Diederik W.J. Dippel

Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials

BACKGROUND In 2015, five randomised trials showed efficacy of endovascular thrombectomy over standard medical care in patients with acute ischaemic stroke caused by occlusion of arteries of the proximal anterior circulation. In this meta-analysis we, the trial investigators, aimed to pool individual patient data from these trials to address remaining questions about whether the therapy is efficacious across the diverse populations included. METHODS We formed the HERMES collaboration to pool patient-level data from five trials (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND IA) done between December, 2010, and December, 2014. In these trials, patients with acute ischaemic stroke caused by occlusion of the proximal anterior artery circulation were randomly assigned to receive either endovascular thrombectomy within 12 h of symptom onset or standard care (control), with a primary outcome of reduced disability on the modified Rankin Scale (mRS) at 90 days. By direct access to the study databases, we extracted individual patient data that we used to assess the primary outcome of reduced disability on mRS at 90 days in the pooled population and examine heterogeneity of this treatment effect across prespecified subgroups. To account for between-trial variance we used mixed-effects modelling with random effects for parameters of interest. We then used mixed-effects ordinal logistic regression models to calculate common odds ratios (cOR) for the primary outcome in the whole population (shift analysis) and in subgroups after adjustment for age, sex, baseline stroke severity (National Institutes of Health Stroke Scale score), site of occlusion (internal carotid artery vs M1 segment of middle cerebral artery vs M2 segment of middle cerebral artery), intravenous alteplase (yes vs no), baseline Alberta Stroke Program Early CT score, and time from stroke onset to randomisation. FINDINGS We analysed individual data for 1287 patients (634 assigned to endovascular thrombectomy, 653 assigned to control). Endovascular thrombectomy led to significantly reduced disability at 90 days compared with control (adjusted cOR 2.49, 95% CI 1.76-3.53; p<0.0001). The number needed to treat with endovascular thrombectomy to reduce disability by at least one level on mRS for one patient was 2.6. Subgroup analysis of the primary endpoint showed no heterogeneity of treatment effect across prespecified subgroups for reduced disability (pinteraction=0.43). Effect sizes favouring endovascular thrombectomy over control were present in several strata of special interest, including in patients aged 80 years or older (cOR 3.68, 95% CI 1.95-6.92), those randomised more than 300 min after symptom onset (1.76, 1.05-2.97), and those not eligible for intravenous alteplase (2.43, 1.30-4.55). Mortality at 90 days and risk of parenchymal haematoma and symptomatic intracranial haemorrhage did not differ between populations. INTERPRETATION Endovascular thrombectomy is of benefit to most patients with acute ischaemic stroke caused by occlusion of the proximal anterior circulation, irrespective of patient characteristics or geographical location. These findings will have global implications on structuring systems of care to provide timely treatment to patients with acute ischaemic stroke due to large vessel occlusion. FUNDING Medtronic.

Time to Treatment With Endovascular Thrombectomy and Outcomes From Ischemic Stroke: A Meta-analysis

