Judith Frayne

Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial

BACKGROUND Whether intravenous tissue plasminogen activator (alteplase) is effective beyond 3 h after onset of acute ischaemic stroke is unclear. We aimed to test whether alteplase given 3-6 h after stroke onset promotes reperfusion and attenuates infarct growth in patients who have a mismatch in perfusion-weighted MRI (PWI) and diffusion-weighted MRI (DWI). METHODS We prospectively and randomly assigned 101 patients to receive alteplase or placebo 3-6 h after onset of ischaemic stroke. PWI and DWI were done before and 3-5 days after therapy, with T2-weighted MRI at around day 90. The primary endpoint was infarct growth between baseline DWI and the day 90 T2 lesion in mismatch patients. Major secondary endpoints were reperfusion, good neurological outcome, and good functional outcome. Patients, caregivers, and investigators were unaware of treatment allocations. Primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00238537. FINDINGS We randomly assigned 52 patients to alteplase and 49 patients to placebo. Mean age was 71.6 years, and median score on the National Institutes of Health stroke scale was 13. 85 of 99 (86%) patients had mismatch of PWI and DWI. The geometric mean infarct growth (exponential of the mean log of relative growth) was 1.24 with alteplase and 1.78 with placebo (ratio 0.69, 95% CI 0.38-1.28; Students t test p=0.239); the median relative infarct growth was 1.18 with alteplase and 1.79 with placebo (ratio 0.66, 0.36-0.92; Wilcoxons test p=0.054). Reperfusion was more common with alteplase than with placebo and was associated with less infarct growth (p=0.001), better neurological outcome (p<0.0001), and better functional outcome (p=0.010) than was no reperfusion. INTERPRETATION Alteplase was non-significantly associated with lower infarct growth and significantly associated with increased reperfusion in patients who had mismatch. Because reperfusion was associated with improved clinical outcomes, phase III trials beyond 3 h after treatment are warranted.

Emergency Administration of Abciximab for Treatment of Patients With Acute Ischemic Stroke: Results of an International Phase III Trial Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II)

Background and Purpose— A previous randomized, placebo-controlled, double-blind study suggested that abciximab may be safe and effective in treatment of acute ischemic stroke. The current phase 3 study was planned to test the relative efficacy and safety of abciximab in patients with acute ischemic stroke with planned treatment within 5 hours since symptoms onset. Methods— An international, randomized, placebo-controlled, double-blind phase 3 trial tested intravenous administration of abciximab in 2 study cohorts using stratification variables of time since onset and stroke severity. The planned enrollment was 1800 patients. The primary cohort enrolled those patients who could be treated within 5 hours of onset of stroke. A companion cohort enrolled patients that were treated 5 to 6 hours after stroke as well as a smaller cohort of patients who could be treated within 3 hours of stroke present on awakening. The primary efficacy measure was the dichotomous modified Rankin Scale score at 3 months as adjusted to the baseline severity of stroke among subjects in the primary cohort. The primary safety outcome was the rate of symptomatic or fatal intracranial hemorrhage that occurred within 5 days of stroke. Results— The trial was terminated prematurely after 808 patients in all cohorts were enrolled by recommendation of an independent safety and efficacy monitoring board due to an unfavorable benefit-risk profile. At 3 months, approximately 33% of patients assigned placebo (72/218) and 32% of patients assigned abciximab (71/221; P=0.944) in the primary cohort were judged to have a favorable response to treatment. The distributions of outcomes on the modified Rankin Scale were similar between the treated and control groups. Within 5 days of enrollment, ≈5.5% of abciximab-treated and 0.5% of placebo-treated patients in the primary cohort had symptomatic or fatal intracranial hemorrhage (P=0.002). The trial also did not demonstrate an improvement in outcomes with abciximab among patients in the companion and wake-up cohorts. Although the number of patients was small, an increased rate of hemorrhage was noted within 5 days among patients in the wake-up population who received abciximab (13.6% versus 5% for placebo). Conclusions— This trial did not demonstrate either safety or efficacy of intravenous administration of abciximab for the treatment of patients with acute ischemic stroke regardless of end point or population studied. There was an increased rate of symptomatic or fatal intracranial hemorrhage in the primary and wake-up cohorts.

