enrolled in the United States/Canada (odds ratio 3·1, confidence intervals 2·0–5·0, vs. Latin America), taking more (7+) prescription medications (odds ratio 1·7, confidence intervals 1·1–2·7, vs. 0–2 medications), and scoring lower on the Stroke Specific Quality of Life scale (odds ratio 1·3, confidence intervals 1·1–1·5, per 10 points) were more likely to withdraw or become lost to follow-up in the study vs. completing the study on assigned antiplatelet therapy. Participants enrolled in the United States/Canada (odds ratio 5·0, confidence intervals 2·4–10·0, vs. Latin America) and taking fewer (0–2) medications (odds ratio 1·9, confidence intervals 1·2–3·1 vs. 3–6 medications) were more likely to request discontinuation of assigned antiplatelet medication vs. completing the study. Conclusion Living with others was not independently predictive of protocol adherence in this cohort. Number of medications and Stroke Specific Quality of Life scale score may be more indicative of likelihood of trial participation and acceptance of long-term antiplatelet regimen.

This study examined the baseline characteristics, racial/ethnic differences, and geographic differences among participants in the Secondary Prevention of Small Subcortical Strokes (SPS3) study. The SPS3 trial enrolled patients who experienced a symptomatic small subcortical stroke (lacunar stroke) within the previous 6 months and an eligible lesion on detected on magnetic resonance imaging. The patients were randomized, in a factorial design, to antiplatelet therapy (aspirin 325 mg daily plus clopidogrel 75 mg daily vs aspirin 325 mg daily plus placebo) and to one of two levels of systolic blood pressure targets ("intensive" [

To characterize cerebral microbleeds (CMBs) in lacunar stroke patients in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial and to assess their relationship with recurrent stroke and death, and response to assigned treatment.SPS3 is a randomized, clinical trial conducted between 2003 and 2011. Patients with recent magnetic resonance imaging (MRI)-documented lacunar infarcts were randomly assigned in a factorial design to target levels of systolic blood pressure (130-149mmHg vs130mmHg; open label) and to antiplatelet treatment (aspirin/clopidogrel vs aspirin/placebo; double-blinded). The current analysis involves 1,278 trial participants who had a baseline axial T2*-weighted gradient echo MRI sequence allowing for CMB detection.CMBs were present in 30% of 1,278 patients (mean age = 63 years). Male gender (odds ratio [OR] = 1.7, 95% confidence interval [CI] = 1.3-2.3), history of hypertension (OR = 1.6, 95% CI = 1.2-2.3), increased systolic blood pressure (1.2 per 20mmHg, 95% CI = 1.1-1.4), nondiabetic status (OR = 1.4, 95% CI = 1.1-1.9), multiple old lacunar infarcts (OR = 1.9, 95% CI = 1.5-2.5), and moderate (OR = 1.7, 95% CI = 1.2-2.3) or severe (OR = 4.2, 95% CI = 3.0-5.9) white matter hyperintensities on MRI were independently associated with CMBs. During a mean follow-up of 3.3 years, overall stroke recurrence was 2.5% per patient-year. Patients with CMBs had an adjusted 2-fold increased risk of recurrent stroke (hazard ratio = 2.1, 95% CI = 1.4-3.1). CMBs were not a risk factor for death. There were no statistically significant interactions between CMBs and treatment assignments.Patients with lacunar stroke and CMBs likely harbor a more advanced form of cerebral small vessel disease in need of efficacious therapeutic strategies. Ann Neurol 2017;82:196-207.

Background and Purpose— In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, addition of clopidogrel to aspirin was associated with an unexpected increase in mortality in patients with lacunar strokes. We assessed the effect of the addition of clopidogrel to aspirin on mortality in a meta-analysis of published randomized trials. Methods— Randomized trials in which clopidogrel was added to aspirin in subjects with vascular disease or vascular risk factors were identified. Trials were restricted to those with a mean follow-up of ≥14 days in which both the combination of aspirin and clopidogrel was tested and mortality was reported. Results— Twelve trials included 90 934 participants (mean age, 63 years; 70% men; median follow-up, 1 year) with 6849 observed deaths. There was no significant increase in mortality with the combination therapy either in 4 short-term (14 days–3 months; OR, 0.93; 95% CI, 0.87–0.99) or in 7 long-term (>3 months; hazard ratio, 0.97; 95% CI, 0.91–1.04) trials after 1 long-term trial (the SPS3 trial) was excluded because of heterogeneity. Addition of clopidogrel was associated with an increase in fatal hemorrhage (OR, 1.35; 95% CI, 0.97–1.90) and a reduction in myocardial infarction (OR, 0.82; 95% CI, 0.74–0.91). Conclusions— The addition of clopidogrel to aspirin has no overall effect on mortality. The SPS3 trial results are outliers, possibly because of a lower prevalence of coronary artery ischemia. Addition of clopidogrel to aspirin increases fatal bleeding and reduces myocardial infarction. Clinical Trial Registration— URL: http//www.clinicaltrials.gov . Unique identifier: NCT00059306.