IMPORTANCE Endovascular thrombectomy with second-generation devices is beneficial for patients with ischemic stroke due to intracranial large-vessel occlusions. Delineation of the association of treatment time with outcomes would help to guide implementation. OBJECTIVE To characterize the period in which endovascular thrombectomy is associated with benefit, and the extent to which treatment delay is related to functional outcomes, mortality, and symptomatic intracranial hemorrhage. DESIGN, SETTING, AND PATIENTS Demographic, clinical, and brain imaging data as well as functional and radiologic outcomes were pooled from randomized phase 3 trials involving stent retrievers or other second-generation devices in a peer-reviewed publication (by July 1, 2016). The identified 5 trials enrolled patients at 89 international sites. EXPOSURES Endovascular thrombectomy plus medical therapy vs medical therapy alone; time to treatment. MAIN OUTCOMES AND MEASURES The primary outcome was degree of disability (mRS range, 0-6; lower scores indicating less disability) at 3 months, analyzed with the common odds ratio (cOR) to detect ordinal shift in the distribution of disability over the range of the mRS; secondary outcomes included functional independence at 3 months, mortality by 3 months, and symptomatic hemorrhagic transformation. RESULTS Among all 1287 patients (endovascular thrombectomy + medical therapy [n = 634]; medical therapy alone [n = 653]) enrolled in the 5 trials (mean age, 66.5 years [SD, 13.1]; women, 47.0%), time from symptom onset to randomization was 196 minutes (IQR, 142 to 267). Among the endovascular group, symptom onset to arterial puncture was 238 minutes (IQR, 180 to 302) and symptom onset to reperfusion was 286 minutes (IQR, 215 to 363). At 90 days, the mean mRS score was 2.9 (95% CI, 2.7 to 3.1) in the endovascular group and 3.6 (95% CI, 3.5 to 3.8) in the medical therapy group. The odds of better disability outcomes at 90 days (mRS scale distribution) with the endovascular group declined with longer time from symptom onset to arterial puncture: cOR at 3 hours, 2.79 (95% CI, 1.96 to 3.98), absolute risk difference (ARD) for lower disability scores, 39.2%; cOR at 6 hours, 1.98 (95% CI, 1.30 to 3.00), ARD, 30.2%; cOR at 8 hours,1.57 (95% CI, 0.86 to 2.88), ARD, 15.7%; retaining statistical significance through 7 hours and 18 minutes. Among 390 patients who achieved substantial reperfusion with endovascular thrombectomy, each 1-hour delay to reperfusion was associated with a less favorable degree of disability (cOR, 0.84 [95% CI, 0.76 to 0.93]; ARD, -6.7%) and less functional independence (OR, 0.81 [95% CI, 0.71 to 0.92], ARD, -5.2% [95% CI, -8.3% to -2.1%]), but no change in mortality (OR, 1.12 [95% CI, 0.93 to 1.34]; ARD, 1.5% [95% CI, -0.9% to 4.2%]). CONCLUSIONS AND RELEVANCE In this individual patient data meta-analysis of patients with large-vessel ischemic stroke, earlier treatment with endovascular thrombectomy + medical therapy compared with medical therapy alone was associated with lower degrees of disability at 3 months. Benefit became nonsignificant after 7.3 hours.

High von Willebrand Factor Levels Increase the Risk of First Ischemic Stroke Influence of ADAMTS13, Inflammation, and Genetic Variability

Background and Purpose— Elevated von Willebrand factor (vWF) concentrations are associated with an increased risk of ischemic heart disease. Several factors influence vWF antigen levels and activity, including blood group, genetic variability, acute-phase response, and proteolysis by A Disintegrin and Metalloprotease with ThromboSpondin motif (ADAMTS13), a determinant of proteolytic cleavage of vWF. We assessed how these factors affect the relation between vWF and the occurrence of stroke to understand the underlying mechanism. Methods— In a case-control study of 124 first-ever ischemic stroke patients and 125 age- and sex-matched controls, we studied vWF antigen (vWF:Ag), vWF ristocetin cofactor activity (vWF:RCo), ADAMTS13 activity, the −1793C/G polymorphism in the vWF gene, and C-reactive protein. Results— vWF antigen and activity levels were significantly higher in cases than in controls. The relative risk of ischemic stroke was highest in individuals in the upper quartile of vWF:Ag (odds ratio, 3.2; 95% CI, 1.4 to 7.5) and vWF:RCo (odds ratio, 2.1; 95% CI, 0.9 to 4.8) compared with individuals in the lowest quartiles. In individuals with ADAMTS13 in the lowest quartile, the relative risk of stroke was 1.7 (95% CI, 0.7 to 3.9) compared with the highest quartile. C-reactive protein, ADAMTS13, and genetic variation did not affect the association between vWF and the relative risk of stroke, whereas blood group did affect the association. Conclusions— vWF antigen and activity are associated with the occurrence of acute ischemic stroke. This relation is unaffected by the severity of the acute-phase response or by genetic variation or degradation.

The Paracetamol (Acetaminophen) In Stroke (PAIS) trial: a multicentre, randomised, placebo-controlled, phase III trial

BACKGROUND High body temperature in the first 12-24 h after stroke onset is associated with poor functional outcome. The Paracetamol (Acetaminophen) In Stroke (PAIS) trial aimed to assess whether early treatment with paracetamol improves functional outcome in patients with acute stroke by reducing body temperature and preventing fever. METHODS In a multicentre, randomised, double-blind, placebo-controlled trial, patients with ischaemic stroke or intracerebral haemorrhage and body temperature between 36 degrees C and 39 degrees C were randomly assigned treatment with paracetamol (6 g daily) or placebo within 12 h from symptom onset. Treatment allocation was based on a computer-generated list of random numbers with varying block size. The primary outcome was improvement beyond expectation on the modified Rankin scale at 3 months, according to the sliding dichotomy approach. This trial is registered, number ISRCTN74418480. FINDINGS Between March, 2003, and May, 2008, 1400 patients were randomly allocated treatment. 260 (37%) of 697 patients receiving paracetamol and 232 (33%) of 703 receiving placebo improved beyond expectation (adjusted odds ratio [OR] 1.20, 95% CI 0.96-1.50). In a post-hoc analysis of patients with baseline body temperature 37-39 degrees C, treatment with paracetamol was associated with improved outcome (1.43, 1.02-1.97). There were 55 serious adverse events in the paracetamol group (8%) and 70 in the placebo group (10%). INTERPRETATION These results do not support routine use of high-dose paracetamol in patients with acute stroke. Paracetamol might have a beneficial effect on functional outcome in patients admitted with a body temperature 37-39 degrees C, but this post-hoc finding needs further study. FUNDING Netherlands Heart Foundation.

