Frequency and Patterns of Brain Infarction in Patients With Embolic Stroke of Undetermined Source: NAVIGATE ESUS Trial.

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<0.001), modified Rankin Scale score >0 (P<0.001), and current tobacco use (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.

Functional Abilities of an International Post-Stroke Population: Standard Assessment of Global Everyday Activities (SAGEA) Scale.

BACKGROUND AND OBJECTIVES: 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. METHODS: 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). CONCLUSIONS: 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.

Rivaroxaban versus aspirin on functional and cognitive outcomes after embolic stroke of undetermined source: NAVIGATE ESUS trial.

BACKGROUND: 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. AIMS: To determine the effect of rivaroxaban compared to aspirin on functional and cognitive outcomes. METHODS: 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. RESULTS: 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, p< 0.001), 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. CONCLUSIONS: 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.

Aspirin Use and Risk of Subdural Hematoma: Updated Meta-Analysis of Randomized Trials.

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.

High-Sensitivity Cardiac Troponin T for Risk Stratification in Patients With Embolic Stroke of Undetermined Source.

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.

Potential Embolic Sources and Outcomes in Embolic Stroke of Undetermined Source in the NAVIGATE-ESUS Trial.

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.

Frequency and Predictors of Major Bleeding in Patients With Embolic Strokes of Undetermined Source: NAVIGATE-ESUS Trial.

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 m2 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.

Atrial Cardiopathy and Nonstenosing Large Artery Plaque in Patients With Embolic Stroke of Undetermined Source.

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.

Intracranial and systemic atherosclerosis in the NAVIGATE ESUS trial: Recurrent stroke risk and response to antithrombotic therapy.

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.

Aortic Arch Atherosclerosis in Patients With Embolic Stroke of Undetermined Source: An Exploratory Analysis of the NAVIGATE ESUS Trial.

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<0.001), prevalence of diabetes mellitus (19% versus 26%, versus 32%; P=0.002), and aortic valvulopathy (10 versus 20 versus 20; P<0.001) increased across no versus noncomplex versus complex AAA, respectively. In multivariable analyses, increasing age, diabetes mellitus, aortic valvulopathy, statin use before randomization, chronic infarcts on imaging, and region were independently associated with any AAA versus no AAA and also with complex AAA versus no AAA. Multiterritorial qualifying infarcts rather than single-territory infarcts were observed in 21% with complex AAA versus 17% noncomplex versus 13% no AAA (P=0.07). Annualized rates of ischemic stroke recurrence were 7.2% versus 4.2% versus 5.6% for complex versus noncomplex versus no AAA, respectively. While prevalence of complex AAA increased with increasing risk score, after adjusting for risk score, we did not observe increased risk of recurrent stroke for patients with complex AAA (hazard ratio, 1.1; 95% CI, 0.53-2.4), although the number of outcomes was limited. In patients with complex AAA, 4 strokes occurred among rivaroxaban-assigned patients and 4 strokes among aspirin-assigned patients. Conclusions- Complex AAA is prevalent in embolic stroke of undetermined source patients and is associated with atherosclerotic burden. Whether complex AAA independently increases recurrent stroke risk and whether a non-vitamin-K oral anticoagulant as compared with aspirin may be effective for reducing recurrent stroke requires additional study. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

Microbleeds in the Secondary Prevention of Small Subcortical Strokes Trial: Stroke, mortality, and treatment interactions.

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 <130mmHg; 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. RESULTS: 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. INTERPRETATION: 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.

Effects of clopidogrel added to aspirin in patients with recent lacunar stroke.

