Importance of accounting for loss to follow-up when comparing mortality between immigrants and long-term residents: a population-based retrospective cohort.

OBJECTIVES: To evaluate the association between immigration status and all-cause mortality in different disease cohorts, and the impact of loss to follow-up on the observed associations. DESIGN: Population-based retrospective cohort study using linked administrative health data in Ontario, Canada. SETTING: We followed adults with a first-ever diagnosis of ischaemic stroke, cancer or schizophrenia between 2002 and 2013 from index event to death, loss to follow-up, or end of follow-up in 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: Our outcomes of interest were all-cause mortality and loss to follow-up. For each disease cohort, we calculated adjusted HRs of death in immigrants compared with long-term residents, adjusting for demographic characteristics and comorbidities, with and without censoring for those who were lost to follow-up. We calculated the ratio of two the HRs and the respective CL using bootstrapping methods. RESULTS: Immigrants were more likely to be lost to follow-up than long-term residents in all disease cohorts. Not accounting for this loss to follow-up overestimated the magnitude of the association between immigration status and mortality in those with ischaemic stroke (HR of death before vs after accounting for censoring: 0.78 vs 0.83, ratio=0.95; 95% CL 0.93 to 0.97), cancer (0.74 vs 0.78, ratio=0.96; 0.95 to 0.96), and schizophrenia (0.54 vs 0.56, ratio=0.97; 0.96 to 0.98). CONCLUSIONS: Immigrants to Canada have a survival advantage that varies by the disease studied. The magnitude of this advantage is modestly overestimated by not accounting for the higher loss to follow-up in immigrants.

Association Between Immigration Status and Acute Stroke Care: A Retrospective Study.

Background and Purpose- Immigrants to high-income countries have a lower incidence of stroke compared with long-term residents; however, little is known about the care and outcomes of stroke in immigrants. Methods- We used linked clinical and administrative data to conduct a retrospective cohort study of adults seen in the emergency department or hospitalized with ischemic stroke or transient ischemic attack between July 1, 2003, and April 1, 2013, and included in the provincial stroke registry. We ascertained immigration status using immigration records and compared processes of stroke care delivery between immigrants (defined as those immigrating after 1985) and long-term residents. In the subgroup with ischemic stroke, we calculated inverse probability treatment weight (IPTW)-adjusted risk ratios for disability on discharge (modified Rankin Scale score of 3 to 5), accounting for demographic characteristics and comorbid conditions to compare outcomes between immigrants and long-term residents. Results- We included 34 987 patients with ischemic stroke or transient ischemic attack, of whom 2649 (7.6%) were immigrants. Immigrants were younger than long-term residents at the time of stroke/transient ischemic attack (median age 67 years versus 76 years; P<0.001). In the subgroup with ischemic stroke, there were no differences in stroke care delivery, except that a higher proportion of immigrants received thrombolysis than long-term residents (21.2% versus 15.5%; P<0.001). Immigrants with ischemic stroke had a higher adjusted risk of being disabled on discharge (adjusted risk ratio, 1.18; 95% CI, 1.13-1.22) compared to long-term residents. Conclusions- Stroke care is similar in Canadian immigrants and long-term residents. Future research is needed to confirm the observed association between immigration status and disability after stroke and to identify factors underlying the association.

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.

Automated CT Perfusion Imaging Versus Non-contrast CT for Ischemic Core Assessment in Large Vessel Occlusion.

