Predictors of Recurrent Venous Thrombosis After Cerebral Venous Thrombosis: Analysis of the ACTION-CVT Study.

BACKGROUND AND OBJECTIVE: Cerebral venous thrombosis (CVT) is a rare cause of stroke carrying a nearly 4% risk of recurrence after 1 year. There are limited data on predictors of recurrent venous thrombosis in patients with CVT. In this study, we aim to identify those predictors. METHODS: This is a secondary analysis of the ACTION-CVT study which is a multicenter international study of consecutive patients hospitalized with a diagnosis of CVT over a 6-year period. Patients with cancer-associated CVT, CVT during pregnancy, or CVT in the setting of known antiphospholipid antibody syndrome were excluded per the ACTION-CVT protocol. The study outcome was recurrent venous thrombosis defined as recurrent venous thromboembolism (VTE) or de novo CVT. We compared characteristics between patients with vs without recurrent venous thrombosis during follow-up and performed adjusted Cox regression analyses to determine important predictors of recurrent venous thrombosis. RESULTS: Nine hundred forty-seven patients were included with a mean age of 45.2 years, 63.9% were women, and 83.6% had at least 3 months of follow-up. During a median follow-up of 308 (interquartile range 120-700) days, there were 5.05 recurrent venous thromboses (37 VTE and 24 de novo CVT) per 100 patient-years. Predictors of recurrent venous thrombosis were Black race (adjusted hazard ratio [aHR] 2.13, 95% CI 1.14-3.98, p = 0.018), history of VTE (aHR 3.40, 95% CI 1.80-6.42, p < 0.001), and the presence of one or more positive antiphospholipid antibodies (aHR 3.85, 95% CI 1.97-7.50, p < 0.001). Sensitivity analyses including events only occurring on oral anticoagulation yielded similar findings. DISCUSSION: Black race, history of VTE, and the presence of one or more antiphospholipid antibodies are associated with recurrent venous thrombosis among patients with CVT. Future studies are needed to validate our findings to better understand mechanisms and treatment strategies in patients with CVT.

Serum alpha-1 antitrypsin in acute ischemic stroke: A prospective pilot study.

BACKGROUND: Alpha-1 antitrypsin (AAT) is a potent anti-protease enzyme which may play a role in arterial wall stability. A variant of its encoding gene has been recently linked to ischemic stroke due to large artery atherosclerosis (LAA). We sought to explore potential relationships between ischemic stroke mechanisms, atherosclerosis burden and serum AAT levels. METHODS: We performed a prospective observational study of consecutive patients with acute ischemic stroke who were admitted to an academic comprehensive stroke center over a three-month period. Blood samples were collected within 24 h of hospital admission, and stroke subtype classification was determined based on modified TOAST criteria. Modified Woodcock scoring system was used to quantify calcification of major cervico-cranial arteries as a surrogate for atherosclerosis burden. Linear regression analysis was used to assess the association between serum AAT levels and calcification scores, both as continuous variables. RESULTS: Among eighteen patients met our inclusion criteria and were enrolled in our study, 10 patients (56%) were men; mean age was 66 (SD 12.5); median NIH stroke scale was 4 (IQR 9.5); 8 patients (44%) had stroke due to LAA. The median serum level of AAT was 140 mg/dl (IQR 41.7) for patients with LAA-related stroke, and 148.5 mg/dl (IQR 37.7) for patients with other stroke mechanisms (p = 0.26). Higher serum AAT levels was associated with lower modified Woodcock calcification scores. (p-value = 0.038) CONCLUSIONS: Measurement of AAT levels in patients with acute stroke is feasible, and there may be associations between AAT levels and stroke mechanism that warrant further study in larger samples.

Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. METHODS: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018. FINDINGS: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups. INTERPRETATION: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. FUNDING: Canadian Institutes for Health Research, Alberta Innovates, and NoNO.

Peri-procedural stroke or death in stenting of symptomatic severe intracranial stenosis.

