Niamh Hannon

Statin Therapy and Outcome After Ischemic Stroke Systematic Review and Meta-Analysis of Observational Studies and Randomized Trials

Background and Purpose— Although experimental data suggest that statin therapy may improve neurological outcome after acute cerebral ischemia, the results from clinical studies are conflicting. We performed a systematic review and meta-analysis investigating the relationship between statin therapy and outcome after ischemic stroke. Methods— The primary analysis investigated statin therapy at stroke onset (prestroke statin use) and good functional outcome (modified Rankin score 0 to 2) and death. Secondary analyses included the following: (1) acute poststroke statin therapy (⩽72 hours after stroke), and (2) thrombolysis-treated patients. Results— The primary analysis included 113 148 subjects (27 studies). Among observational studies, statin treatment at stroke onset was associated with good functional outcome at 90 days (pooled odds ratio [OR], 1.41; 95% confidence interval [CI], 1.29–1.56; P<0.001), but not 1 year (OR, 1.12; 95% CI, 0.9–1.4; P=0.31), and with reduced fatality at 90 days (pooled OR, 0.71; 95% CI, 0.62–0.82; P<0.001) and 1 year (OR, 0.80; 95% CI, 0.67–0.95; P=0.01). In the single randomized controlled trial reporting 90-day functional outcome, statin treatment was associated with good outcome (OR, 1.5; 95% CI, 1.0–2.24; P=0.05). No reduction in fatality was observed on meta-analysis of data from 3 randomized controlled trials (P=0.9). In studies restricted to of thrombolysis-treated patients, an association between statins and increased fatality at 90 days was observed (pooled OR, 1.25; 95% CI, 1.02–1.52; P=0.03, 3 studies, 4339 patients). However, this association was no longer present after adjusting for age and stroke severity in the largest study (adjusted OR, 1.14; 95% CI, 0.90–1.44; 4012 patients). Conclusion— In the largest meta-analysis to date, statin therapy at stroke onset was associated with improved outcome, a finding not observed in studies restricted to thrombolysis-treated patients. Randomized trials of statin therapy in acute ischemic stroke are needed.

Carotid plaque inflammation on 18F-fluorodeoxyglucose positron emission tomography predicts early stroke recurrence.

Symptomatic carotid stenosis is associated with a 3‐fold risk of early stroke recurrence compared to other stroke subtypes. Current carotid imaging techniques rely on estimating plaque‐related lumen narrowing but do not evaluate intraplaque inflammation, a key mediator of plaque rupture and thromboembolism. Using combined 18F‐fluorodeoxyglucose positron‐emission tomography (FDG‐PET)/computed tomography, we investigated the relation between inflammation‐related FDG uptake and stroke recurrence.

Stroke Associated with Atrial Fibrillation – Incidence and Early Outcomes in the North Dublin Population Stroke Study

Background: Prospective population-based studies are important to accurately determine the incidence and characteristics of stroke associated with atrial fibrillation (AF), while avoiding selection bias which may complicate hospital-based studies. Methods: We investigated AF-associated stroke within the North Dublin Population Stroke Study, a prospective cohort study of stroke/transient ischaemic attack in 294,592 individuals, according to recommended criteria for rigorous stroke epidemiological studies. Results: Of 568 stroke patients ascertained in the first year, 31.2% (177/568) were associated with AF (90.4%, i.e. 160/177 ischaemic infarcts). The crude incidence rate of all AF-associated stroke was 60/100,000 person-years (95% CI = 52–70). Prior stroke was almost twice as common in AF compared to non-AF groups (21.9 vs. 12.8%, p = 0.01). The frequency of AF progressively increased across ischaemic stroke patients stratified by increasing stroke severity (NIHSS 0–4, 29.7%; 5–9, 38.1%; 10–14, 43.8%; ≥15, 53.3%, p < 0.0001). The 90-day trajectory of recovery of AF-associated stroke was identical to that of non-AF stroke, but Rankin scores in AF stroke remained higher at 7, 28 and 90 days (p < 0.001 for all). Discussion: AF-associated stroke occurred in one third of all patients and was associated with a distinct profile of recurrent, severe and disabling stroke. Targeted strategies to increase anticoagulation rates may provide a substantial benefit to prevent severe disabling stroke at a population level.