PURPOSE: There is increasing use of automated computed tomography perfusion (CTP) to aid thrombectomy decision in emergent large vessel occlusion. It is important to understand the performance of these software packages in predicting ischemic core and tissue-at-risk in the real-world setting. The aim of this study was to evaluate whether ischemic core on non-contrast CT (NCCT) and automated CTP correspond and predict infarct extent after thrombectomy for ischemic stroke. METHODS: Consecutive patients with acute anterior circulation large vessel occlusion undergoing successful thrombectomy (TICI 2b/3) were studied. All patients had baseline CT, CTP with RAPID post-processing software (RAPID-CTP), and post-thrombectomy 24 h CT. Ischemic cores were assessed by two blinded raters independently using the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) on each modality. The interrater agreement for ASPECTS, and correlation between baseline CT-ASPECTS, RAPID-CTP-ASPECTS, and 24h CT-ASPECTS were calculated. RESULTS: A total of 86 patients with a mean age of 70.3 years (SD 16.5) were studied. The median baseline CT-ASPECTS was 9.5 (interquartile range, IQR 8-10), median RAPID-CTP-ASPECTS was 9 (IQR 8-10), and mean RAPID-CTP-ischemic core volume was 14.4 ml (SD 27.9 ml). The mean mismatch volume (difference of Tmax > 6s and cerebral blood flow (CBF) < 30%) was 128.6 ml (SD 126.0 ml). There was substantial correlation between baseline and 24h CT-ASPECTS (rs: 0.62; p < 0.001), but poor correlation between RAPID-CTP-ASPECTS and RAPID-CTP ischemic core volume with 24h NCCT-ASPECTS (rs: 0.21; p = 0.06 and -0.16; p = 0.15 respectively). The positive predictive value of any established infarct for baseline CT-ASPECTS was 81%, while that of RAPID-CTP-ASPECTS was 64%. CONCLUSION: In this series of successfully revascularized patients, ischemic core as estimated by RAPID-CTP-ASPECTS did not correlate with the baseline CT and tended to depict a larger infarct core than the infarct extent as assessed by 24h CT-ASPECTS.

Rural-Urban Differences in Stroke Risk Factors, Incidence, and Mortality in People With and Without Prior Stroke.

Background Rural residence is associated with stroke incidence and mortality, but little is known about potential rural/urban differences in ambulatory stroke care. Methods and Results We used the CANHEART (Cardiovascular Health in Ambulatory Care Research Team) cohort, created from linked administrative databases from the province of Ontario, Canada, and divided into primary (N=6 207 032) and secondary (N=75 823) prevention cohorts based on the absence or presence of prior stroke. We defined rural communities as those with a population size of ≤10 000 and within each of the primary and secondary prevention cohorts, compared cardiovascular risk factors and care between rural and urban areas. We then calculated sex-/age-standardized rates of stroke incidence and mortality per 1000 person-years between January 1, 2008 and December 31, 2012 and used cause-specific hazard models to compare outcomes in rural versus urban areas adjusting for age, sex, income, ethnicity, smoking, physical activity and comorbid conditions, and accounting for the competing risk of death in the model for the occurrence of stroke incidence. In the primary prevention cohort, rural residents were less likely than urban ones to be screened for diabetes mellitus (70.9% versus 81.3%) and hyperlipidemia (66.2% versus 78.4%) and less likely to achieve diabetes mellitus control (hemoglobin A1c ≤7% in 51.3% versus 54.3%; P<0.001 for all comparisons). In the secondary prevention cohort, the prevalence and treatment of risk factors were similar in rural and urban residents. After adjustment for sociodemographic and comorbid conditions, rural residence was associated with higher rates of stroke and all-cause mortality in both the primary prevention (adjusted hazard ratio [aHR] for stroke, 1.06; 95% CI, 1.04-1.09; aHR for mortality, 1.09; 95% CI, 1.08-1.10) and the secondary prevention cohort (aHR for stroke, 1.11; 95% CI, 1.02-1.19; aHR for mortality, 1.07; 95% CI, 1.03-1.11). Conclusions In this population-based study of over 6 million people with universal access to physician and hospital services, risk factors were more prevalent but less likely to be controlled in rural than in urban residents without prior stroke, whereas in those with prior stroke, risk factor prevalence and treatment were similar. Rural residence was associated with the rate of stroke and death even after adjustment for risk factors. Future efforts should focus not only on control of known vascular risk factors but also on addressing other determinants of health in rural communities.