In Vivo Characterization and Quantification of Atherosclerotic Carotid Plaque Components With Multidetector Computed Tomography and Histopathological Correlation

Objective—In a previous in vitro study we have demonstrated that atherosclerotic plaque components can be characterized with multidetector computed tomography (MDCT) based on differences in Hounsfield values (HV). Now we evaluated the use of MDCT in vivo to characterize and quantify atherosclerotic carotid plaque components compared with histology as reference standard. Methods and Results—Fifteen symptomatic patients with carotid stenosis (>70%) underwent MDCT angiography before carotid endarterectomy (CEA). From each CEA specimen 3 histological sections and corresponding MDCT images were selected. The HV of the major plaque components were assessed. The measured HV were: 657±416HU, 88±18HU, and 25±19HU for calcifications, fibrous tissue, and lipid core, respectively. The cut-off value to differentiate lipid core from fibrous tissue and fibrous tissue from calcifications was based on these measurements and set at 60 HU and 130 HU, respectively. Regression plots showed good correlations (R2>0.73) between MDCT and histology except for lipid core areas, which had a good correlation (R2=0.77) only in mildly calcified (0% to 10%) plaques. Conclusions—MDCT is able to quantify total plaque area, calcifications, and fibrous tissue in atherosclerotic carotid plaques in good correlation with histology. Lipid core can only be adequately quantified in mildly calcified plaques.

The diagnostic accuracy of magnetic resonance imaging and cerebrospinal fluid cytology in leptomeningeal metastasis

Abstract Diagnostic decision making in the case of patients suspected of having leptomeningeal metastasis (LM) can be very difficult. The results of cerebrospinal fluid (CSF) cytology can be repeatedly negative, and the predictive value of gadolinium-enhanced magnetic resonance imaging (MRI) is not well known. We report the results of CSF cytology and Gd MRI in 61 patients with known cancer, suspected of having LM. We combined our data with those from a similar study and calculated the sensitivity and specificity of CSF and Gd MRI, in the absence of a “gold standard diagnosis.” CSF cytology was positive for LM in 35 patients and MRI in 38. With CSF cytology sensitivity 75% and specificity 100%, with Gd MRI sensitivity was 76% but specificity only 77%. We conclude that Gd MRI provides strong support in the diagnosis of LM in patients with cancer who have negative results on CSF cytology.

Effect of Paracetamol (Acetaminophen) on Body Temperature in Acute Ischemic Stroke A Double-Blind, Randomized Phase II Clinical Trial

Background and Purpose— Body temperature is a strong predictor of outcome in acute stroke. However, it is unknown whether antipyretic treatment leads to early and clinically worthwhile reduction of body temperature in patients with acute stroke, especially when they have no fever. The main purpose of this trial was to study whether early treatment of acute ischemic stroke patients with acetaminophen (paracetamol) reduces body temperature. Methods— Seventy-five patients with acute ischemic stroke confined to the anterior circulation were randomized to treatment with either 500 mg (low dose) or 1000 mg (high dose) acetaminophen or with placebo, administered as suppositories 6 times daily during 5 days. Body temperatures were measured with a rectal electronic thermometer at the start of treatment and after 24 hours and with an infrared tympanic thermometer at 2-hour intervals during the first 24 hours and at 6-hour intervals thereafter. The primary outcome measure was rectal temperature at 24 hours after the start of treatment. Results— Treatment with high-dose acetaminophen resulted in 0.4°C lower body temperatures than placebo treatment at 24 hours (95% CI 0.1°C to 0.7°C). The mean reduction from baseline temperature with high-dose acetaminophen was 0.3°C (95% CI 0°C to 0.6°C) higher than that in placebo-treated patients. Treatment with low-dose acetaminophen did not result in lower body temperatures. After 5 days of treatment, no differences in temperature were found between the placebo and the high- or low-dose acetaminophen groups. Conclusions— Treatment with a daily dose of 6000 mg acetaminophen may result in a small, but potentially beneficial, decrease in body temperature shortly after ischemic stroke, even in normothermic and subfebrile patients. Further studies should determine whether this effect is reproducible and whether early reduction of body temperature leads to improved outcome.