BACKGROUND AND PURPOSE: There are limited data on predictors of 30-day stroke or death in patients with symptomatic intracranial atherosclerosis (sICAS) undergoing stenting. We aim to determine the factors associated with stroke or death at 30 days in the stenting arm of the SAMMPRIS trial. METHODS: This is a post-hoc analysis of the SAMMPRIS trial including patients who underwent angioplasty/stenting. We compared patient-specific variables, lesion-specific variables, procedure-specific variables, and FDA-approved indications between patients with and without the primary outcome (stroke or death at 30 days). Logistic regression analyses were performed to evaluate associations with the primary outcome. RESULTS: We identified 213 patients, 30 of whom (14.1%) met the primary outcome. Smoking status and lesion length were associated with the primary outcome: the odds of stroke or death for non-smokers versus smokers (adjusted OR 4.46, 95% CI 1.79 to 11.1, p=0.001) and for increasing lesion length in millimeters (adjusted OR 1.20, 95% CI 1.02 to 1.39, p=0.029). These had a modest predictive value: absence of smoking history (sensitivity 66.7%, specificity 65.4%) and lesion length (area under curve 0.606). Furthermore, event rates were not significantly different between patients with and without the FDA-approved indication for stenting (15.9% vs 12%, p=0.437). CONCLUSION: In SAMMPRIS patients who underwent angioplasty/stenting, neither clinical and neuroimaging variables nor the FDA indication for stenting reliably predicted the primary outcome. Further work in identifying reliable biomarkers of stroke/death in patients with sICAS is needed before considering new clinical trials of stenting. TRIAL REGISTRATION NUMBER: SAMMPRIS NCT00576693; Results.

Field triage for endovascular stroke therapy: a population-based comparison.

BACKGROUND: Endovascular therapy (EVT) for stroke improves outcomes but is time sensitive. OBJECTIVE: To compare times to treatment and outcomes between patients taken to the closest primary stroke center (PSC) with those triaged in the field to a more distant comprehensive stroke center (CSC). METHODS: During the study, a portion of our region allowed field triage of patients who met severity criteria to a more distant CSC than the closest PSC. The remaining patients were transported to the closest PSC. We compared times to treatment and clinical outcomes between those two groups. Additionally, we performed a matched-pairs analysis of patients from both groups on stroke severity and distance to CSC. RESULTS: Over 2 years, 232 patients met inclusion criteria and were closest from the field to a PSC; 144 were taken to the closest PSC and 88 to the more distant CSC. The median additional transport time to the CSC was 7 min. Times from scene departure to alteplase and arterial puncture were faster in the direct group (50 vs 62 min; 93 vs 152 min; p<0.001 for both). Among patients who were independent before the stroke, the OR for less disability in the direct group was 1.47 (95% CI 1.13 to 1.93, p=0.003), and 2.06 (95% CI 1.10 to 3.89, p=0.01) for the matched pairs. CONCLUSIONS: In a densely populated setting, for patients with stroke who are EVT candidates and closest to a PSC from the field, triage to a slightly more distant CSC is associated with faster time to EVT, no delay to alteplase, and less disability at 90 days.

Yield of diagnostic imaging in atraumatic convexity subarachnoid hemorrhage.

INTRODUCTION: Atraumatic convexity subarachnoid hemorrhage is a subtype of spontaneous subarachnoid hemorrhage that often presents a diagnostic challenge. Common etiologies include cerebral amyloid angiopathy, vasculopathies, and coagulopathy; however, aneurysm is rare. Given the broad differential of causes of convexity subarachnoid hemorrhage, we assessed the diagnostic yield of common tests and propose a testing strategy. METHODS: We performed a single-center retrospective study on consecutive patients with atraumatic convexity subarachnoid hemorrhage over a 2-year period. We obtained and reviewed each patient's imaging and characterized the frequency with which each test ultimately diagnosed the cause. Additionally, we discuss clinical features of patients with convexity subarachnoid hemorrhage with respect to the mechanism of hemorrhage. RESULTS: We identified 70 patients over the study period (mean (SD) age 64.70 (16.9) years, 35.7% men), of whom 58 patients (82%) had a brain MRI, 57 (81%) had non-invasive vessel imaging, and 27 (38.5%) underwent catheter-based angiography. Diagnoses were made using only non-invasive imaging modalities in 40 patients (57%), while catheter-based angiography confirmed the diagnosis in nine patients (13%). Further clinical history and laboratory testing yielded a diagnosis in an additional 17 patients (24%), while the cause remained unknown in four patients (6%). CONCLUSION: The etiology of convexity subarachnoid hemorrhage may be diagnosed in most cases via non-invasive imaging and a thorough clinical history. However, catheter angiography should be strongly considered when non-invasive imaging fails to reveal the diagnosis or to better characterize a vascular malformation. Larger prospective studies are needed to validate this algorithm.