Postpartum Period Is a Risk Factor for Cerebral Venous Thrombosis.

Background and Purpose- Pregnancy and the postpartum period are generally considered to be risk factors for cerebral venous thrombosis (CVT), but no controlled studies have quantified the risk. Methods- Case-control study using data of consecutive adult patients with CVT from 5 academic hospitals and controls from the Dutch MEGA study (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis). Men, women over the age of 50, women using oral contraceptives or with a recent abortion or miscarriage were excluded. We adjusted for age and history of cancer, and stratified for pregnancy versus postpartum, and 0 to 6 versus 7 to 12 weeks postpartum. Results- In total 163/813 cases and 1230/6296 controls were included. Cases were younger (median 38 versus 41 years) and more often had a history of cancer (14% versus 4%) than controls. In total 41/163 (25%) cases and 82/1230 (7%) controls were pregnant or postpartum (adjusted odds ratio, 3.8; 95% CI, 2.4-6.0). The association was fully attributable to an increased risk of CVT during the postpartum period (adjusted odds ratio, 10.6; 95% CI, 5.6-20.0). We found no association between pregnancy and CVT (adjusted odds ratio, 1.2; 95% CI, 0.6-2.3). The risk was highest during the first 6 weeks postpartum (adjusted odds ratio, 18.7; 95% CI, 8.3-41.9). Conclusions- Women who have recently delivered are at increased risk of developing CVT, while there does not seem to be an increased risk of CVT during pregnancy.

Cerebral Venous Thrombosis in Older Patients.

BACKGROUND AND PURPOSE: Cerebral venous thrombosis (CVT) is rare in older patients. We investigated whether clinical features and outcomes differ in older and younger patients. METHODS: We used data from a multicenter observational registry of consecutive adult patients with CVT admitted between 1987 and 2016. We compared demographics, clinical manifestations, and outcomes between older (upper quartile of the age distribution) and younger (lower 3 quartiles of the age distribution) patients. RESULTS: Data for 843 patients with CVT were available. The median age was 43 years (interquartile range, 30-55 years). Older patients (≥55 years; n=222) were less often women than younger patients (48% versus 71%; P<0.001) and less often reported headache (63% versus 87%; P<0.001). Cancer was more common in older patients (24% versus 9%; P<0.001), especially solid malignancies (19% versus 5%; P<0.001). Outcome at follow-up was worse in older patients (modified Rankin Scale, 3-6; adjusted odds ratio, 2.68; 95% confidence interval, 1.78-4.03; mortality, adjusted odds ratio, 2.13; 95% confidence interval, 1.09-4.19). CONCLUSIONS: The sex ratio of CVT is evenly distributed in older patients, probably because of the dissipation of hormonal influences. Malignancy should be considered as a potential precipitant in older patients with CVT.

Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing CT to recanalization times (ESCAPE) trial: methodology.

ESCAPE is a prospective, multicenter, randomized clinical trial that will enroll subjects with the following main inclusion criteria: less than 12 h from symptom onset, age > 18, baseline NIHSS >5, ASPECTS score of >5 and CTA evidence of carotid T/L or M1 segment MCA occlusion, and at least moderate collaterals by CTA. The trial will determine if endovascular treatment will result in higher rates of favorable outcome compared with standard medical therapy alone. Patient populations that are eligible include those receiving IV tPA, tPA ineligible and unwitnessed onset or wake up strokes with 12 h of last seen normal. The primary end-point, based on intention-to-treat criteria is the distribution of modified Rankin Scale scores at 90 days assessed using a proportional odds model. The projected maximum sample size is 500 subjects. Randomization is stratified under a minimization process using age, gender, baseline NIHSS, baseline ASPECTS (8-10 vs. 6-7), IV tPA treatment and occlusion location (ICA vs. MCA) as covariates. The study will have one formal interim analysis after 300 subjects have been accrued. Secondary end-points at 90 days include the following: mRS 0-1; mRS 0-2; Barthel 95-100, EuroQOL and a cognitive battery. Safety outcomes are symptomatic ICH, major bleeding, contrast nephropathy, total radiation dose, malignant MCA infarction, hemicraniectomy and mortality at 90 days.

Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Neuroprotection with NA-1 (Tat-NR2B9c), an inhibitor of postsynaptic density-95 protein, has been shown in a primate model of stroke. We assessed whether NA-1 could reduce ischaemic brain damage in human beings. METHODS: For this double-blind, randomised, controlled study, we enrolled patients aged 18 years or older who had a ruptured or unruptured intracranial aneurysm amenable to endovascular repair from 14 hospitals in Canada and the USA. We used a computer-generated randomisation sequence to allocate patients to receive an intravenous infusion of either NA-1 or saline control at the end of their endovascular procedure (1:1; stratified by site, age, and aneurysm status). Both patients and investigators were masked to treatment allocation. The primary outcome was safety and primary clinical outcomes were the number and volume of new ischaemic strokes defined by MRI at 12-95 h after infusion. We used a modified intention-to-treat (mITT) analysis. This trial is registered with ClinicalTrials.gov, number NCT00728182. FINDINGS: Between Sept 16, 2008, and March 30, 2011, we randomly allocated 197 patients to treatment-12 individuals did not receive treatment because they were found to be ineligible after randomisation, so the mITT population consisted of 185 individuals, 92 in the NA-1 group and 93 in the placebo group. Two minor adverse events were adjudged to be associated with NA-1; no serious adverse events were attributable to NA-1. We recorded no difference between groups in the volume of lesions by either diffusion-weighted MRI (adjusted p value=0·120) or fluid-attenuated inversion recovery MRI (adjusted p value=0·236). Patients in the NA-1 group sustained fewer ischaemic infarcts than did patients in the placebo group, as gauged by diffusion-weighted MRI (adjusted incidence rate ratio 0·53, 95% CI 0·38-0·74) and fluid-attenuated inversion recovery MRI (0·59, 0·42-0·83). INTERPRETATION: Our findings suggest that neuroprotection in human ischaemic stroke is possible and that it should be investigated in larger trials. FUNDING: NoNO Inc and Arbor Vita Corp.

Vessel wall MRI to differentiate between reversible cerebral vasoconstriction syndrome and central nervous system vasculitis: preliminary results.

BACKGROUND AND PURPOSE: Prospective differentiation between reversible cerebral vasoconstriction syndrome and central nervous system vasculitis can be challenging. We hypothesized that high-resolution vessel wall MRI would demonstrate arterial wall enhancement in central nervous system vasculitis but not in reversible cerebral vasoconstriction syndrome. METHODS: We identified all patients with multifocal segmental narrowing of large intracranial arteries who had high-resolution vessel wall MRI and follow-up angiography at our institute over a 4-year period and performed a detailed chart review. RESULTS: Three patients lacked arterial wall enhancement, and these all had reversal of arterial narrowing within 3 months. Four patients demonstrated arterial wall enhancement, and these had persistent or progressive arterial narrowing at a median follow-up of 17 months (range, 6-36 months) with final diagnoses of central nervous system vasculitis (3) and cocaine vasculopathy (1). CONCLUSIONS: Preliminary results suggest that high-resolution contrast-enhanced vessel wall MRI may enable differentiation between reversible cerebral vasoconstriction syndrome and central nervous system vasculitis.

Eccentric narrowing and enhancement of symptomatic middle cerebral artery stenoses in patients with recent ischemic stroke.

