International Journal of Stroke

Transient ischemic attacks are common and place patients at risk of subsequent stroke. The 2007 EXPRESS and SOS-TIA studies demonstrated the efficacy of rapid treatment initiation. We hypothesized that with these findings having informed subsequent transient ischemic attacks management protocols, transient ischemic attacks prognosis in contemporary (2008 and later) patient cohorts would be more favorable than in historical cohorts.

A systematic review and meta-analysis of cohort studies and randomized control trial placebo-arms of transient ischemic attack (published 2008–2015). The primary outcome was stroke. Secondary outcomes were mortality, transient ischemic attack, and myocardial infarction. Studies were excluded if the outcome of transient ischemic attack patients was not reported separately. The systematic review included all studies of transient ischemic attack. The meta-analysis excluded studies of restricted transient ischemic attack patient types (e.g. only patients with atrial fibrillation). The pooled cumulative risks of stroke recurrence were estimated from study-specific estimates at 2, 7, 30, and 90 days post-transient ischemic attack, using a multivariate Bayesian model.

We included 47 studies in the systematic review and 40 studies in the meta-analysis. In the systematic review (191,202 patients), stroke at 2 days was reported in 13/47 (27.7%) of studies, at 7 days in 20/47 (42.6%), at 30 days in 12/47 (25.5%), and at 90 days in 33/47 (70.2%). Studies included in the meta-analysis recruited 68,563 patients. The cumulative risk of stroke was 1.2% (95% credible interval (CI) 0.6–2.2), 3.4% (95% CI 2.0–5.5), 5.0% (95% CI 2.9–8.9), and 7.4% (95% CI 4.3–12.4) at 2, 7, 30, and 90 days post-transient ischemic attack, respectively.

In contemporary settings, transient ischemic attack prognosis is more favorable than reported in historical cohorts where a meta-analysis suggests stroke risk of 3.1% at two days.

Low-density lipoprotein (LDL) cholesterol has been long associated with the risk for ischemic stroke, myocardial infarction, and cardiovascular death. For more than a decade, the main pharmacological option to prevent stroke and myocardial infarction through LDL-cholesterol lowering was the use of statins. During the recent years, two novel classes of drugs have proven their efficacy and safety to reduce LDL-cholesterol and prevent cardiovascular events in large, well-conducted randomized controlled trials: ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

The present review summarizes the evidence arising from the latest trials of lipid-lowering treatment for cardiovascular outcomes prevention and discusses their implications for secondary prevention strategies in patients with ischemic stroke.

There is strong evidence which confirms the hypothesis that the lower the LDL-cholesterol, the less frequent the cardiovascular events are and underlines the importance of treating our ischemic stroke patients with intensive statin treatment aiming at low LDL-cholesterol levels. The very low levels of LDL cholesterol seem to be safe, even in the mid/long term but longer follow-up data are needed. Currently there are no tools to reliably predict cardiovascular outcomes in the specific population of ischemic stroke patients.

Stroke physicians should aim for low LDL-cholesterol levels by intensive statin treatment in all ischemic stroke patients. For those patients who are at the highest risk for recurrent stroke or another cardiovascular event and have unacceptable LDL-cholesterol levels despite intensive statin treatment, PCSK9 inhibitors should be considered.

Intravenous thrombolysis with alteplase within a time window up to 4.5 h is the only approved pharmacological treatment for acute ischemic stroke. We studied whether acute ischemic stroke patients with penumbral tissue identified on magnetic resonance imaging 4.5–9 h after symptom onset benefit from intravenous thrombolysis compared to placebo.

Acute ischemic stroke patients with salvageable brain tissue identified on a magnetic resonance imaging were randomly assigned to receive standard dose alteplase or placebo. The primary end point was disability at 90 days assessed by the modified Rankin scale, which has a range of 0–6 (with 0 indicating no symptoms at all and 6 indicating death). Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events.