The efficacy of adjusted-dose warfarin for prevention of stroke in atrial fibrillation patients with stage 3 chronic kidney disease (CKD) is unknown.Patients with stage 3 CKD participating in the Stroke Prevention in Atrial Fibrillation 3 trials were assessed to determine the effect of warfarin anticoagulation on stroke and major hemorrhage, and whether CKD status independently contributed to stroke risk. High-risk participants (n = 1044) in the randomized trial were assigned to adjusted-dose warfarin (target international normalized ratio 2 to 3) versus aspirin (325 mg) plus fixed, low-dose warfarin (subsequently shown to be equivalent to aspirin alone). Low-risk participants (n = 892) all received 325 mg aspirin daily. The primary outcome was ischemic stroke (96%) or systemic embolism (4%).Among the 1936 participants in the two trials, 42% (n = 805) had stage 3 CKD at entry. Considering the 1314 patients not assigned to adjusted-dose warfarin, the primary event rate was double among those with stage 3 CKD (hazard ratio 2.0, 95% CI 1.2, 3.3) versus those with a higher estimated GFR (eGFR). Among the 516 participants with stage 3 CKD included in the randomized trial, ischemic stroke/systemic embolism was reduced 76% (95% CI 42, 90; P0.001) by adjusted-dose warfarin compared with aspirin/low-dose warfarin; there was no difference in major hemorrhage (5 patients versus 6 patients, respectively).Among atrial fibrillation patients participating in the Stroke Prevention in Atrial Fibrillation III trials, stage 3 CKD was associated with higher rates of ischemic stroke/systemic embolism. Adjusted-dose warfarin markedly reduced ischemic stroke/systemic embolism in high-risk atrial fibrillation patients with stage 3 CKD.

BACKGROUND We assessed the ability of myeloperoxidase (MPO) to identify the risk for major adverse cardiac events (MACE) in patients who present with ischemic symptoms suggestive of acute coronary syndrome and have a normal cardiac troponin I (cTnI) value. METHODS We used Siemens (n = 400) and Abbott (n = 350) assays to measure MPO and cTnI in plasma samples from 400 patients. Event rates (myocardial infarction, cardiac death, percutaneous coronary intervention, coronary artery bypass grafting) were estimated by the Kaplan–Meier method and compared with the log-rank statistic. RESULTS At the 30-day follow-up, the adjusted hazard ratios for MACE were 3.9 (P < 0.001) for increased cTnI and 2.7 (P = 0.006) for increased MPO for the Siemens assays and were 5.5 (P < 0.001) for increased cTnI and 2.9 (P = 0.001) for increased MPO for the Abbott assays. Similar findings were observed with 6 months of follow-up. Patients who initially had a normal cTnI value and an increased Siemens MPO value demonstrated a higher rate of MACE at 30 days than those in whom both values were normal (16.1% vs 3.6%, P = 0.002) and 6 months (18.1% vs 5.0%, P = 0.002). Similarly, patients who had an increased Abbott MPO result demonstrated a higher MACE rate at 30 days (12.3% vs 3.9%, P = 0.03) and at 6 months (16.2% vs 5.1%, P = 0.01) than those with normal values. CONCLUSIONS A combination of MPO and cTnI allowed the identification of a greater proportion of patients at risk for MACE than the use of cTnI alone. Increased MPO values remained predictive of future cardiac events even when the cTnI value was normal.