Cardiac Biomarkers Predict Large Vessel Occlusion in Patients with Ischemic Stroke.

BACKGROUND AND PURPOSE: Cardiac biomarkers may help identify stroke mechanisms and may aid in improving stroke prevention strategies. There is limited data on the association between these biomarkers and acute ischemic stroke (AIS) caused by large vessel occlusion (LVO). We hypothesized that cardiac biomarkers (cardiac troponin and left atrial diameter [LAD]) would be associated with the presence of LVO. METHODS: Data were abstracted from a single center prospective AIS database over 18 months and included all patients with AIS with CT angiography of the head and neck. The presence of LVO was defined as proximal LVO of the internal carotid artery terminus, middle cerebral artery (M1 or proximal M2), or basilar artery. Univariate analyses and predefined multivariable models were performed to determine the association between cardiac biomarkers (positive troponin [troponin ≥0.1 ng/mL] and LAD on transthoracic echocardiogram) and LVO adjusting for demographic factors (age and sex), risk factors (hypertension, diabetes, hyperlipidemia, history of stroke, congestive heart failure, coronary heart disease, and smoking), and atrial fibrillation (AF). RESULTS: We identified 1234 patients admitted with AIS; 886 patients (71.8%) had vascular imaging to detect LVO. Of those with imaging available, 374 patients (42.2%) had LVO and 207 patients (23.4%) underwent thrombectomy. There was an association between positive troponin and LVO after adjusting for age, sex and other risk factors (adjusted OR 1.69 [1.08-2.63], P = .022) and this association persisted after including AF in the model (adjusted OR 1.60 [1.02-2.53], P = 0.043). There was an association between LAD and LVO after adjusting for age, sex, and risk factors (adjusted OR per mm 1.03 [1.01-1.05], P = 0.013) but this association was not present when AF was added to the model (adjusted OR 1.01 [0.99-1.04], P = .346). Sensitivity analyses using thrombectomy as an outcome yielded similar findings. CONCLUSIONS: Cardiac biomarkers, particularly serum troponin levels, are associated with acute LVO in patients with ischemic stroke. Prospective studies are ongoing to confirm this association and to test whether anticoagulation reduces the risk of recurrent embolism in this patient population.

Association between age and outcomes following thrombectomy for anterior circulation emergent large vessel occlusion is determined by degree of recanalisation.

BACKGROUND: Older patients undergoing thrombectomy for emergent large vessel occlusion have worse outcomes. However, complete or near-complete reperfusion (modified Thrombolysis in Cerebral Ischemia (mTICI) score of 2 c/3) is associated with improved outcomes compared with partial recanalisation (mTICI 2b). OBJECTIVE: To examine the relationship between outcomes and age separately for the mTICI 2c/3, 2b and 0-2a groups in patients undergoing thrombectomy for anterior circulation emergent large vessel occlusion. METHODS: Retrospective review of 157 consecutive patients undergoing thrombectomy at a single centre with an occlusion of the internal carotid artery (ICA), M1 or proximal M2 segments of the middle cerebral artery (MCA). Angiograms were graded in a blinded fashion. Patients were divided into three groups: mTICI 0-2a, mTICI 2b, and mTICI 2c/3. Demographics and workflow parameters were compared. Outcomes at 90 days were compared as a function of age, using both the conventional modified Rankin scale (mRs) and utility weighted mRs (UWmRs). RESULTS: There were 72, 61 and 24 patients in the mTICI 2c/3, 2b and 0-2a groups, respectively. Outcomes were significantly worse with increasing age for the mTICI 2b group, but not for the mTICI 0-2a and 2c/3 groups (P=0.0002). With increasing age, outcomes of the mTICI 2b group approached those of the mTICI 0-2a group. However, outcomes of the mTICI 2c/3 groups were similar for all ages. This association was present for both the original mRs and UWmRs. CONCLUSION: Increasing age was associated with worse outcomes for those with partial (mTICI 2b) recanalisation, not in patients with complete (mTICI 2c/3) recanalisation.

Sex differences in 90-day outcomes after mechanical thrombectomy for acute ischemic stroke.