The trial was stopped early for slow recruitment after the enrollment of 119 (61 alteplase, 58 placebo) of 264 patients planned. Median time to intravenous thrombolysis was 7 h 42 min. The primary endpoint showed no significant difference in the modified Rankin scale distribution at day 90 (odds ratio alteplase versus placebo, 1.20; 95% CI, 0.63–2.27, P = 0.58). One symptomatic intracranial hemorrhage occurred in the alteplase group. Mortality at 90 days did not differ significantly between the two groups (11.5 and 6.8%, respectively; P = 0.53).

Intravenous alteplase administered between 4.5 and 9 h after the onset of symptoms in patients with salvageable tissue did not result in a significant benefit over placebo. (Supported by Boehringer Ingelheim, Germany; ISRCTN 71616222).

Studies regarding long-term outcomes of ischemic stroke subtypes are scarce in low- and middle-income countries. We aimed to measure the five-year prognosis of ischemic stroke subtypes in Joinville, Brazil.

All first-ever ischemic strokes that occurred in Joinville in 2010 were followed-up for five years.

We included 334 ischemic stroke patients. Over five years, 156 died, 51 had a recurrent stroke, and 128 were free of recurrent stroke. The overall cumulative risk of death was 17% (95% CI, 13% to 22%) at 30 days and 47% (95% CI, 41% to 52%) after five years. Undetermined with incomplete investigation ischemic stroke had a significantly worse survival probability (β −4.91; 95% CI, −6.31 to −3.50; p < 0.001), followed by cardioembolic ischemic stroke (β −3.07; 95% CI, −4.32 to −1.83; p < 0.001) and large artery disease ischemic stroke (β −1.95; 95% CI, −3.30 to −0.60; p = 0.005). The survival probability of undetermined with negative investigation or cryptogenic ischemic stroke did not differ significantly from small artery disease ischemic stroke (β −1.022; 95% CI, −3.37 to −1.43; p = 0.414). The five-year mortality for small artery disease ischemic stroke was 30% (95% CI, 22% to 39%) and 47% (95% CI, 35% to 60%) for large artery ischemic stroke. The risk of stroke recurrence was 2% in the first year and 5% in the second year. The proportion of disability among survivors in the first month ranged from 8% (95% CI, 3–15) for small artery disease ischemic stroke to 40% (95% CI, 30–52) for cardioembolic ischemic stroke patients.

Cardioembolic and undetermined with incomplete investigation ischemic stroke sub-types have a poor long-term prognosis. An alarming finding was that our patients with both small and large artery ischemic stroke had higher five-year mortality rates compared with subjects from high-income countries.

Stroke is a leading cause of morbidity and mortality in Brazil, where there are significant imbalances in access to specialized stroke care. Telemedicine networks allow patients to receive neurological evaluation and intravenous thrombolysis in underserved areas, where performance measures are challenging.

To describe the impact caused by adequate stroke care training, using realistic simulation, in a developing country telestroke network.

Retrospective observational study comparing the number of all stroke diagnoses, thrombolysis rate, door-to-needle time and symptomatic intracranial hemorrhage after intravenous thrombolysis, during one year providing just algorithms and orientation in stroke care to spoke facilities (phase 1), with the results achieved along one year after the beginning of ongoing live training sessions (phase 2).

The mean number of patients diagnosed with stroke increased from 7.5 to 16.58 per month (P = 0.019) rising from 90 patients during phase 1 to 199 in phase 2. There was a reduction in the mean door-to-needle time from 137.1 to 95.5 min (−41.58; 95% CI −62.77 to −20.40). The thrombolysis and symptomatic intracranial hemorrhage rates had a non-significant decrease from 21.31% to 18.18% (OR 0.82; 95% CI 0.39 to 1.71) and 12.5% to 7.69% (OR 0.58; 95% CI 0.046 to 7.425), respectively.

Realistic simulation stroke care training provided by stroke centers to spoke facilities seems to significantly reduce door-to-needle time and enhance adherence in a telestroke network.