Background: We sought to determine the diagnostic accuracy of the cardiac troponin I (cTnI) VITROS® Troponin I-ES assay for early detection of acute myocardial infarction (AMI) and for risk prediction of adverse events in patients with symptoms of acute coronary syndrome (ACS). Methods: cTnI was measured on admission and approximately 6 h postadmission in 381 patients. The 99th percentile cTnI concentration (0.034 μg/L) and change [delta (δ)] between admission and follow-up concentrations were evaluated in diagnostic sensitivity and specificity calculations. Risk of cardiac event or death within 60 days was evaluated by Cox proportional hazards regression. Results: AMI occurred in 52 patients. Diagnostic sensitivities (95% CI) of admission and follow-up cTnIs for AMI were 69% (55%–81%) and 94% (84%–99%), respectively. The corresponding specificities (95% CI) were 78% (73%–82%) and 81% (77%–85%), and ROC curve areas were 0.82 vs 0.96 (P < 0.001). Deltas between admission and follow-up cTnI >30% had a sensitivity of 75% (95% CI 61%–86%) and a specificity of 91% (95% CI 87%–94%). During follow-up, 1 cardiac death, 2 noncardiac deaths, 52 AMIs, 6 coronary artery bypass grafts, and 43 percutanous coronary interventions occurred in 62 patients. A δ cTnI >30%, when added to either initial cTnI >0.034 μg/L or follow-up cTnI >0.034 μg/L, improved risk stratification for cardiac event or death (P < 0.001). Conclusions: Admission cTnI measured by the VITROS ES assay is a sensitive biomarker for detection of AMI. Utilizing >30% cTnI δ in addition to either the baseline or follow-up concentration improved both specificity and risk assessment in patients presenting with symptoms of ACS.

Background: Cardiac troponin is the preferred biomarker for detecting acute myocardial injury and infarction (MI). We studied whether multiple biomarkers of numerous pathophysiological pathways would increase the diagnostic accuracy for detecting MI. Methods: Seven biomarkers [myeloperoxidase, soluble CD40 ligand, placental growth factor, matrix metalloproteinase 9 (MMP-9), high-sensitivity C-reactive protein (hsCRP), cardiac troponin I (cTnI), N-terminal pro–B-type natriuretic peptide] and estimated glomerular filtration rate were measured in 457 patients presenting on admission with symptoms suggestive of acute coronary syndrome. Twenty-five patients (5.4%) received MI diagnoses. Clinical sensitivities and specificities were evaluated from 99th-percentile reference values. Forward and backward stepwise logistic regression modeling techniques were used to identify biomarkers that were independently predictive of MI. Results: Biomarker sensitivities ranged from 20% to 96%, and specificities ranged from 19% to 89%. MMP-9 had the highest sensitivity, but its specificity was 19%. cTnI demonstrated a sensitivity of 72% (95% CI, 51%–88%) and a specificity of 89% (95% CI, 85%–92%). In multivariate models, cTnI (P < 0.001) and either hsCRP (P = 0.009) or MMP-9 (P = 0.03) were independently predictive of MI. Addition of hsCRP or MMP-9 increased the specificity to 95% (95% CI, 92%–97%) or 91% (95% CI, 88%–94%), respectively, but reduced the sensitivity to 56% (95% CI, 35%–76%) and 68% (95% CI, 47%–85%) relative to cTnI alone. Conclusions: Our findings indicate that the most clinically accurate biomarker for the early diagnosis of MI is the use of cTnI alone, rather than a multiple-biomarker approach, when an analytically robust cardiac troponin assay based on the 99th percentile is used.

We demonstrate the performance of the bioMérieux VIDAS Troponin I Ultra assay for diagnostic accuracy for detection of myocardial infarction (MI) and risk stratification.cTnI was measured in 545 patients from 2 clinical centers with symptoms suggestive of ACS at admission, with an additional specimen at 4-12 h (453 patients). The 99th percentile value (0.01 microg/l) was used to assess clinical accuracy for diagnosis of acute MI. Primary endpoint for risk stratification was first of cardiac event or death in 302 patients (one center) followed for 60 days.157 (28.8%) patients ruled in for an MI during index hospitalization. Sensitivities and specificities were 88.1% (95% CI 81.9 to 92.4%) and 79.9% (CI 75.5 to 83.6%) for baseline and 100% (CI 96.5 to 100%) and 79.4% (CI 74.4 to 83.4%) for follow-up specimens. ROC curve areas increased from 0.912 (CI 0.879 to 0.944) at baseline to 0.994 (CI 0.988 to 0.999) at second sampling (n=453, p0.01); with no differences between sites. Primary endpoint rate for the 223 patients (74%) with normal cTnI on presentation was lower than the 79 patients (26%) with cTnI0.01 ug/l (5.9% vs. 42.3%, p0.0001). The relative risk for the0.01 ug/l group was 8.9 (CI 4.6 to 17).The VIDAS cTnI assay is a sensitive diagnostic method for the early detection of MI and predicts increased risk for adverse events in patients with symptoms suggestive of ACS.