BACKGROUND: Lacunar infarcts are a frequent type of stroke caused mainly by cerebral small-vessel disease. The effectiveness of antiplatelet therapy for secondary prevention has not been defined. METHODS: We conducted a double-blind, multicenter trial involving 3020 patients with recent symptomatic lacunar infarcts identified by magnetic resonance imaging. Patients were randomly assigned to receive 75 mg of clopidogrel or placebo daily; patients in both groups received 325 mg of aspirin daily. The primary outcome was any recurrent stroke, including ischemic stroke and intracranial hemorrhage. RESULTS: The participants had a mean age of 63 years, and 63% were men. After a mean follow-up of 3.4 years, the risk of recurrent stroke was not significantly reduced with aspirin and clopidogrel (dual antiplatelet therapy) (125 strokes; rate, 2.5% per year) as compared with aspirin alone (138 strokes, 2.7% per year) (hazard ratio, 0.92; 95% confidence interval [CI], 0.72 to 1.16), nor was the risk of recurrent ischemic stroke (hazard ratio, 0.82; 95% CI, 0.63 to 1.09) or disabling or fatal stroke (hazard ratio, 1.06; 95% CI, 0.69 to 1.64). The risk of major hemorrhage was almost doubled with dual antiplatelet therapy (105 hemorrhages, 2.1% per year) as compared with aspirin alone (56, 1.1% per year) (hazard ratio, 1.97; 95% CI, 1.41 to 2.71; P<0.001). Among classifiable recurrent ischemic strokes, 71% (133 of 187) were lacunar strokes. All-cause mortality was increased among patients assigned to receive dual antiplatelet therapy (77 deaths in the group receiving aspirin alone vs. 113 in the group receiving dual antiplatelet therapy) (hazard ratio, 1.52; 95% CI, 1.14 to 2.04; P=0.004); this difference was not accounted for by fatal hemorrhages (9 in the group receiving dual antiplatelet therapy vs. 4 in the group receiving aspirin alone). CONCLUSIONS: Among patients with recent lacunar strokes, the addition of clopidogrel to aspirin did not significantly reduce the risk of recurrent stroke and did significantly increase the risk of bleeding and death. (Funded by the National Institute of Neurological Disorders and Stroke and others; SPS3 ClinicalTrials.gov number, NCT00059306.).

Left Ventricular Geometry on Transthoracic Echocardiogram and Prognosis after Lacunar Stroke: The SPS3 Trial.

BACKGROUND: The spectrum, prevalence, and prognostic implications 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 renal function (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 consequences of chronic hypertension.

Vertebrobasilar ectasia in patients with lacunar stroke: the secondary prevention of small subcortical strokes trial.

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 with recent lacunar stroke, VBE was predictive of death but not of recurrent stroke or major hemorrhage. In these exploratory analyses, the frequency of VBE was directly related to diastolic blood pressure but inversely related to systolic blood pressure.

Vitamin K antagonists and risk of subdural hematoma: meta-analysis of randomized clinical trials.

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.

Predictors of mortality in patients with lacunar stroke in the secondary prevention of small subcortical strokes trial.

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<13 g/dL (HR, 1.6), renal function (HR, 1.3 per estimated glomerular filtration rate decrease of 20 mL/min), and body mass index (HR, 1.8 per 10 kg/m2 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<0.001). 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.

Clinical correlates of infarct shape and volume in lacunar strokes: the Secondary Prevention of Small Subcortical Strokes trial.

BACKGROUND AND PURPOSE: Infarct size and location are thought to correlate with different mechanisms of lacunar infarcts. We examined the relationship between the size and shape of lacunar infarcts and vascular risk factors and outcomes. METHODS: We studied 1679 participants in the Secondary Prevention of Small Subcortical Stroke trial with a lacunar infarct visualized on diffusion-weighted imaging. Infarct volume was measured planimetrically, and shape was classified based on visual analysis after 3-dimensional reconstruction of axial MRI slices. RESULTS: Infarct shape was ovoid/spheroid in 63%, slab in 12%, stick in 7%, and multicomponent in 17%. Median infarct volume was smallest in ovoid/spheroid relative to other shapes: 0.46, 0.65, 0.54, and 0.90 mL, respectively (P<0.001). Distributions of vascular risk factors were similar across the 4 groups except that patients in the ovoid/spheroid and stick groups were more often diabetic and those with multicomponent had significantly higher blood pressure at study entry. Intracranial stenosis did not differ among groups (P=0.2). Infarct volume was not associated with vascular risk factors. Increased volume was associated with worse functional status at baseline and 3 months. Overall, 162 recurrent strokes occurred during an average of 3.4 years of follow-up with no difference in recurrent ischemic stroke rate by shape or volume. CONCLUSIONS: In patients with recent lacunar stroke, vascular risk factor profile was similar among the different infarct shapes and sizes. Infarct size correlated with worse short-term functional outcome. Neither shape nor volume was predictive of stroke recurrence. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306.