Stroke mimics are frequently treated with thrombolysis in clinical practice and thrombolytic trials. Although alteplase in stroke mimics has proven to be safe, safety of tenecteplase in stroke mimics has not been assessed in an ischemic stroke study setting. We aimed to assess clinical characteristics and safety of stroke mimics treated with thrombolysis in the Norwegian Tenecteplase Stroke Trial. We also aimed to identify possible predictors of stroke mimics as compared to patients with acute cerebral ischemia.

Norwegian Tenecteplase Stroke Trial was a phase-3 trial investigating safety and efficacy of tenecteplase vs. alteplase in patients with suspected acute cerebral ischemia. Two groups were defined based on diagnose at discharge: patients with a different diagnose than ischemic stroke or transient ischemic attack (stroke mimics group) and patients diagnosed with ischemic stroke or transient ischemic attack (acute cerebral ischemia group). Logistic regression analyses were performed with stroke mimics vs. acute cerebral ischemia as dependent variable to identify predictors of stroke mimics.

Of 1091 randomized patients, 181 (16.6%) were stroke mimics. Migraine (22.2%) and peripheral vertigo (11.4%) were the two most frequent stroke mimic-diagnoses. There was no symptomatic intracerebral hemorrhage in the stroke mimics group. Stroke mimics were independently associated with age ≤60 years (OR 2.75, p < 0.001), female sex (OR 1.48, p = 0.026), no history of myocardial infarction (OR 2.03, p = 0.045), systolic BP ≤ 150 mmHg (OR 2.33, p < 0.001), NIHSS ≤ 6 points (OR 1.83, p = 0.011), sensory loss (OR 1.55, p = 0.015), and no facial paresis (OR 2.41, p < 0.001) on admission.

Thrombolysis with tenecteplase seems to be as safe as with alteplase in stroke mimics. Predictors were identified for stroke mimics which may contribute to differentiate stroke mimics from acute cerebral ischemia in future stroke trials.

Rapid therapeutic decisions in acute stroke patients leading to earlier initiation of revascularization therapies are associated with better outcome. An association between regular working hours and reduced time to initiation of intravenous thrombolysis has been reported. However, its influence on mechanical thrombectomy (MT) remains uncertain. We aimed to analyze the effects of admission time on door-to-groin time and stroke outcome in a large prospective stroke registry of the Neurovascular Net Ruhr in Germany.

Procedural times of a total of 512 patients treated with MT were analyzed. Admission to hospital during regular working days and hours (Monday to Friday, 8 am to 4 pm) was compared with admission outside these times. Door-to-groin time and the difference in NIH Stroke Scale between admission and discharge served as primary outcome parameters. Long-term functional outcome was centrally assessed with modified Rankin scale.

MT outside regular working hours was associated with a significant mean initiation delay of 20 min. By multivariate regression analysis, every 20 min delay of MT reduced the difference in NIHSS score between admission and discharge by 0.76 points (95% CI −1.24 to −0.28, p = 0.002). Favorable long-term outcome did not differ between both treatment groups.

Treatment outside regular working hours caused a significant delay in the initiation of MT, which was associated with a decreased short-term clinical efficacy of thrombectomy. Strategies like compulsory attendance of the interventional neuroradiologist at the hospital 24/7 might result in shorter door-to-groin times and consecutive in better stroke outcome.

Symptoms of transient ischemic attack are believed to fully resolve within 24 h of onset. Emerging evidence suggests that there may be prolonged functional and psychological impact, although studies have not been able to robustly identify whether these are the effect of transient ischemic attack or changes usually associated with ageing. We describe trajectories of disability and risk of anxiety and depression among patients seen at transient ischemic attack clinics over 12 months, compared to healthy controls.

Thirty transient ischemic attack clinics across England participated. A total of 1320 participants were included: 373 diagnosed with transient ischemic attack, 186 with minor stroke, 310 with “possible transient ischemic attack,” 213 with another condition mimicking a transient ischemic attack and 238 controls recruited from primary care providers. Participants completed questionnaires after diagnosis then after 3, 6 and 12 months. Outcomes were the Nottingham Extended Activities of Daily Living Scale and the Hospital Anxiety and Depression Scale. Mixed effects regression was used to estimate group differences and trajectories.