Cardiac troponin (cTn) assays were compared in 490 unselected patients with symptoms suggestive of acute coronary syndrome with varying renal functions for risk stratification. cTnI (Dade, Newark, NJ; Beckman, Chaska, MN; and Tosoh, South San Francisco, CA) and cTnT (Roche, Indianapolis, IN) measurements and estimated glomerular filtration rates (eGFRs) were obtained and classified along sex-derived cutoffs. The cTn levels were increased in 14% to 25% of patients. In 68%, the eGFR was 60 mL/min/1.73 m2 or more; in 17%, it was between 41 and 59; and in 15%, it was 40 or less. There were 36 deaths and 9 cardiac events. Risk stratification was significant at 30 days and 6 months (Por = .05). Relative risks ranged from 3.1 to 3.7, and cumulative event rates ranged from 22.4% to 24.2% for an increased troponin level compared with 6.7% to 8.9% for a normal level. The 6-month event rate with an eGFR less than 60 mL/min/1.73 m2 and an increased troponin level ranged from 29.9% to 50.8% compared with 4.9% to 6.6% for a normal troponin level and an eGFR greater than 60 mL/min/1.73 m2 (P.05). The eGFR in combination with an increased cTn level demonstrated the most powerful stratification.

Background Cognitive impairment is frequent in lacunar stroke patients. The prevalence and pattern among Spanish-speaking patients are unknown and have not been compared across regions or with English-speaking patients. Aims The aim of this study was to characterize cognitive impairment in Spanish-speaking patients and compare it with English-speaking patients. Methods The baseline neuropsychological test performance and the prevalence of mild cognitive impairment, defined as a z-score ≤ -1·5 on memory and/or non-memory tests, were evaluated in Spanish-speaking patients in the Secondary Prevention of Small Subcortical Strokes trial. Results Out of 3020 participants, 1177 were Spanish-speaking patients residing in Latin America ( n = 693), the United States ( n = 121), and Spain ( n = 363). Low education (zero- to eight-years) was frequent in Spanish-speaking patients (49–57%). Latin American Spanish-speaking patients had frequent post-stroke upper extremity motor impairment (83%). Compared with English-speaking patients, all Spanish-speaking patient groups had smaller memory deficits and larger non-memory/motor deficits, with Latin American Spanish-speaking patients showing the largest deficits median z-score -1·3 to −0·6 non-memory tests; ≤5·0 for Grooved Pegboard; −0·7 to −0·3 for memory tests). The prevalence of mild cognitive impairment was high and comparable with English-speaking patients in the United States and Latin American Spanish-speaking patients but not the Spanish group: English-speaking patients = 47%, Latin American Spanish-speaking patients = 51%, US Spanish-speaking patients = 40%, Spanish Spanish-speaking patients = 29%, with >50% characterized as non-amnestic in Spanish-speaking patient groups. Older age [odds ratio per 10 years =1·52, confidence interval = 1·35–1·71), lower education (odds ratio 0–4 years = 1·23, confidence interval = 0·90–1·67), being a Latin American resident (odds ratio = 1·31, confidence interval = 0·87–1·98), and post-stroke disability (odds ratio Barthel Index Conclusions Mild cognitive impairment in Secondary Prevention of Small Subcortical Strokes Spanish-speaking patients with recent lacunar stroke is highly prevalent but has a different pattern to that observed in English-speaking patients. A combination of socio-demographics, stroke biology, and stroke care may account for these differences.