Clopidogrel Plus Aspirin Versus Warfarin in Patients With Stroke and Aortic Arch Plaques

Background and Purpose— Severe atherosclerosis in the aortic arch is associated with a high risk of recurrent vascular events, but the optimal antithrombotic strategy is unclear. Methods— This prospective randomized controlled, open-labeled trial, with blinded end point evaluation (PROBE design) tested superiority of aspirin 75 to 150 mg/d plus clopidogrel 75 mg/d (A+C) over warfarin therapy (international normalized ratio 2–3) in patients with ischemic stroke, transient ischemic attack, or peripheral embolism with plaque in the thoracic aorta >4 mm and no other identified embolic source. The primary end point included cerebral infarction, myocardial infarction, peripheral embolism, vascular death, or intracranial hemorrhage. Follow-up visits occurred at 1 month and then every 4 months post randomization. Results— The trial was stopped after 349 patients were randomized during a period of 8 years and 3 months. After a median follow-up of 3.4 years, the primary end point occurred in 7.6% (13/172) and 11.3% (20/177) of patients on A+C and on warfarin, respectively (log-rank, P=0.2). The adjusted hazard ratio was 0.76 (95% confidence interval, 0.36–1.61; P=0.5). Major hemorrhages including intracranial hemorrhages occurred in 4 and 6 patients in the A+C and warfarin groups, respectively. Vascular deaths occurred in 0 patients in A+C arm compared with 6 (3.4%) patients in the warfarin arm (log-rank, P=0.013). Time in therapeutic range (67% of the time for international normalized ratio 2–3) analysis by tertiles showed no significant differences across groups. Conclusions— Because of lack of power, this trial was inconclusive and results should be taken as hypothesis generating. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00235248.

Accuracy of national mortality codes in identifying adjudicated cardiovascular deaths.

Objective: This study investigated the sensitivity and specificity of the national mortality codes in identifying cardiovascular disease (CVD) deaths and documents methods of verification.

Management of cholesterol to reduce the burden of stroke in Asia: consensus statement.

Stroke is a major cause of morbidity and mortality in Asia, and its pattern is changing. The incidence of haemorrhagic stroke is declining while the incidence of ischaemic stroke caused by large artery atherothromboembolism is increasing secondary to an increase in the prevalence of hypercholesterolemia. The Working Group on Stroke and Lipids Management in Asia Consensus Panel assembled leading experts from the region to reach a consensus on how to address this challenge. The group discussed the observational epidemiology of the relationship between cholesterol and risk of stroke, the clinical trial evidence base for cholesterol-lowering for stroke prevention, and issues specific to stroke and lipid management for Asian doctors and patients. Stroke guidelines from many of the Asian countries have recently recommended consideration of statins for recurrent stroke prevention in patients with previous ischaemic stroke or transient ischaemic attack. However, because these recommendations have yet to be

Fatal ischemic stroke complicating acute multifocal placoid pigment epitheliopathy: histopathological findings.

A previously healthy 29-year-old man was admitted to a tertiary referral center with acute left hemiparesis followed shortly by de novo convulsive status epilepticus. This was in the context of a 2-month history of flu-like symptoms, severe headaches, and retinopathy recently diagnosed as acute multifocal placoid pigment epitheliopathy. Neuroimaging demonstrated bilateral, multiple territory cerebral infarction. Despite intravenous methylprednisolone and craniotomy for the management of raised intracranial pressure, the patient deteriorated and died 14 days later. At autopsy, multiple infarcts of varying ages within a 10-day period were seen in association with a segmental giant cell vasculopathy of meningeal arteries.

Effectiveness of a shared team approach between nurses and doctors for improved risk factor management in survivors of stroke: a cluster randomized controlled trial.

