In this long-term follow-up of a randomized trial comparing endarterectomy with stenting for carotid-artery stenosis, the risks of periprocedural stroke, myocardial infarction, or death and ...subsequent ipsilateral stroke did not differ between groups over a 10-year period.
We previously reported the outcomes up to 4 years in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).
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No significant difference was shown between patients assigned to stenting and those assigned to endarterectomy with respect to the composite primary end point of periprocedural stroke, myocardial infarction, or death and subsequent ipsilateral stroke. At baseline, the mean age of the patients was 69 years, and at that age the average life expectancy is 15 years for men and 17 years for women.
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As such, long-term treatment differences should be central to treatment decisions. We now report whether the outcomes after stenting . . .
Summary Background Multipotent adult progenitor cells are a bone marrow-derived, allogeneic, cell therapy product that modulates the immune system, and represents a promising therapy for acute ...stroke. We aimed to identify the highest, well-tolerated, and safest single dose of multipotent adult progenitor cells, and if they were efficacious as a treatment for stroke recovery. Methods We did a phase 2, randomised, double-blind, placebo-controlled, dose-escalation trial of intravenous multipotent adult progenitor cells in 33 centres in the UK and the USA. We used a computer-generated randomisation sequence and interactive voice and web response system to assign patients aged 18–83 years with moderately severe acute ischaemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 8–20 to treatment with intravenous multipotent adult progenitor cells (400 million or 1200 million cells) or placebo between 24 h and 48 h after symptom onset. Patients were ineligible if there was a change in NIHSS of four or more points during at least a 6 h period between screening and randomisation, had brainstem or lacunar infarct, a substantial comorbid disease, an inability to undergo an MRI scan, or had a history of splenectomy. In group 1, patients were enrolled and randomly assigned in a 3:1 ratio to receive 400 million cells or placebo and assessed for safety through 7 days. In group 2, patients were randomly assigned in a 3:1 ratio to receive 1200 million cells or placebo and assessed for safety through the first 7 days. In group 3, patients were enrolled, randomly assigned, and stratified by baseline NIHSS score to receive 1200 million cells or placebo in a 1:1 ratio within 24–48 h. Patients, investigators, and clinicians were masked to treatment assignment. The primary safety outcome was dose-limiting toxicity effects. The primary efficacy endpoint was global stroke recovery, which combines dichotomised results from the modified Rankin scale, change in NIHSS score from baseline, and Barthel index at day 90. Analysis was by intention to treat (ITT) including all patients in groups 2 and 3 who received the investigational agent or placebo. This study is registered with ClinicalTrials.gov , number NCT01436487. Findings The study was done between Oct 24, 2011, and Dec 7, 2015. After safety assessments in eight patients in group 1, 129 patients were randomly assigned (67 to receive multipotent adult progenitor cells and 62 to receive placebo) in groups 2 and 3 (1200 million cells). The ITT populations consisted of 65 patients who received multipotent adult progenitor cells and 61 patients who received placebo. There were no dose-limiting toxicity events in either group. There were no infusional or allergic reactions and no difference in treatment-emergent adverse events between the groups (64 99% of 65 patients in the multipotent adult progenitor cell group vs 59 97% of 61 in the placebo group). There was no difference between the multipotent adult progenitor cell group and placebo groups in global stroke recovery at day 90 (odds ratio 1·08 95% CI 0·55–2·09, p=0·83). Interpretation Administration of multipotent adult progenitor cells was safe and well tolerated in patients with acute ischaemic stroke. Although no significant improvement was observed at 90 days in neurological outcomes with multipotent adult progenitor cells treatment, further clinical trials evaluating the efficacy of the intervention in an earlier time window after stroke (<36 h) are planned. Funding Athersys Inc.
RATIONALE:Prospective cohort studies question the value of HDL-C (high-density lipoprotein cholesterol) for stroke risk prediction.
OBJECTIVE:Investigate the relationship between long-term functional ...recovery and HDL proteome and function.
METHODS AND RESULTS:Changes in HDL protein composition and function (cholesterol efflux capacity) in patients after acute ischemic stroke at 2 time points (24 hours, 35 patients; 96 hours, 20 patients) and in 35 control subjects were measured. The recovery from stroke was assessed by 3 months, the National Institutes of Health Stroke Scale and modified Rankin scale scores. When compared with control subject after adjustments for sex and HDL-C levels, 12 proteins some of which participate in acute phase response and platelet activation (APMAP adipocyte plasma membrane-associated protein, GPLD1 phosphate inositol-glycan specific phospholipase D, APOE apolipoprotein E, IHH Indian hedgehog protein, ITIH4 inter-alpha-trypsin inhibitor chain H4, SAA2 serum amyloid A2, APOA4 apolipoprotein A-IV, CLU clusterin, ANTRX2 anthrax toxin receptor 2, PON1 serum paraoxonase/arylesterase, SERPINA1 alpha-1-antitrypsin, and APOF apolipoprotein F) were significantly (adjusted P<0.05) altered in stroke HDL at 96 hours. The first 8 of these proteins were also significantly altered at 24 hours. Consistent with inflammatory remodeling, cholesterol efflux capacity was reduced by 32% (P<0.001) at both time points. Baseline stroke severity adjusted regression model showed that changes within 96-hour poststroke in APOF, APOL1, APMAP, APOC4 (apolipoprotein C4), APOM (apolipoprotein M), PCYOX1 (prenylcysteine oxidase 1), PON1, and APOE correlate with stroke recovery scores (R=0.38–0.73, adjusted P<0.05). APOF (R=0.73) and APOL1 (R=0.60) continued to significantly correlate with recovery scores after accounting for tPA (tissue-type plasminogen activator) treatment.