Background and Purpose: Noninvasive fractional flow reserve (FFR) on time-of-flight magnetic resonance angiography (TOF-MRA) may be used to identify high-risk intracranial lesions. We tested whether FFR was associated with vascular territory of the qualifying lacunar stroke in participants of the Secondary Prevention of Small Subcortical Strokes (SPS3) trial and the utility of FFR for predicting recurrent stroke during the trial. Methods: SPS3 was a randomized trial investigating optimal blood pressure target and antiplatelet regimen in patients with recent, symptomatic, MRI-confirmed lacunar stroke patients TOF-MRA proximate to study entry was adequate and available for 2169 of 3020 study patients. Signal intensity (SI) was measured in the background, and proximal and distal aspects of 7 intracranial arteries (internal carotid, middle cerebral, basilar, and vertebral). Adjusted FFR was then calculated in each artery: FFR = [distal SI - background SI] / [proximal SI - background SI] and divided into quartiles by artery. Associations between the vascular territory of the qualifying infarct and the FFR quartile of the relevant artery were investigated using contingency tables and chi-square tests. Risks for recurrent stroke associated with FFR quartiles were evaluated using Cox Proportional Hazards models (model adjusted for assigned treatment groups). Results: Mean age of the 2169 patients included was 63 yr with 63% male; hypertension, diabetes, and prior lacunar stroke were present in 75%, 36%, and 10% respectively. Median FFRs varied by artery with the lowest in the basilar (0.793) and highest in the middle cerebral arteries (left 1.154; right 1.176). A recurrent stroke occurred in 195 patients during a mean follow-up of 3.5 years (annualized rate 2.5% per patient-year).No significant association was found between the FFR tertiles and the vascular territory of the qualifying infarct. Quartiles of adjusted FFR in any of the 7 arteries were not found to be predictive of recurrent stroke. Conclusion: In this large well-characterized cohort of lacunar stroke patients, FFR was not associated with the location of the qualifying subcortical infarct and did not predict the risk of recurrent stroke.

Background— Approximately 7000 intracerebral hemorrhages (ICHs) annually in the US are caused by use of antithrombotic therapies. We review the incidence, risk factors, and predictors of ICH in patients receiving long-term anticoagulation or antiplatelet therapy. Summary of Review— ICH rates range from 0.3% to 0.6% per year during oral anticoagulation in recent reports. Major risk factors are advanced patient age, elevated blood pressure, intensity of anticoagulation, and previous cerebral ischemia. Combining antiplatelet agents with anticoagulation and the combined use of aspirin plus clopidogrel appear to increase ICH risk. Modest blood pressure-lowering halves the frequency of ICH during antiplatelet therapy. Conclusion— ICH is an uncommon, but often fatal, complication of antithrombotic therapy that particularly afflicts patients with previous stroke. Recent data support that keeping international normalized ratio ≤3.0, control of hypertension, and avoiding the combination of aspirin with warfarin reduce its frequency.

Background: In patients with end-stage renal disease (ESRD), the ability of single and multiple biomarker monitoring to predict adverse outcomes has not been well established. This study determined the prognostic value of multiple biomarkers for all-cause death over 2 years in 399 ESRD patients.Methods: The risk of all-cause death was determined by use of multiple biomarkers based on concentrations for a reference population (normal) and cutoffs based on tertile distributions in the ESRD group. Biomarkers studied included N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hsCRP; Dade Behring and Roche assays), and cardiac troponin T (cTnT; Roche) and I (cTnI; Dade Behring and Beckman Coulter assays). Relative risks of death were estimated and survival curves computed.Results: A total of 101 deaths occurred during 594 patient-years of follow-up. Increased NT-proBNP concentrations were not predictive of death on the basis of the normal cutoffs. However, tertile analysis of NT-proBNP was significantly predictive of death and had a ROC area under the curve equivalent to or better than any of the other biomarkers. Biomarkers independently predictive of survival were hsCRP (P Conclusions: Although mechanisms likely vary for causation, increased plasma hsCRP, cTnT, and cTnI above the cutoffs for our reference (normal) population were all independently predictive of subsequent death in ESRD patients. Tertile analysis for NT-proBNP also demonstrated prognostic value.

