The neutral results of the SAINT II trial have again highlighted difficulties translating neuroprotective efficacy from bench to bedside. Animal studies are susceptible to study quality biases, which ...may lead to overstatement of efficacy. We report the impact of study quality on published estimates of the efficacy of NXY-059 in animal models of stroke.
We conducted a systematic review and stratified meta-analysis of published studies describing the efficacy of NXY-059 in experimental focal cerebral ischemia.
Overall, NXY-059 improved infarct volume by 43.3% (95% CI, 34.7 to 52.8). Only 2 of 9 publications reported randomization, concealment of treatment allocation, and blinded outcome assessment. Studies not reporting these quality items gave substantially higher estimates of efficacy than did higher-quality studies.
The reported efficacy of NXY-059 in animal models of stroke is confounded by low study quality. The failure of SAINT II highlights the need for substantial improvements in the design, conduct, and reporting of animal studies; journals can play an important role in this by adopting standards for animal studies similar to those agreed over 10 years ago for clinical trials.
Background and purpose
We investigated whether the annual volume of patients with acute ischemic stroke referred from a primary stroke center (PSC) for endovascular treatment (EVT) is associated with ...treatment times and functional outcome.
Methods
We used data from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) registry (2014–2017). We included patients with acute ischemic stroke of the anterior circulation who were transferred from a PSC to a comprehensive stroke center (CSC) for EVT. We examined the association between EVT referral volume of PSCs and treatment times and functional outcome using multivariable regression modeling. The main outcomes were time from arrival at the PSC to groin puncture (PSC‐door‐to‐groin time), adjusted for estimated ambulance travel times, time from arrival at the CSC to groin puncture (CSC‐door‐to‐groin time), and modified Rankin Scale (mRS) score at 90 days after stroke.
Results
Of the 3637 patients in the registry, 1541 patients (42%) from 65 PSCs were included. Mean age was 71 years (SD ± 13.3), median National Institutes of Health Stroke Scale score was 16 (interquartile range IQR: 12–19), and median time from stroke onset to arrival at the PSC was 53 min (IQR: 38–90). Eighty‐three percent had received intravenous thrombolysis. EVT referral volume was not associated with PSC‐door‐to‐groin time (adjusted coefficient: −0.49 min/annual referral, 95% confidence interval CI: −1.27 to 0.29), CSC‐door‐to‐groin time (adjusted coefficient: −0.34 min/annual referral, 95% CI: −0.69 to 0.01) or 90‐day mRS score (adjusted common odds ratio: 0.99, 95% CI: 0.96–1.01).
Conclusions
In patients transferred from a PSC for EVT, higher PSC volumes do not seem to translate into better workflow metrics or patient outcome.
We investigated whether the annual volume of patients with acute ischemic stroke referred from a primary stroke center (PSC) for endovascular treatment (EVT) is associated with treatment times and functional outcome using multivariable regression modeling. We included 1541 patients from 65 PSCs. EVT referral volume was not associated with PSC‐door‐to‐groin time (adjusted coefficient: −0.49 min/annual referral, 95% confidence interval CI: −1.27 to 0.29) or 90‐day modified Rankin Scale score (adjusted common odds ratio: 0.99, 95% CI: 0.96–1.01).
The occurrence of pneumonia after stroke is associated with a higher risk of poor outcome or death. We assessed the temporal profile of pneumonia after stroke and its association with poor outcome at ...several time points to identify the most optimal period for testing pneumonia prevention strategies.
We analyzed individual patient data stored in the VISTA (Virtual International Stroke Trials Archive) from randomized acute stroke trials with an inclusion window up to 24 hours after stroke onset and assessed the occurrence of pneumonia in the first 90 days after stroke. Adjusted odds ratios and hazard ratios were calculated for the association between pneumonia and poor outcome and death by means of logistic and Cox proportional hazard regression, respectively, at different times of follow-up.
Of 10 821 patients, 1017 (9.4%) had a total of 1076 pneumonias. Six hundred eighty-nine (64.0%) pneumonias occurred in the first week after stroke. The peak incidence was on the third day and the median time of onset was 4.0 days after stroke (interquartile range, 2-12). The presence of a pneumonia was associated with an increased risk of poor outcome (adjusted odds ratio, 4.8 95% CI, 3.8-6.1) or death (adjusted hazard ratio, 4.1 95% CI, 3.7-4.6). These associations were present throughout the 90 days of follow-up.
Two out of 3 pneumonias in the first 3 months after stroke occur in the first week, with a peak incidence on the third day. The most optimal period to assess pneumonia prevention strategies is the first 4 days after stroke. However, pneumonia occurring later was also associated with poor functional outcome or death.