OBJECTIVE: To characterize the vessel wall imaging findings and enhancement patterns in the middle cerebral artery of patients with presumed atherosclerotic disease and recent infarction in the territory of the affected artery. DESIGN: Case series. SETTING: University hospital. PATIENTS: We included patients with (1) 2 or more risk factors for atherosclerotic disease; (2) middle cerebral artery stenosis shown on computed tomography, magnetic resonance, or conventional angiography; and (3) recent infarction in the territory of the affected artery. INTERVENTION: 3-T contrast-enhanced high-resolution magnetic resonance imaging. RESULTS: Eight patients were identified: 6 had an eccentric M1 stenosis, 1 had an eccentric proximal M2 stenosis, and 1 had a distal M2 stenosis with inconclusive eccentricity. Enhancement of the lesion was observed in all patients who underwent scanning within 5 months of the index event. Four intracranial atherosclerotic plaques were found in asymptomatic vessels (1 contralateral middle cerebral artery and 3 other intracranial arteries), and none of these had enhancement. CONCLUSION: Patients with presumed intracranial atherosclerosis of the middle cerebral arteries have eccentric plaques that enhance after the administration of contrast medium when imaging is performed within weeks to months of a cerebral infarct within the arterial territory.

Urgency of carotid endarterectomy for secondary stroke prevention: results from the Registry of the Canadian Stroke Network.

BACKGROUND AND PURPOSE: The benefit of carotid endarterectomy for preventing recurrent stroke is maximal when surgery is performed within 2 weeks after ischemic stroke or transient ischemic attack; the benefit is reduced when surgery is delayed >2 weeks and essentially lost if delayed >3 months. Guidelines recommend endarterectomy within 2 weeks poststroke/transient ischemic attack for patients with symptomatic carotid stenosis. This study examined time to endarterectomy at designated stroke centers as a measure of evidence-based best practices for stroke prevention. METHODS: From the Registry of the Canadian Stroke Network, we identified all consecutive patients presenting with acute ischemic stroke or transient ischemic attack at 12 provincial stroke centers (Ontario, Canada, 2003 to 2006) and selected those with unilateral symptomatic carotid stenosis of moderate (50% to 69%) or severe (70% to 99%) degree. Using linkages to administrative databases, we identified patients who underwent carotid endarterectomy within 6 months after the symptomatic event and calculated the time intervals between the index event and surgery. We compared the timing of surgery according to age, sex, degree of stenosis, index event, geographic region, and year. Logistic regression assessed variables associated with early surgery. RESULTS: One hundred five patients underwent endarterectomy for unilateral symptomatic carotid stenosis (50% to 99%) within 6 months of the index event. The median time from index event to surgery was 30 days (interquartile range, 10 to 81). Only one third (38 of 105) received endarterectomy within the recommended 2-week target timeframe, and in one fourth (26 of 105), surgery was delayed >3 months. Surgery within 2 weeks was more likely if the index event was a transient ischemic attack rather than a stroke. Access to early endarterectomy varied markedly between hospitals across the province and improved over time from 2003 to 2006. CONCLUSIONS: In this hospital-based cohort, the majority of patients undergoing carotid endarterectomy after a transient ischemic attack or stroke had surgery delayed well beyond the period of maximum effectiveness. To enhance secondary stroke prevention, greater efforts are needed to minimize delays to diagnosis and surgical treatment for patients with symptomatic carotid stenosis.

Stroke secondary to post-partum coronary artery dissection.

BACKGROUND: There is an increased risk of stroke during pregnancy and the puerperium. This risk is greatest in the post-partum period. Embolic sources secondary to cardiac abnormalities and cerebral arterial dissection are recognized as potential etiologies. CASE: A 32-year-old woman presented with left-sided weakness eight days post-partum. Imaging studies identified infarction in the territory of the right middle cerebral artery. Cardiac investigations revealed acute myocardial infarction secondary to dissection of the left main coronary artery. The patient underwent coronary artery bypass grafting with significant recovery of cardiac function. At two years post-presentation, her neurological deficits have resolved. DISCUSSION: Myocardial infarction secondary to coronary artery dissection has been long-recognized. Cerebral arterial dissection in association with pregnancy is also well-documented. This is a rare case of a patient presenting with stroke secondary to acute myocardial infarction secondary to coronary artery dissection.