CONCLUSIONS:Changes in HDL proteins during early acute phase of stroke associate with recovery. Monitoring HDL proteins may provide clinical biomarkers that inform on stroke recuperation.
Stroke occurs more commonly after carotid artery stenting than after carotid endarterectomy. Details regarding stroke type, severity, and characteristics have not been reported previously. We ...describe the strokes that have occurred in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).
CREST is a randomized, open-allocation, controlled trial with blinded end-point adjudication. Stroke was a component of the primary composite outcome. Patients who received their assigned treatment within 30 days of randomization were included. Stroke was adjudicated by a panel of board-certified vascular neurologists with secondary central review of clinically obtained brain images. Stroke type, laterality, timing, and outcome were reported. A periprocedural stroke occurred among 81 of the 2502 patients randomized and among 69 of the 2272 in the present analysis. Strokes were predominantly minor (81%, n=56), ischemic (90%, n=62), in the anterior circulation (94%, n=65), and ipsilateral to the treated artery (88%, n=61). There were 7 hemorrhages, which occurred 3 to 21 days after the procedure, and 5 were fatal. Major stroke occurred in 13 (0.6%) of the 2272 patients. The estimated 4-year mortality after stroke was 21.1% compared with 11.6% for those without stroke. The adjusted risk of death at 4 years was higher after periprocedural stroke (hazard ratio, 2.78; 95% confidence interval, 1.63-4.76).
Stroke, particularly severe stroke, was uncommon after carotid intervention in CREST, but stroke was associated with significant morbidity and was independently associated with a nearly 3-fold increased future mortality. The delayed timing of major and hemorrhagic stroke after revascularization suggests that these strokes may be preventable.
Summary Background Neuroprotection with NA-1 (Tat-NR2B9c), an inhibitor of postsynaptic density-95 protein, has been shown in a primate model of stroke. We assessed whether NA-1 could reduce ...ischaemic brain damage in human beings. Methods For this double-blind, randomised, controlled study, we enrolled patients aged 18 years or older who had a ruptured or unruptured intracranial aneurysm amenable to endovascular repair from 14 hospitals in Canada and the USA. We used a computer-generated randomisation sequence to allocate patients to receive an intravenous infusion of either NA-1 or saline control at the end of their endovascular procedure (1:1; stratified by site, age, and aneurysm status). Both patients and investigators were masked to treatment allocation. The primary outcome was safety and primary clinical outcomes were the number and volume of new ischaemic strokes defined by MRI at 12–95 h after infusion. We used a modified intention-to-treat (mITT) analysis. This trial is registered with ClinicalTrials.gov , number NCT00728182. Findings Between Sept 16, 2008, and March 30, 2011, we randomly allocated 197 patients to treatment—12 individuals did not receive treatment because they were found to be ineligible after randomisation, so the mITT population consisted of 185 individuals, 92 in the NA-1 group and 93 in the placebo group. Two minor adverse events were adjudged to be associated with NA-1; no serious adverse events were attributable to NA-1. We recorded no difference between groups in the volume of lesions by either diffusion-weighted MRI (adjusted p value=0·120) or fluid-attenuated inversion recovery MRI (adjusted p value=0·236). Patients in the NA-1 group sustained fewer ischaemic infarcts than did patients in the placebo group, as gauged by diffusion-weighted MRI (adjusted incidence rate ratio 0·53, 95% CI 0·38–0·74) and fluid-attenuated inversion recovery MRI (0·59, 0·42–0·83). Interpretation Our findings suggest that neuroprotection in human ischaemic stroke is possible and that it should be investigated in larger trials. Funding NoNO Inc and Arbor Vita Corp.
In this randomized comparison of stenting and endarterectomy as treatment for carotid-artery stenosis, there was no significant difference in the rate of the composite primary end point of stroke, ...myocardial infarction, or death (7.2% and 6.8%, respectively; P=0.51). Stroke was more common with carotid-artery stenting than carotid endarterectomy; myocardial infarction was more common with carotid endarterectomy. The 4-year rate of stroke or death was 6.4% for carotid-artery stenting and 4.7% for carotid endarterectomy (P=0.03).