Stroke Subtype Classification to Mechanism-Specific and Undetermined Categories by TOAST, A-S-C-O, and Causative Classification System Direct Comparison in the North Dublin Population Stroke Study

Background and Purpose— Reliable etiologic classification of ischemic stroke may enhance clinical trial design and identification of subtype-specific environmental and genetic risk factors. Although new classification systems (Causative Classification System [CCS] and ASCO [A for atherosclerosis, S for small vessel disease, C for cardiac source, O for other cause]) have been developed to improve subtype assignment, few comparative data exist from large studies. We hypothesized that both CCS and ASCO would reduce the proportion of patients classified as cause undetermined compared with the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) scheme in a large population-based stroke study. Methods— A single rater classified all first-ever ischemic strokes in the North Dublin Population Stroke Study, a population-based study of 294 529 North Dublin residents. Published algorithms for TOAST, CCS, and ASCO were applied. Results— In 381 first-ever ischemic stroke patients, CCS assigned fewer patients as cause undetermined (26.2% versus 39.4%; P<0.000001), with increased assignment of cardio-aortic embolism (relative increase 6.9%; P=0.004), large artery atherosclerosis (relative increase 44.1%; P=0.00006), small artery occlusion (relative increase 27.3%; P=0.00006), and other causes (relative increase 91.7%; P=0.001) compared with TOAST. When ASCO grade 1 evidence was applied, fewer patients were classified as small artery disease (relative decrease 29.1%; P=0.007) and more as large artery/atherothrombotic (relative increase 17.6%; P=0.03). ASCO grade 1 did not reduce the proportion of cause undetermined cases compared with TOAST (42.3% versus 39.4%; P=0.2). Agreement between systems ranged from good (&kgr;=0.61 for TOAST/ASCO grade 1 small artery category) to excellent (&kgr;=0.95 for TOAST/CCS and ASCO grade 1/CCS cardio/aorto-embolism category). Application of ASCO grades 1 to 3 indicated evidence of large artery/atherosclerosis (73.3%), cardio-embolism (31.3%), small artery (64.7%), and other cause (12%) in TOAST-undetermined cases. Conclusion— Both CCS and ASCO schemes showed good-to-excellent agreement with TOAST, but each had specific characteristics compared with TOAST for subtype assignment and data retention. The feasibility of a single combined classification system should be considered.

Population-Based Study of ABCD2 Score, Carotid Stenosis, and Atrial Fibrillation for Early Stroke Prediction After Transient Ischemic Attack The North Dublin TIA Study

Background and Purpose— Transient ischemic attack (TIA) etiologic data and the ABCD2 score may improve early stroke risk prediction, but studies are required in population-based cohorts. We investigated the external validity of the ABCD2 score, carotid stenosis, and atrial fibrillation for prediction of early recurrent stroke after TIA. Methods— Patients with TIA in the North Dublin city population (N=294 529) were ascertained by using overlapping hospital and community sources. The relations between individual ABCD2 items, carotid stenosis, atrial fibrillation, and early stroke were examined. Results— In confirmed TIA cases (n=443), carotid stenosis predicted 90-day stroke (hazard ratio=2.56; 95% CI, 1.27 to 5.15, P=0.003). Stroke risk rose with increasing grade of carotid stenosis, ranging from 5.4% (95% CI, 3.3% to 8.7%) with <50% stenosis to 17.2% (95% CI, 9.7% to 29.7%) with severe stenosis/occlusion (hazard ratio=3.3; 95% CI, 1.5 to 7.4, P=0.002). In confirmed TIA cases (n=443), the ABCD2 score performed no better than chance for prediction of 90-day stroke (c-statistic=0.55; 95% CI, 0.45 to 0.64), largely related to the 24.2% (8/33) of patients who experienced a recurrence and had low ABCD2 scores (0–3). However, in nonspecialist-suspected TIA cases (n=700), the predictive utility improved for stroke at 28 (c-statistic=0.61; 95% CI, 0.50 to 0.72) and 90 (c-statistic=0.61; 95% CI, 0.52 to 0.71) days. Conclusions— In a population-based TIA cohort, significant predictive information was provided by carotid stenosis. The ABCD2 score had predictive utility in patients with TIA suspected by nonspecialists. Low scores occurred in several patients with stroke recurrences, suggesting that caution is needed before using the score in isolation.

Diagnostic Usefulness of the ABCD2 Score to Distinguish Transient Ischemic Attack and Minor Ischemic Stroke From Noncerebrovascular Events. The North Dublin TIA Study