Objective
To report the presence of intracerebral hemorrhage and porencephaly, both present at birth, in two preterm infants with a mutation in the collagen 4 A1 gene.
Methods
Two preterm infants ...with antenatal intracerebral hemorrhage and established porencephaly, as well as their affected mother and grandfather, underwent neurological and ophthalmological examination and magnetic resonance imaging of the brain. Mutation analysis of the COL4A1 gene was performed in the infants and in their mother.
Results
Both infants had a novel G1580R mutation in the COL4A1 gene, encoding procollagen type IV α1. A history of mild antenatal trauma was present in the first but not in the second infant. Both preterm infants were asymptomatic at birth. The intracerebral hemorrhage and porencephaly were diagnosed with cranial ultrasound examination and were subsequently confirmed with magnetic resonance imaging. Leukoencephalopathy was present in the mother and in her father.
Interpretation
Mutation of the COL4A1 gene appears to be a risk factor of antenatal intracerebral hemorrhage followed by porencephaly in the preterm newborn. Ann Neurol 2009;65:12–18
Summary Most in-hospital deaths of patients with stroke, traumatic brain injury, or postanoxic encephalopathy after cardiac arrest occur after a decision to withhold or withdraw life-sustaining ...treatments. Decisions on treatment restrictions in these patients are generally complex and are based only in part on evidence from published work. Prognostic models to be used in this decision-making process should have a strong discriminative power. However, for most causes of acute brain injury, prognostic models are not sufficiently accurate to serve as the sole basis of decisions to limit treatment. These decisions are also complicated because patients often do not have the capacity to communicate their preferences. Additionally, surrogate decision makers might not accurately represent the patient's preferences. Finally, in the acute stage, prediction of how a patient would adapt to a life with major disability is difficult.
Summary Stroke is a major burden to patients and society, and resources spent on stroke research must be used efficiently and produce good value in terms of improvements in human health. However, ...many instances of poor value from stroke research funding have resulted from the way in which stroke research topics have been chosen and how studies have been designed, conducted, analysed, regulated, managed, disseminated, or reported. A cooperative effort of European stroke researchers aimed to identify sources of inefficiency and waste, recommend approaches to increase value, and highlight examples of best practice in stroke research. Evidence suggests that progress has been made, but there is room for much improvement; researchers, funders, regulators, and other stakeholders in stroke research might consider these recommendations when planning new research.
Background and Purpose- Open-cell carotid artery stents are associated with a higher peri-procedural stroke risk than closed-cell stents. However, the effect of stent design on long-term durability ...of carotid artery stenting (CAS) is unknown. We compared the medium- to long-term risk of restenosis and ipsilateral stroke between patients treated with open-cell stents versus closed-cell stents in the ICSS (International Carotid Stenting Study). Methods- Patients with symptomatic carotid stenosis were randomized to CAS or endarterectomy and followed with duplex ultrasound for a median of 4.0 years. We analyzed data from patients with completed CAS procedures, known stent design, and available ultrasound follow-up. The primary outcome, moderate or higher restenosis (≥50%) was defined as a peak systolic velocity of >1.3 m/s on ultrasound or occlusion of the treated internal carotid artery and analyzed with interval-censored models. Results- Eight hundred fifty-five patients were allocated to CAS. Seven hundred fourteen patients with completed CAS and known stent design were included in the current analysis. Of these, 352 were treated with open-cell and 362 with closed-cell stents. Moderate or higher restenosis occurred significantly less frequently in patients treated with open-cell (n=113) than closed-cell stents (n=154; 5-year risks were 35.5% versus 46.0%; unadjusted hazard ratio, 0.68; 95% CI, 0.53-0.88). There was no significant difference in the risk of severe restenosis (≥70%) after open-cell stenting (n=27) versus closed-cell stenting (n=43; 5-year risks, 8.6% versus 12.7%; unadjusted hazard ratio, 0.63; 95% CI, 0.37-1.05). The risk of ipsilateral stroke beyond 30 days after treatment was similar with open-cell and closed-cell stents (hazard ratio, 0.78; 95% CI, 0.35-1.75). Conclusions- Moderate or higher restenosis after CAS occurred less frequently in patients treated with open-cell stents than closed-cell stents. However, both stent designs were equally effective at preventing recurrent stroke during follow-up. Clinical Trial Registration- URL: http://www.isrctn.com/. Unique identifier: ISRCTN25337470.
Complex vascular anatomy might increase the risk of procedural stroke during carotid artery stenting (CAS). Randomized controlled trial evidence that vascular anatomy should inform the choice between ...CAS and carotid endarterectomy (CEA) has been lacking.