BACKGROUND: It is largely unknown whether functional outcomes after mechanical thrombectomy for large vessel occlusion (LVO) ischemic strokes differ by sex in non-clinical trial populations. We investigated sex differences in 90-day outcomes among ischemic stroke patients receiving mechanical thrombectomy. METHODS: This was a prospective cohort of adults treated with mechanical thrombectomy for LVO at a single academic comprehensive stroke center from July 2015 to April 2017. Data on independence (mRS ≤2) at hospital discharge and 90 days were collected prospectively. Multiple logistic regression was used to determine the association between sex and 90-day independence, first adjusting for demographics, pre-stroke mRS, and NIHSS, then by co-morbidities and time to thrombectomy, and finally by vessel recanalization and use of intravenous thrombolysis. RESULTS: We included 279 patients, 52% of whom were female. Compared with males, females were older (median years (IQR) 81 (75-88) vs. 71.5 (60-81), P<0.001) and had higher baseline NIHSS (mean SD 18.2±7.5 vs . 16.0±7.1, P=0.02). Similar proportions of males and females had pre-stroke mRS ≤2 (73.3% vs.67.1%, P=0.27). In multivariate analyses, males and females had a similar likelihood of being independent at discharge (aOR 0.71 (95%CI 0.32 to 1.58)), but females were less likely to be independent at 90 days (aOR 0.37 95% CI 0.16 to 0.87). CONCLUSIONS: In patients treated with mechanical thrombectomy for LVOs at a large comprehensive stroke center, females were less likely to be independent at 90 days. Future research should investigate contributors to poor outcomes post-discharge in females with LVOs, along with potential interventions to improve outcomes.

Early Elevated Troponin Levels After Ischemic Stroke Suggests a Cardioembolic Source.

BACKGROUND AND PURPOSE: Elevated cardiac troponin is a marker of cardiac disease and has been recently shown to be associated with embolic stroke risk. We hypothesize that early elevated troponin levels in the acute stroke setting are more prevalent in patients with embolic stroke subtypes (cardioembolic and embolic stroke of unknown source) as opposed to noncardioembolic subtypes (large-vessel disease, small-vessel disease, and other). METHODS: We abstracted data from our prospective ischemic stroke database and included all patients with ischemic stroke during an 18-month period. Per our laboratory, we defined positive troponin as ≥0.1 ng/mL and intermediate as ≥0.06 ng/mL and <0.1 ng/mL. Unadjusted and adjusted regression models were built to determine the association between stroke subtype (embolic stroke of unknown source and cardioembolic subtypes) and positive and intermediate troponin levels, adjusting for key confounders, including demographics (age and sex), clinical characteristics (hypertension, hyperlipidemia, diabetes mellitus, renal function, coronary heart disease, congestive heart failure, current smoking, and National Institutes of Health Stroke Scale score), cardiac variables (left atrial diameter, wall-motion abnormalities, ejection fraction, and PR interval on ECG), and insular involvement of infarct. RESULTS: We identified 1234 patients, of whom 1129 had admission troponin levels available; 10.0% (113/1129) of these had a positive troponin. In fully adjusted models, there was an association between troponin positivity and embolic stroke of unknown source subtype (adjusted odds ratio, 4.46; 95% confidence interval, 1.03-7.97; P=0.003) and cardioembolic stroke subtype (odds ratio, 5.00; 95% confidence interval, 1.83-13.63; P=0.002). CONCLUSIONS: We found that early positive troponin after ischemic stroke may be independently associated with a cardiac embolic source. Future studies are needed to confirm our findings using high-sensitivity troponin assays and to test optimal secondary prevention strategies in patients with embolic stroke of unknown source and positive troponin.

Primary Intraventricular Hemorrhage: Clinical Characteristics and Outcomes.

BACKGROUND: Primary intraventricular hemorrhage (IVH) in adults is a rare neurologic disorder. The typical course, etiology, complications, and outcomes have not been well established. MATERIALS AND METHODS: Consecutive patient records with a diagnosis of intracerebral hemorrhage admitted between May 2009 and June 2014 at a tertiary care center were retrospectively reviewed. Subjects were included in the study cohort if all neurologists and the radiology report agreed that the subject had an isolated IVH. Patients with intraparenchymal hemorrhage, subarachnoid hemorrhage, malignancy with hemorrhagic components, and hemorrhagic transformation of ischemic stroke were excluded. The electronic medical record, imaging report, and imaging studies were reviewed. FINDINGS: Of 1692 cases reviewed, 33 (1.9%) had primary IVH. The most common presenting symptoms included altered mental status (48.5%), headache, (39.4%), and nausea (24.2%). In 36.3%, hypertension was found to be a contributing factor; 27.2% were attributed solely to hypertension. Vascular abnormalities were the primary etiology in 21.3% of patients. When observing outcomes, 61.8% were discharged home or to rehab, whereas 20.5% died or were placed in hospice care. A higher Graeb score was associated with an increased likelihood of death or hospice (8 versus 5, P = .02) CONCLUSION: This study is one of few to describe the etiology, contributing factors, and outcomes of primary IVH. As in prior studies, hypertension was a contributing factor, and vascular lesions were less common than expected. More research is necessary to further define the course and characteristics of this rare type of intracerebral hemorrhage.