Background and Purpose— Transient ischemic attack (TIA) diagnosis is frequently difficult in clinical practice. Noncerebrovascular symptoms are often misclassified as TIA by nonspecialist physicians. Clinical prediction rules such as ABCD2 improve the identification of patients with TIA at high risk of early stroke. We hypothesized that the ABCD2 score may partly improve risk stratification due to improved discrimination of true TIA and minor ischemic stroke (MIS) from noncerebrovascular events. Methods— Consecutive patients with TIA were identified within a prospective population-based cohort study of stroke and TIA. The cohort was expanded by inclusion of patients with MIS and noncerebrovascular events referred to a daily TIA clinic serving the population. Diagnosis was assigned by a trained stroke physician independent of ABCD2 score. Results— Five hundred ninety-four patients were included (292 [49.2%] TIA, 45 [7.6%] MIS, and 257 [43.3%] noncerebrovascular). The mean ABCD2 score showed a graded increase across diagnostic groups (MIS mean 4.8 [SD 1.4] versus TIA mean 3.9 [SD 1.5] versus noncerebrovascular mean 2.9 [SD 1.5]; P<0.00001). The ABCD2 score discriminated well between noncerebrovascular and cerebrovascular events—TIA (c-statistic 0.68; 95% CI, 0.64 to 0.72), any vascular event (TIA+MIS; c-statistic 0.7; 95% CI, 0.66 to 0.74), and MIS (c-statistic 0.81; 95% CI, 0.75 to 0.87)—from noncerebrovascular events. Of ABCD2 items, unilateral weakness (OR, 4.5; 95% CI, 3.1 to 6.6) and speech disturbance (OR, 2.5; 95% CI, 1.6, 4.1) were most likely overrepresented in TIA compared with noncerebrovascular groups. Conclusion— The ABCD2 score had significant diagnostic usefulness for discrimination of true TIA and MIS from noncerebrovascular events, which may contribute to its predictive usefulness.

Association between acute statin therapy, survival, and improved functional outcome after ischemic stroke: the North Dublin Population Stroke Study.

Background and Purpose— Statins improve infarct volume and neurological outcome in animal stroke models. We investigated the relationship between statin therapy and ischemic stroke outcome in the North Dublin Population Stroke Study. Methods— A population-based prospective cohort study was performed using rigorous ascertainment methods. Prestroke and acute (≤72 hours) poststroke medications were recorded. Modified Rankin score and fatality were assessed at 7, 28, and 90 days and 1 year. Results— Of 448 ischemic stroke patients, statins were prescribed before stroke onset in 30.1% (134/445) and were begun acutely (≤72 hours) in an additional 42.5% (189/445). On logistic regression analysis, adjusting for age, prestroke disability (modified Rankin scale), NIHSS score, hypertension, and aspirin, new poststroke statin therapy was independently associated with improved early and late survival (compared with statin untreated patients: OR for death, 0.12; CI, 0.03–0.54 at 7 days; OR, 0.19; CI, 0.07–0.48 at 90 days; OR, 0.26; CI, 0.12–0.55 at 1 year; P≤0.006 for all). Similar findings were observed for statin therapy before stroke onset (adjusted OR for death compared with statin-untreated-patients, 0.04; CI, 0.00–0.33; P=0.003 at 7 days; OR, 0.23; CI, 0.09–0.58; P=0.002 at 90 days; OR, 0.48; CI, 0.23–1.01; P=0.05 at 1 year). Conclusions— Statin therapy at stroke onset and newly begun statins were associated with improved early and late outcomes, supporting data from experimental studies. Randomized trials of statin therapy for treatment of acute stroke are needed.

Incidence, Event Rates, and Early Outcome of Stroke in Dublin, Ireland: The North Dublin Population Stroke Study

Background and Purpose— The World Health Organization has emphasized the importance of international population-based data for unbiased surveillance of stroke incidence and outcome. To date, few such studies have been conducted using recommended gold-standard ascertainment methods. We conducted a large, population-based stroke study in Dublin, Ireland. Methods— Using gold-standard ascertainment methods, individuals with stroke and transient ischemic attack occurring over a 12-month period (December 1, 2005–November 30, 2006) in North Dublin were identified. Disability was assessed using the modified Rankin score and stroke severity (<72 hours) by the National Institutes of Health Stroke Scale. Stroke-related deaths were confirmed by review of medical files, death certificates, pathology, and coroners records. Crude and standardized (to European and World Health Organization standard populations) rates of incidence, risk factors, severity, and early outcome (mortality, case-fatality, disability) were calculated, assuming a Poisson distribution for the number of events. Results— Seven hundred one patients with new stroke or transient ischemic attack were ascertained (485 first-ever stroke patients, 83 recurrent stroke patients, 133 first-ever transient ischemic attack patients). Crude frequency rates (all rates per 1000 person-years) were: 1.65 (95% CI, 1.5–1.79; first-ever stroke), 0.28 (95% CI, 0.22–0.35; recurrent stroke), and 0.45 (95% CI, 0.37–0.53; first-ever transient ischemic attack). Age-adjusted stroke rates were higher than those in 9 other recent population-based samples from high-income countries. High rates of subtype-specific risk factors were observed (atrial fibrillation, 31.3% and smoking, 29.1% in ischemic stroke; warfarin use, 21.2% in primary intracerebral hemorrhage; smoking, 53.9% in subarachnoid hemorrhage; P<0.01 for all compared with other subtypes). Compared with recent studies, 28-day case-fatality rates for primary intracerebral hemorrhage (41%; 95% CI, 29.2%–54.1%) and subarachnoid hemorrhage (46%; 95% CI, 28.8%–64.5%) were greater in Dublin. Conclusions— Using gold-standard methods for case ascertainment, we found high incidence rates of stroke in Dublin compared with those in similar high-income countries; this is likely explained in part by high rates of subtype-specific risk factors.