One-hundred eighty-four patients with symptomatic internal carotid artery stenosis who were randomly assigned to CAS or CEA in the ICSS (International Carotid Stenting Study) underwent magnetic resonance (n=126) or computed tomographic angiography (n=58) at baseline and brain magnetic resonance imaging before and after treatment. We investigated the association between aortic arch configuration, angles of supra-aortic arteries, degree, length of stenosis, and plaque ulceration with the presence of ≥1 new ischemic brain lesion on diffusion-weighted magnetic resonance imaging (DWI+) after treatment.
Forty-nine of 97 patients in the CAS group (51%) and 14 of 87 in the CEA group (16%) were DWI+ (odds ratio OR, 6.0; 95% confidence interval CI, 2.9-12.4;
<0.001). In the CAS group, aortic arch configuration type 2/3 (OR, 2.8; 95% CI, 1.1-7.1;
=0.027) and the degree of the largest internal carotid artery angle (≥60° versus <60°; OR, 4.1; 95% CI, 1.7-10.1;
=0.002) were both associated with DWI+, also after correction for age. No predictors for DWI+ were identified in the CEA group. The DWI+ risk in CAS increased further over CEA if the largest internal carotid artery angle was ≥60° (OR, 11.8; 95% CI, 4.1-34.1) than if it was <60° (OR, 3.4; 95% CI, 1.2-9.8; interaction
=0.035).
Complex configuration of the aortic arch and internal carotid artery tortuosity increase the risk of cerebral ischemia during CAS, but not during CEA. Vascular anatomy should be taken into account when selecting patients for stenting.
URL: http://www.isrctn.com/ISRCTN25337470. Unique identifier: ISRCTN25337470.
Surgical and catheter-based cardiovascular procedures and adjunctive pharmacology have an inherent risk of neurological complications. The current diversity of neurological endpoint definitions and ...ascertainment methods in clinical trials has led to uncertainties in the neurological risk attributable to cardiovascular procedures and inconsistent evaluation of therapies intended to prevent or mitigate neurological injury. Benefit-risk assessment of such procedures should be on the basis of an evaluation of well-defined neurological outcomes that are ascertained with consistent methods and capture the full spectrum of neurovascular injury and its clinical effect. The Neurologic Academic Research Consortium is an international collaboration intended to establish consensus on the definition, classification, and assessment of neurological endpoints applicable to clinical trials of a broad range of cardiovascular interventions. Systematic application of the proposed definitions and assessments will improve our ability to evaluate the risks of cardiovascular procedures and the safety and effectiveness of preventive therapies.
In patients with space-occupying hemispheric infarction, surgical decompression reduces the risk of death and increases the chance of a favorable outcome. Uncertainties, however, still remain about ...the benefit of this treatment for specific patient groups.
To assess whether surgical decompression for space-occupying hemispheric infarction is associated with a reduced risk of death and an increased chance of favorable outcomes, as well as whether this association is modified by patient characteristics.
MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the Stroke Trials Registry were searched from database inception to October 9, 2019, for English-language articles that reported on the results of randomized clinical trials of surgical decompression vs conservative treatment in patients with space-occupying hemispheric infarction.
Published and unpublished randomized clinical trials comparing surgical decompression with medical treatment alone were selected.
Patient-level data were extracted from the trial databases according to a predefined protocol and statistical analysis plan. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline and the Cochrane Collaboration's tool for assessing risk of bias were used. One-stage, mixed-effect logistic regression modeling was used for all analyses.
The primary outcome was a favorable outcome (modified Rankin Scale mRS score ≤3) at 1 year after stroke. Secondary outcomes included death, reasonable (mRS score ≤4) and excellent (mRS score ≤2) outcomes at 6 months and 1 year, and an ordinal shift analysis across all levels of the mRS. Variables for subgroup analyses were age, sex, presence of aphasia, stroke severity, time to randomization, and involved vascular territories.
Data from 488 patients from 7 trials from 6 countries were available for analysis. The risk of bias was considered low to moderate for 6 studies. Surgical decompression was associated with a decreased chance of death (adjusted odds ratio, 0.16; 95% CI, 0.10-0.24) and increased chance of a favorable outcome (adjusted odds ratio, 2.95; 95% CI, 1.55-5.60), without evidence of heterogeneity of treatment effect across any of the prespecified subgroups. Too few patients were treated later than 48 hours after stroke onset to allow reliable conclusions in this subgroup, and the reported proportions of elderly patients reaching a favorable outcome differed considerably among studies.
The results suggest that the benefit of surgical decompression for space-occupying hemispheric infarction is consistent across a wide range of patients. The benefit of surgery after day 2 and in elderly patients remains uncertain.
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