Three-Month Outcomes Are Poor in Stroke Patients with Cancer Despite Acute Stroke Treatment.

INTRODUCTION: Stroke risk is increased in cancer patients. Prognosis in these patients is poor, with higher in-hospital mortality and increased subsequent mortality. However, data on stroke in cancer patients are limited, specifically regarding acute stroke treatment and functional outcomes. We aim to determine the functional outcomes of cancer patients admitted with acute stroke. MATERIALS AND METHODS: We retrospectively reviewed patients carrying a diagnosis of cancer who were admitted with acute ischemic stroke between March 2013 and February 2016. Demographics, cerebrovascular risk factors, stroke characteristics including acute treatment, and characteristics of their cancer history and treatment were abstracted. The primary outcome measures included in-hospital mortality and 3-month functional outcome (as assessed by the modified Rankin Scale [mRS] score, with mRS scores of 3-6 considered poor functional outcome). Further outcome measures included length of stay and discharge destination. FINDINGS: Forty-nine patients met the inclusion criteria, with a median admission National Institutes of Health Stroke Scale score of 8. Twelve patients (24.4%) underwent acute stroke treatment. The most common stroke etiology was hypercoagulability of malignancy (21, 42.9%). The three-month mortality was 46.9%; half of survivors had poor functional outcome. Functional outcomes did not differ by cancer type, stage, or year since diagnosis; on multivariate analysis only high admission NIHSS score was associated with poor functional outcome (P = .002). CONCLUSION: Nearly half of patients with cancer and stroke die within 3 months, and functional outcome is poor for 50% of 3-month survivors despite consideration of acute stroke treatment. Future research should address the role of hypercoagulability in the outcome prediction of stroke patients with cancer.

Continuous aspiration prior to intracranial vascular embolectomy (CAPTIVE): a technique which improves outcomes.

BACKGROUND: Modern stent retriever-based embolectomy for patients with emergent large vessel occlusion improves outcomes. Techniques aimed at achieving higher rates of complete recanalization would benefit patients. OBJECTIVE: To evaluate the clinical impact of an embolectomy technique focused on continuous aspiration prior to intracranial vascular embolectomy (CAPTIVE). METHODS: A retrospective review was performed of 95 consecutive patients with intracranial internal carotid artery or M1 segment middle cerebral artery occlusion treated with stent retriever-based thrombectomy over an 11-month period. Patients were divided into a conventional local aspiration group (traditional group) and those treated with a novel continuous aspiration technique (CAPTIVE group). We compared both early neurologic recovery (based on changes in National Institute of Health Stroke Scale (NIHSS) score), independence at 90 days (modified Rankin score 0-2), and angiographic results using the modified Thrombolysis in Cerebral Ischemia (TICI) scale including the TICI 2c category. RESULTS: There were 56 patients in the traditional group and 39 in the CAPTIVE group. Median age and admission NIHSS scores were 78 years and 19 in the traditional group and 77 years and 19 in the CAPTIVE group. Median times from groin puncture to recanalization in the traditional and CAPTIVE groups were 31 min and 14 min, respectively (p<0.0001). While rates of TICI 2b/2c/3 recanalization were similar (81% traditional vs 100% CAPTIVE), CAPTIVE offered higher rates of TICI 2c/3 recanalization (79.5% vs 40%, p<0.001). Median discharge NIHSS score was 10 in the traditional group and 3 in the CAPTIVE group; this difference was significant. There was also an increased independence at 90 days (25% traditional vs 49% CAPTIVE). CONCLUSIONS: The CAPTIVE embolectomy technique may result in higher recanalization rates and better clinical outcomes.