Predictors of stroke recurrence in patients with recent lacunar stroke and response to interventions according to risk status: secondary prevention of small subcortical strokes trial.

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 no significant interactions between treatment effects and stroke 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 factors and recurrence risk.

Cognitive impairment in lacunar strokes: the SPS3 trial.

OBJECTIVE: Lacunar strokes are a leading cause of cognitive impairment and vascular dementia. However, adequate characterization of cognitive impairment is lacking. The aim of this study was to estimate the prevalence and characterize the neuropsychological impairment in lacunar stroke patients. METHODS: All English-speaking participants in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial (National Clinical Trial 00059306) underwent neuropsychological testing at baseline. Raw scores were converted to z scores using published norms. Those with impairment (z ≤ -1.5) in memory and/or nonmemory domains were classified as having mild cognitive impairment (MCI). RESULTS: Among the 1,636 participants, average z scores on all tests were < 0, with the largest deficits seen on tests of episodic memory (range of means, -0.65 to -0.92), verbal fluency (mean, -0.89), and motor dexterity (mean, -2.5). Forty-seven percent were classified as having MCI (36% amnestic, 37% amnestic multidomain, 28% nonamnestic). Of those with modified Rankin score 0-1 and Barthel score = 100, 41% had MCI. Younger age (odds ratio [OR] per 10-year increase, 0.87), male sex (OR, 1.3), less education (OR, 0.13-0.66 for higher education levels compared to 0-4 years education), poststroke disability (OR, 1.4), and impaired activities of daily living (OR, 1.8) were independently associated with MCI. INTERPRETATION: In this large, well-characterized cohort of lacunar stroke patients, MCI was present in nearly half, including many with minimal or no physical disabilities. Cognitive dysfunction in lacunar stroke patients may commonly be overlooked in clinical practice but may be as important as motor and sensory sequelae.

Aspirin therapy and risk of subdural hematoma: meta-analysis of randomized clinical trials.

BACKGROUND: Subdural hematomas are an important bleeding complication of antithrombotic therapies. We sought to characterize the risk of subdural hematoma associated with antiplatelet therapy. METHODS: Trials were gathered from the Cochrane Central Register of Controlled Trials and from recent meta-analyses of trials regarding antiplatelet therapy for the primary prevention of stroke. Randomized trials published since 1980 comparing antiplatelet therapy with placebo or control and reporting subdural hematoma were included in the analysis. For recent large trials that did not report subdural hematomas, unpublished results were sought. Two reviewers independently extracted data on study design and subdural hematomas, with differences resolved by joint review and consensus. RESULTS: Four published trials were identified that compared aspirin with placebo/control involving 6565 participants (mean age 66 years) with 8 total subdural hematomas. Unpublished data from 5 aspirin trials with 90,689 participants reported 18 total subdural hematomas. The incidence of subdural hematomas varied from 0.02 per 1000 patient-years for primary prevention trials of middle-aged health professionals to 1 to 2 per 1000 patient-years for older patients with atrial fibrillation. Pooled data from all 9 trials revealed an odds ratio of 1.6 (95% confidence interval 0.8-3.5; heterogeneity P = .8; I(2) index 0%) for antiplatelet therapy and risk of subdural hematoma. CONCLUSIONS: Based on the limited available data, it is uncertain whether aspirin therapy increases the risk of subdural hematoma: the observed 1.6-fold increased risk was not statistically significant. The incidence of subdural hematoma during aspirin therapy is low but varies widely depending upon the age of the patient population.