Background and Purpose— Transient ischemic attacks (TIAs) are infrequent in patients with atrial fibrillation, and little is known about the long-term prognosis and response to antithrombotic therapy. Methods— This study was a pooled analysis of participants in 2 randomized trials, the European Atrial Fibrillation Trial and the Stroke Prevention in Atrial Fibrillation III Trial, comparing those with prior TIA to those with prior stroke. Results— Among 834 atrial fibrillation patients with prior TIA (n=222), prior ischemic stroke (n=551), or both (n=61), the mean age was 71 years, 64% were men, and 56% had hypertension. The frequency of major vascular risk factors was similar for both types of cerebral ischemia. The annualized rate of ischemic stroke during aspirin therapy was 7% per year (95% confidence interval, 4 to 12) for prior TIA and 11% per year (95% confidence interval, 9 to 15) for prior stroke ( P =0.08 for rate difference) and was reduced by 56% ( P =0.09) and 63% ( P Conclusions— Atrial fibrillation patients with TIA have a lower long-term risk of subsequent stroke than those with prior stroke, but their stroke risk during aspirin therapy is still high. For atrial fibrillation patients with either type of cerebral ischemia, recent or remote, secondary prevention with adjusted-dose warfarin instead of aspirin results in substantial absolute reductions in ischemic stroke.

Background— Abnormal plasma markers of a prothrombotic state have been described in atrial fibrillation (AF), but no such marker has yet been shown to reliably predict future stroke or cardiovascular outcome in AF. We hypothesized that raised plasma levels of von Willebrand factor (vWf, an index of endothelial damage/dysfunction) and/or soluble P-selectin (sP-sel, an index of platelet activation) might predict vascular events in AF. Methods and Results— We measured vWf and sP-sel levels by ELISA in 994 participants receiving aspirin in the Stroke Prevention in Atrial Fibrillation III trial, at study entry or after 3 months, and related these indices to the subsequent incidence of stroke and vascular events. Plasma vWf levels were a significant predictor of both stroke ( P =0.03) and vascular events ( P P =0.02). No significant relationships were found between sP-sel levels and outcome. Conclusion— Among patients with AF who received aspirin, raised levels of vWf (endothelial damage/dysfunction) were predictive of stroke and vascular events, but raised sP-sel levels (platelet activation) were not associated with increased cardiovascular risk. Endothelial damage/dysfunction (or vWf itself) may play an important role in the mechanisms behind stroke and cardiovascular outcome among aspirin-treated AF patients and might represent a target for novel therapies or an adjunctive aid to risk stratification in AF.

We evaluated the risk assessment value of a commercial cardiac troponin (cTn; Ortho Vitros ECi, Ortho-Clinical Diagnostics, Raritan, NJ) I assay in patients with symptoms of myocardial ischemia suggestive of acute coronary syndrome and compared findings with those for a commercial cTnT assay in the same population. The cTn levels were measured by both assays in plasma samples from 273 patients during 24 hours after admission. Baseline and maximum concentrations were used for risk stratification; cutoffs were the 99th percentile and 10% coefficient of variation. End points were all-cause death and cardiac events within 60 days. Relative risks (RRs) were estimated using Cox proportional hazards regression models and Kaplan-Meier curves. RRs of cardiac events and death were significantly higher with increased baseline and maximum concentrations using either cTnI cutoff. The respective mortality rates for baseline cTnI of more than 0.08 μg/L vs 0.08 μg/L or less were 17.4% vs 2.9% ( P = .001); cardiac event rates were 11.5% vs 3.6% ( P = .03). Exclusion of patients with ST-segment elevation had no significant effect on rates for either assay. Mortality was higher in the intermediate (0.09–0.2 μg/L) than in the low (≤0.08 μg/L) group for cTnI, with directionally similar results for cTnT. Our findings validate the Ortho cTnI assay as a risk stratification biomarker in patients with symptoms of myocardial ischemia.

Study Objective. To determine whether urinary 11-dehydrothromboxane B 2 (d-TXB 2 ) is a marker of aspirin resistance and define the relationship between aspirin dosage and concentrations of this thromboxane metabolite, Design. Randomized, crossover study. Setting. Two outpatient clinical centers. Patients. Forty-eight patients (mean age 70 yrs) with vascular disease (52% clinical coronary artery disease, 29% cerebrovascular disease, 46% atrial fibrillation). Intervention. Levels of serum thromboxane B 2 and d-TXB 2 were measured after patients were treated initially with aspirin 325 mg/day for 4 weeks, then again after random assignment to receive aspirin 81, 325, or 1300 mg/day for 4 weeks, and then again after resumption of 325 mg/day for 4 weeks. Measurements and Main Results. During treatment with aspirin 325 mg/day, the mean ± SD serum thromboxane B 2 level was 0.9 ± 1,2 ng/ml and median (interquartile range) was 0.4 (0.2-0.9) ng/ml. Mean urinary d-TXB 2 was 16 ± 7.9 ng/mmol creatinine, with a median of 15 (9.9-23) ng/mmol creatinine with aspirin 325 mg/day. After 4 weeks of aspirin 81 mg/day, levels of serum thromboxane B 2 (p