Limited evidence exists on the benefits of organized care for improving risk factor control in patients with stroke or transient ischaemic attack. The effectiveness of an individualized management programme in reducing absolute cardiovascular disease risk in this high‐risk population was determined.

Community-Based Intervention to Improve Cardiometabolic Targets in Patients With Stroke: A Randomized Controlled Trial

Background and Purpose— Many guidelines for secondary prevention of stroke focus on controlling cardiometabolic risk factors. We investigated the effectiveness of a management program for attaining cardiometabolic targets in survivors of stroke/transient ischemic attack. Methods— Randomized controlled trial of survivors of stroke/transient ischemic attack aged ≥18 years. General practices were randomized to usual care (control) or an intervention comprising specialist review of care plans and nurse education in addition to usual care. The outcome is attainment of pre-defined cardiometabolic targets based on Australian guidelines. Multivariable regression was undertaken to determine efficacy and identify factors associated with attaining targets. Results— Overall, 283 subjects were randomized to the intervention and 280 to controls. Although we found no between-group difference in overall cardiometabolic targets achieved at 12 months, the intervention group more often achieved control of low-density lipoprotein cholesterol (odds ratio, 1.97; 95% confidence interval, 1.18–3.29) than controls. At 24 months, no between-group differences were observed. Medication adherence was ≥80% at follow-up, but uptake of lifestyle/behavioral habits was poor. Older age, being male, being married/living with partner, and having greater functional ability or a history of diabetes mellitus were associated with attaining targets. Conclusions— The intervention in this largely negative trial only had a detectable effect on attaining target for lipids but not for other factors at 12 months or any factor at 24 months. This limited effect may be attributable to inadequate uptake of behavioral/lifestyle interventions, highlighting the need for new or better approaches to achieve meaningful behavioral change. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: ACTRN12608000166370.

Long-term unmet needs and associated factors in stroke or TIA survivors: An observational study

Objective: To extensively investigate long-term unmet needs in survivors of stroke or TIA and to identify factors associated with these unmet needs. Methods: Community-dwelling adults were invited to participate in a survey ≥2 years after discharge for stroke/TIA. Unmet needs were assessed across 5 domains: activities and participation, environmental factors, body functions, post–acute care, and secondary prevention. Factors associated with unmet needs were determined with multivariable negative binomial regression. Results: Of 485 participants invited to complete the survey, 391 (81%) responded (median age 73 years, 67% male). Most responders (87%) reported unmet needs in ≥1 of the measured domains, particularly in secondary prevention (71%). Factors associated with fewer unmet needs included older age (incident rate ratio [IRR] 0.62, 95% confidence interval [CI] 0.50–0.77), greater functional ability (IRR 0.33, 95% CI 0.17–0.67), and reporting that the general practitioner was the most important in care (IRR 0.69, 95% CI 0.57–0.84). Being depressed (IRR 1.61, 95% CI 1.23–2.10) and receiving community services after stroke (IRR 1.45, 95% CI 1.16–1.82) were associated with more unmet needs. Conclusions: Survivors of stroke/TIA reported considerable unmet needs ≥2 years after discharge, particularly in secondary prevention. The factors associated with unmet needs could help guide policy decisions, particularly for tailoring care and support services provided after discharge.

Cerebrovascular disease in type 1A glycogen storage disease

Glycogen storage diseases are a group of genetic disorders involving pathways for storage of glycogen and its utilization to maintain blood glucose. Clinical manifestations include hypoglycaemia, hepatomegaly, delayed adolescence and hyperlipidaemia. Hyperlipidaemia is frequent and patients surviving long enough are thought to be at increased risk of atherosclerosis. However, no cases have previously been reported. Presented is a 27-year-old male with glycogen storage disease type 1A who sustained a pontine infarction due to basilar artery stenosis. It is believed the cause of this infarction was accelerated atherosclerosis. This is of major significance to those with this disease process who are now surviving into their third and later decades due to improved management of this condition.