At baseline, confirmed transient ischemic attack patients scored 1.31 HADS-Anxiety points (s.e. = 0.28; p < 0.001) , 0.51 HADS-Depression points (s.e. = 0.26; p = 0.056), and 2.6 NEADL points (s.e. = 1.1; p = 0.020) worse than controls. At 12 months, the deficits were 0.78 (s.e. = 0.30; p = 0.008), 0.97 (s.e. = 0.23; p < 0.001), and 0.96 (s.e. = 0.92; p = 0.294) respectively. Differences among patients diagnosed with minor stroke were like or worse than transient ischemic attack patients.

Transient ischemic attack clinic patients may have functional and emotional impairments compared to the general population irrespective of final diagnosis. The presence of emotional symptoms or risk of developing anxiety or depression did not always fully recover and may increase.

A clinical large anterior vessel occlusion (LAVO)-prediction scale could reduce treatment delays by allocating intra-arterial thrombectomy (IAT)-eligible patients directly to a comprehensive stroke center.

To subtract, validate and compare existing LAVO-prediction scales, and develop a straightforward decision support tool to assess IAT-eligibility.

We performed a systematic literature search to identify LAVO-prediction scales. Performance was compared in a prospective, multicenter validation cohort of the Dutch acute Stroke study (DUST) by calculating area under the receiver operating curves (AUROC). With group lasso regression analysis, we constructed a prediction model, incorporating patient characteristics next to National Institutes of Health Stroke Scale (NIHSS) items. Finally, we developed a decision tree algorithm based on dichotomized NIHSS items.

We identified seven LAVO-prediction scales. From DUST, 1316 patients (35.8% LAVO-rate) from 14 centers were available for validation. FAST-ED and RACE had the highest AUROC (both >0.81, p < 0.01 for comparison with other scales). Group lasso analysis revealed a LAVO-prediction model containing seven NIHSS items (AUROC 0.84). With the GACE (Gaze, facial Asymmetry, level of Consciousness, Extinction/inattention) decision tree, LAVO is predicted (AUROC 0.76) for 61% of patients with assessment of only two dichotomized NIHSS items, and for all patients with four items.

External validation of seven LAVO-prediction scales showed AUROCs between 0.75 and 0.83. Most scales, however, appear too complex for Emergency Medical Services use with prehospital validation generally lacking. GACE is the first LAVO-prediction scale using a simple decision tree as such increasing feasibility, while maintaining high accuracy. Prehospital prospective validation is planned.

CT perfusion may improve diagnostic accuracy in posterior circulation stroke. The posterior circulation Acute Stroke Prognosis Early CT score (pc-ASPECTS) on Computed Tomography Angiography source images (CTA-SI) predicts functional outcome in patients with basilar artery occlusion.

We assessed the prognostic value of pc-ASPECTS on CT perfusion in patients with vertebral and basilar artery occlusion (VBAO) in comparison with CTA-SI.

Whole-brain CT perfusion from consecutive stroke patients with VBAO at four stroke centers was retrospectively analyzed. pc-ASPECTS – a 10-point score assessing hypoattenuation on CTA-SI – was calculated from CT perfusion parameters as focally reduced cerebral blood flow or cerebral blood volume, focally increased time to peak of the deconvolved tissue residue function (Tmax) or mean transit time. Two investigators independently reviewed the images. Reliability was assessed with intraclass correlation coefficient. Good outcome was defined as modified Rankin scale ≤3 at three months.