Atrial fibrillation is a prevalent risk marker for preventable stroke. To date, 20 randomized clinical trials involving 13,843 participants have assessed antithrombotic therapies for prevention of stroke in atrial fibrillation. Here, these trials are considered, along with 8 additional randomized trials involving an additional 20,000 patients that are underway. These trials provide a wealth of solid evidence on which to individualize patient management to prevent stroke. A formerly neglected cause of major stroke, atrial fibrillation is now the focus of intensive clinical research aimed at stroke prevention.

Objectives We determined diagnostic accuracy and risk stratification using delta changes for the cardiac troponin I (cTnI) Centaur Ultra assay for ruling out acute myocardial infarction (AMI) and for risk prediction of adverse events in patients with symptoms of acute coronary syndrome. Design and methods cTnI was measured on admission and 6–24 h in 371 patients. Optimal deltas (percent change, absolute value of percent change, change, absolute value of change) were determined from ROC curve analysis. Risk stratification was performed for cardiac events and death within 60 days. Results AMI during hospitalization occurred in 49 patients and endpoints in 11 patients. Diagnostic accuracy by ROC curve was optimal (0.96) using the absolute value of change delta. Diagnostic specificities utilizing the 99th percentile (40 ng/L) for admission and follow-up samples were 84% and 81%, compared to: [90% percent change delta] 89.7%; [66.7% absolute value of percent change delta] 85.5%, [217 ng/L change delta] 99.0% and [55 ng/L absolute value of change delta] 93.7%. All four delta values showed substantially greater risk when the initial cTn value was normal. Conclusions Utilizing delta cTnI values improves clinical specificity, diagnostic accuracy and risk assessment in patients presenting with symptoms of ACS.

Background— This study determined the prevalence of increased cardiac troponin I (cTnI) and T (cTnT) in end-stage renal disease (ESRD) patients and whether an increased troponin was predictive of death. Methods and Results— Serum was obtained from 733 ESRD patients and measured for cTnI and cTnT. Relative risks were estimated using Cox proportional hazards regressions univariately and adjusted for age, time on dialysis, and coronary artery disease. Kaplan-Meier curves compared time to event data between groups. Greater percentages of patients had an increased cTnT versus cTnI at each cutoff, as follows: 99th percentile, 82% versus 6%; 10% coefficient of variation, 53% versus 1.0%; and receiver operator characteristic, 20% versus 0.4%. Increased versus normal cTnT was predictive of increased mortality using all cutoffs and only above the 99th percentile for cTnI. Two-year cumulative mortality rates increased ( P 99th percentile) cTnT were 5.0 (CI, 2.5 to 10; P P P =0.008) and 2.1 (CI, 1.3 to 3.3; P =0.007). Age, coronary artery disease, and time on dialysis were also independent predictors of mortality. Conclusions— Increases in cTnT and cTnI in ESRD patients show a 2- to 5-fold increase in mortality, with a greater number of patients having an increased cTnT.

Numerous studies have evaluated cardiac troponin I (cTnI), cardiac troponin T (cTnT), and creatine kinase-MB for risk stratification of acute coronary syndrome (ACS) patients. Two metaanalyses have demonstrated the ability of cTnI or cTnT to predict adverse outcomes (1)(2). A substudy of the FRISC II trial showed that the prognostic value of cTnT in ACS patients could be attributed to its correlation with the underlying severity of coronary artery stenosis (3). Because of analytical and clinical differences among troponin assays (4)(5)(6)(7), the cardiology (8)(9) and laboratory medicine (10) communities have endorsed the need for evidence-based studies before individual assays are accepted into clinical practice. Few studies have investigated the role of point-of-care (POC) testing for assessing adverse outcomes in ACS patients. One study using qualitative POC assays for cTnI and cTnT showed both assays to be independent predictors of cardiac events at 30 days after admission in ACS patients (11). In a consensus document from the European Society of Cardiology (ESC) and the American College of Cardiology (ACC), myocardial infarction (MI) was redefined as any amount of myocardial necrosis in the presence of myocardial ischemia, as indicated by an increased cardiac troponin (I or T) above the 99th percentile of a reference population (9). Because many troponin assays lack acceptable precision at the 99th percentile cutoff and assay precision may be important for risk stratification, a revised cutoff has been recommended as the index for myocardial damage, as the lowest troponin concentration closest to the 99th percentile that can be measured with 10% imprecision (CV) (5). We investigated the prognostic value of a whole-blood quantitative POC cTnI assay for risk stratification of ACS patients admitted in routine clinical practice for all-cause death, cardiac death, and cardiac events …