The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial

BACKGROUND In adults with acute stroke, infections occur commonly and are associated with an unfavourable functional outcome. In the Preventive Antibiotics in Stroke Study (PASS) we aimed to establish whether or not preventive antimicrobial therapy with a third-generation cephalosporin, ceftriaxone, improves functional outcome in patients with acute stroke. METHODS In this multicentre, randomised, open-label trial with masked endpoint assessment, patients with acute stroke were randomly assigned to intravenous ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to stroke unit care, or standard stroke unit care without preventive antimicrobial therapy; assignments were made within 24 h after symptom onset. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale and analysed by intention to treat. The primary analysis was by ordinal regression of the primary outcome. Secondary outcomes included death, infection rates, antimicrobial use, and length of hospital stay. Participants and caregivers were aware of treatment allocation but assessors of outcome were masked to group assignment. This trial is registered with controlled-trials.com, number ISRCTN66140176. FINDINGS Between July 6, 2010, and March 23, 2014, a total of 2550 patients from 30 sites in the Netherlands, including academic and non-academic medical centres, were randomly assigned to the two treatment groups: 1275 patients to ceftriaxone and 1275 patients to standard treatment (control group). 12 patients (seven in the ceftriaxone group and five in the control group) withdrew consent immediately after randomisation, leaving 2538 patients available for the intention-to-treat-analysis (1268 in the ceftriaxone group and 1270 in the control group). 2514 (99%) of 2538 patients (1257 in each group) completed 3-month follow-up. Preventive ceftriaxone did not affect the distribution of functional outcome scores on the modified Rankin Scale at 3 months (adjusted common odds ratio 0·95 [95% CI 0·82-1·09], p=0·46). Preventive ceftriaxone did not result in an increased occurrence of adverse events. Overgrowth infection with Clostridium difficile occurred in two patients (<1%) in the ceftriaxone group and none in the control group. INTERPRETATION Preventive ceftriaxone does not improve functional outcome at 3 months in adults with acute stroke. The results of our trial do not support the use of preventive antibiotics in adults with acute stroke. FUNDING Netherlands Organization for Health Research and Development, Netherlands Heart Foundation, and the European Research Council.

Stroke-Associated Infection Is an Independent Risk Factor for Poor Outcome after Acute Ischemic Stroke: Data from the Netherlands Stroke Survey

Background: Infections are a common and serious threat to patients with acute ischemic stroke. The aim of this study was to assess the effect of infection on mortality and functional outcome at discharge and at 1 year. Methods: From a consecutive cohort study in 11 centers, the Netherlands Stroke Survey, we selected 521 patients with ischemic stroke admitted to hospital within 48 h of onset. Stroke-associated infection was defined as infection occurring within 7 days after admission. Poor outcome (modified Rankin score >2) was recorded at discharge and at 1 year. Results: Stroke-associated infection occurred in 78 patients (15%); 39 of these (7.5%) had pneumonia and 23 (4.4%) had urinary tract infection. Overall, 276 patients (53%) had a poor outcome at 1 year. Poor outcome was recorded in 69 patients with stroke-associated infection (88%), and 37 of the 78 patients with stroke-associated infection (47%) had died at 1 year. After adjustment for confounders, stroke-associated infection was associated with poor outcome at discharge [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.0–6.7] and at 1 year (OR 3.8, 95% CI 1.8–8.9). Pneumonia had a stronger association with poor outcome at 1 year (OR 10, 95% CI 2.2–46). Conclusions: This study suggests that stroke-associated infection, in particular pneumonia, is independently associated with poor functional outcome after ischemic stroke.

Survival of Patients with Dementia

The evidence on survival in dementia is summarized. There are no reliable data on survival after onset of dementia or after first contact with medical services. People with dementia in outpatient clinics and nursing homes have 2‐year survival rates of 75% (range 60%‐95%) and 50% (range 30%‐65%), respectively. Differences in survival between patients with senile dementia of the Alzheimers type (SDAT) and multi infarct dementia (MID) are small. Women in nursing homes have a better prognosis than men (2‐year survival rates, 60% vs 40%). Dementia patients have a considerable excess mortality when compared to the vital statistics. There is no evidence for improvement of survival rates during recent decades. Recommendations for future studies are made