We included 60 patients with VBAO. After assessment of four CT perfusion maps simultaneously, area-under-ROC curve (AROC) was 0.83 (95%CI 0.72–0.93) for cerebral blood volume, 0.76 (95%CI 0.64–0.89) for cerebral blood flow, 0.77 (95%CI 0.64–0.89) for Tmax, 0.70 (95%CI 0.56–0.84) for mean transit time versus area-under-ROC curve 0.64 (95%CI 0.50–0.79) for CTA-SI. Cerebral blood volume had greater accuracy compared with CTA-SI for poor outcome (p = 0.04). In logistic regression analysis, cerebral blood volume pc-ASPECTS≤8 was independently associated with poor outcome (OR 9.3 95%CI 2.2–41; p = 0.003, adjusted for age and clinical severity). Inter-rater agreement was substantial for cerebral blood volume pc-ASPECTS (intraclass correlation coefficient 0.82 95%CI 0.71–0.90 versus 0.67 for CTA-SI 95%CI 0.43–0.81).

Cerebral blood volume pc-ASPECTS may identify VBAO patients at higher risk of disability.

Surgical removal of spontaneous intracerebral hemorrhage may reduce secondary destruction of brain tissue. However, large surgical trials of craniotomy have not demonstrated definitive improvement in clinical outcomes. Minimally invasive surgery may limit surgical tissue injury, and recent evidence supports testing these approaches in large clinical trials.

MISTIE III is an investigator-initiated multicenter, randomized, open-label phase 3 study investigating whether minimally invasive clot evacuation with thrombolysis improves functional outcomes at 365 days compared to conservative management. Patients with supratentorial intracerebral hemorrhage clot volume ≥ 30 mL, confirmed by imaging within 24 h ofknown symptom onset,and intact brainstem reflexes were screened with a stability computed tomography scan at least 6 h after diagnostic scan. Patients who met clinical and imaging criteria (no ongoing coagulopathy; no suspicion of aneurysm, arteriovenous malformation, or any other vascular anomaly; and stable hematoma size on consecutive scans) were randomized to either minimally invasive surgery plus thrombolysis or medical therapy. The sample size of 500 was based on findings of a phase 2 study.

The primary outcome measure is dichotomized modified Rankin Scale 0–3 vs. 4–6 at 365 days adjusting for severity variables. Clinical secondary outcomes include dichotomized extended Glasgow Outcome Scale and all-cause mortality at 365 days; rate and extent of parenchymal blood clot removal; patient disposition at 365 days; efficacy at 180 days; type and intensity of ICU management; and quality of life measures. Safety was assessed at 30 days and throughout the study.

The ENhanced Control of Hypertension And Thrombolysis strokE study (ENCHANTED) trial was initiated as a 2 × 2 partial-factorial active-comparison, prospective, randomized, open, blinded endpoint clinical trial to evaluate in thrombolysis-eligible acute ischemic stroke (AIS) patients whether: (1) Arm A – low-dose (0.6 mg/kg body weight) intravenous (iv) alteplase has noninferior efficacy and lower risk of symptomatic intracerebral hemorrhage (sICH) compared with standard-dose (0.9 mg/kg body weight) iv alteplase; and (2) Arm B – early intensive blood pressure (BP) lowering (systolic target 130–140 mmHg) has superior efficacy and lower risk of ICH compared with guideline-recommended BP control (systolic target <180 mmHg). Arm A was completed in 2016; Arm B is now concluding.

To outline in detail and make public the predetermined statistical analysis plan (SAP) for the ‘BP control’ arm of this study.

All data collected by participating researchers will be reviewed and formally assessed. Information pertaining to the baseline characteristics of patients, their process of care, and the delivery of treatments will be outlined, and for each item, statistically relevant descriptive elements will be described. For the trial outcomes, the most appropriate statistical comparisons to be made between groups are planned and described.

A SAP was developed for the results of the BP control arm of this study that is transparent, available to the public, verifiable, and predetermined before completion of data collection.

We have developed a predetermined SAP for the ENCHANTED BP control arm to be followed to avoid analysis bias arising from prior knowledge of the study findings.

ClinicalTrials.gov (NCT01422616); ISRCTN Register (ISRCTN82387104); Australian New Zealand Clinical Trial Registry (ACTRN12611000236998); EU Clinical Trials Register (2011-005545-12); and Clinical Trials Registry – India (REF/2017/05/014334).