Obstructive sleep apnea (OSA) is associated with hypertension (HTN) and cardiovascular disease. Transient episodes of hypoxia, hypercapnia, and blood pressure elevation during OSA may lead to neural damage and subsequently white matter disease (WMD). As WMD is usually the result of chronic small vessel ischemia, a relationship between OSA and cerebrovascular disease may exist. This case series aimed to establish a relationship between OSA and WMD. Sixty-two patients without cerebrovascular disease who had both a polysomnogram and brain magnetic resonance imaging were identified. All patients carried the diagnosis of HTN. WMD was evaluated using the age-related white matter changes scale. Although half of the study population had WMD on magnetic resonance imaging, no association was found between WMD with severity of OSA (P=0.9). Our results are limited by the small sample size and by coexistent HTN in all patients. Further studies are needed to elucidate the relationship between OSA and WMD, especially among nonhypertensive patients. Future research should also address if OSA treatment has any effect on WMD.

Background: The clinical implications of vertebrobasilar ectasia (VBE) in patients with cerebral small-artery disease are not well defined. We investigated whether VBE is associated with recurrent stroke, major hemorrhage, and death in a large cohort of patients with recent lacunar stroke. Methods: Maximum diameters of the vertebral and basilar arteries were measured by magnetic resonance angiography and computed tomographic angiography in 2621 participants in the Secondary Prevention of Small Subcortical Strokes trial. VBE was defined a priori as basilar artery greater than 4.5 mm and/or vertebral artery greater than 4.0 mm. Patient characteristics and risks of stroke recurrence and mortality during follow-up (median, 3.5 years) were compared between patients with and without VBE. Results: VBE affecting 1 or more arteries was present in 200 (7.6%) patients. Patient features independently associated with VBE were increasing age, male sex, white race ethnicity, hypertension, and higher baseline diastolic blood pressure. Baseline systolic blood pressure was inversely associated with VBE. After adjustment for other risk factors, VBE was not predictive of recurrent stroke (hazard ratio [HR], 1.3; 95% confidence interval [CI], .85-1.9) or major hemorrhage (HR, 1.5; CI, .94-2.6), but was of death (HR, 1.7; CI, 1.1-2.7). Conclusions: In this large well-characterized cohort of patients withrecentlacunarstroke,VBEwaspredictiveof deathbutnotof recurrentstrokeor major hemorrhage. In these exploratory analyses, the frequency of VBE was directly related to diastolic blood pressure but inversely related to systolic blood

Background and Purpose: Intracranial arterial dolichoectasia (IADE) is associated with atherothrombotic strokes, but its relationship with lacunar infarcts is less certain. We investigated the prevalence of IADE and associated risk of recurrent stroke and death in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial. Methods: Maximum diameter of the intracranial internal carotid artery (ICA), middle cerebral artery (MCA), vertebral artery (VA), and basilar artery (BA) were measured on 2794 MRAs with IADE defined a priori as >7.0 mm for ICA, >4.0 mm for MCA, >4.0 mm for VA, and >4.5 mm for BA. Patient characteristics and outcomes were compared between patients with and without IADE. Results: IADE was present in ≥1 artery in 210 (7.1%) patients, none in ICA, 5 MCA, 163 BA, and 116 VA. Patients with IADE were more often older (65 vs. 63 years; p = 0.01) male (81% vs. 61 %; p Conclusion: In this large well characterized cohort of lacunar stroke patients, dilatation of BA was independently associated with death but not recurrent stroke, and IADE in other arteries did not predict stroke or death. IAED in lacunar stroke patients seems to be unrelated to the mechanism and severity of small vessel disease.