Stroke recurrence within the time window recommended for carotid endarterectomy

Objective: In the North Dublin Population Stroke Study, we investigated the risk of recurrent stroke within the 14-day time window recommended for endarterectomy. Methods: In a population-based prospective cohort study, all ischemic stroke patients were identified over 1 year and categorized into those with (CS-positive) and without (CS-negative) ipsilateral carotid stenosis (CS) (≥50% lumen narrowing). Nonprocedural stroke recurrence was determined at 72 hours and 7 and 14 days. Results: Of 365 ischemic stroke patients with carotid imaging, 51 were excluded due to posterior circulation or nonlateralizing stroke, ipsilateral carotid occlusion, or intracranial stenosis, leaving 314 included for analysis (36 CS-positive and 278 CS-negative). Recurrent stroke occurred in 5.6% (2/36) CS-positive and 0.4% (1/278) CS-negative patients by 72 hours of symptom onset (p =0.003), 5.6% (2/36) CS-positive and 0.7% (2/278) CS-negative patients (p =0.01) by 7 days, and in 8.3% (3/36) CS-positive and 1.8% (5/278) CS-negative patients by 14 days (p =0.02). On multivariable Cox regression analysis, CS was the only independent predictor of recurrence at 72 hours (adjusted hazard ratio [HR] 36.1, 95% confidence interval [CI] 1.6–837.5, p =0.03), and 7 days (HR 9.1, 1.1–79.2, p =0.05), with a trend at 14 days (HR 4.6, 0.9–22.8, p =0.06). Conclusions: Although only a minority of patients with symptomatic CS had a recurrent stroke within 14 days, early recurrent stroke risk was high, particularly within the first 72 hours. Earlier carotid revascularization or improved acute medical treatment may reduce recurrence in this high-risk group. Neurology® 2011;77:738–743

Improved Late Survival and Disability After Stroke With Therapeutic Anticoagulation for Atrial Fibrillation A Population Study

Background and Purpose— Although therapeutic anticoagulation improves early (within 1 month) outcomes after ischemic stroke in hospital-admitted patients with atrial fibrillation, no information exists on late outcomes in unselected population-based studies, including patients with all stroke (ischemic and hemorrhagic). Methods— We identified patients with atrial fibrillation and stroke in a prospective, population-based study in North Dublin. Clinical characteristics, stroke subtype, stroke severity (National Institutes of Health Stroke Scale), prestroke antithrombotic medication, and International Normalized Ratio (INR) at onset were documented. Modified Rankin Scale (mRS) score was measured before stroke and at 7, 28, and 90 days; 1 year; and 2 years after stroke. Results— One hundred seventy-five patients had atrial fibrillation–associated stroke and medication data at stroke onset (159 ischemic, 16 hemorrhagic); 17% of those with ischemic stroke were anticoagulated before stroke (27 of 159.) On multivariable analysis, therapeutic INR was associated with improved late survival after ischemic stroke (adjusted 2-year odds ratio for death=0.08; 95% CI, 0.01 to 0.78; P=0.03). This survival benefit persisted when patients with hemorrhagic stroke were included (2-year survival; 70.5% therapeutic INR, 14.3% nontherapeutic INR; log-rank P<0.001; odds ratio for death=0.27; 95% CI, 0.09 to 0.88; P=0.03). Admission INR was inversely correlated with early and late modified Rankin Scale score (2-year Spearman &rgr;=−0.65; P<0.0003). An INR of 2 to 3 at ischemic stroke onset was associated with greater early (72 hours to 28 days) modified Rankin Scale score improvement (P=0.04) and good functional outcome (modified Rankin Scale score=0 to 2) at 1 year (adjusted odds ratio=4.8; 95% CI, 1.45 to 23.8; P=0.04). Conclusions— In addition to improving short-term outcome in selected hospital-treated patient groups, therapeutic anticoagulation may provide important benefits for long-term stroke outcomes in unselected populations.