In this randomized comparison of stenting and endarterectomy as treatment for carotid-artery stenosis, there was no significant difference in the rate of the composite primary end point of stroke, myocardial infarction, or death (7.2% and 6.8%, respectively).
Carotid-artery atherosclerosis is an important cause of ischemic stroke.
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Carotid endarterectomy has been established as effective treatment for both symptomatic patients and asymptomatic patients.
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Carotid-artery stenting is another option for treatment. The results of randomized trials comparing carotid-artery stenting and carotid endarterectomy for use in symptomatic patients are conflicting.
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The primary aim of the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) was to compare the outcomes of carotid-artery stenting with those of carotid endarterectomy among patients with symptomatic or asymptomatic extracranial carotid stenosis.
Methods
Study Design
CREST is a randomized, controlled trial with blinded end-point adjudication. Ethics review . . .
Studies of carotid artery disease have suggested that high-grade stenosis can affect cognition, even without stroke. The presence and degree of cognitive impairment in such patients have not been ...reported and compared with a demographically matched population-based cohort.
We studied cognition in 1000 consecutive CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) patients, a treatment trial for asymptomatic carotid disease. Cognitive assessment was after randomization but before assigned treatment. The cognitive battery was developed in the general population REGARDS Study (Reasons for Geographic and Racial Differences in Stroke), involving Word List Learning Sum, Word List Recall, and Word List fluency for animal names and the letter F. The carotid stenosis patients were >45 years old with ≥70% asymptomatic carotid stenosis and no history of prevalent stroke. The distribution of cognitive performance for the patients was standardized, accounting for age, race, and education using performance from REGARDS, and after further adjustment for hypertension, diabetes, dyslipidemia, and smoking. Using the Wald Test, we tabulated the proportion of
scores less than the anticipated deviate for the population-based cohort for representative percentiles.
There were 786 baseline assessments. Mean age was 70 years, 58% men, and 52% right-sided stenosis. The overall
score for patients was significantly below expected for higher percentiles (
<0.0001 for 50th, 75th, and 95th percentiles) and marginally below expected for the 25th percentile (
=0.015). Lower performance was attributed largely to Word List Recall (
<0.0001 for all percentiles) and for Word List Learning (50th, 75th, and 95th percentiles below expected,
≤0.01). The scores for left versus right carotid disease were similar.
Baseline cognition of patients with severe carotid stenosis showed below normal cognition compared to the population-based cohort, controlling for demographic and cardiovascular risk factors. This cohort represents the largest group to date to demonstrate that poorer cognition, especially memory, in this disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02089217.
Minocycline is a promising anti-inflammatory and protease inhibitor that is effective in multiple preclinical stroke models. We conducted an early phase trial of intravenous minocycline in acute ...ischemic stroke.
Following an open-label, dose-escalation design, minocycline was administered intravenously within 6 hours of stroke symptom onset in preset dose tiers of 3, 4.5, 6, or 10 mg/kg daily over 72 hours. Minocycline concentrations for pharmacokinetic analysis were measured in a subset of patients. Subjects were followed for 90 days.
Sixty patients were enrolled, 41 at the highest dose tier of 10 mg/kg. Overall age (65±13.7 years), race (83% white), and sex (47% female) were consistent across the doses. The mean baseline National Institutes of Health Stroke Scale score was 8.5±5.8 and 60% received tissue plasminogen activator. Minocycline infusion was well tolerated with only 1 dose limiting toxicity at the 10-mg/kg dose. No severe hemorrhages occurred in tissue plasminogen activator-treated patients. Pharmacokinetic analysis (n=22) revealed a half-life of approximately 24 hours and linearity of parameters over doses.
Minocycline is safe and well tolerated up to doses of 10 mg/kg intravenously alone and in combination with tissue plasminogen activator. The half-life of minocycline is approximately 24 hours, allowing every 24-hour dosing. Minocycline may be an ideal agent to use with tissue plasminogen activator.
The purpose of this study was to compare health-related quality of life (HRQOL) outcomes in patients treated with carotid artery stenting (CAS) versus carotid endarterectomy (CEA).
In CREST (Carotid ...Revascularization Endarterectomy versus Stenting Trial), the largest randomized trial of carotid revascularization to date, there was no significant difference in the primary composite endpoint, but rates of stroke and myocardial infarction (MI) differed between CAS and CEA. To help guide individualized clinical decision making, we compared HRQOL among patients enrolled in the CREST study. We also performed exploratory analyses to evaluate the association between periprocedural complications and HRQOL.
We measured HRQOL at baseline, and after 2 weeks, 1 month, and 1 year among 2,502 patients randomly assigned to either CAS or CEA in the CREST study. The HRQOL was assessed using the Medical Outcomes Study Short-Form 36 (SF-36) and 6 disease-specific scales designed to study HRQOL in patients undergoing carotid revascularization.
At both 2 weeks and 1 month, CAS patients had better outcomes for multiple components of the SF-36, with large differences for role physical function, pain, and the physical component summary scale (all p < 0.01). On the disease-specific scales, CAS patients reported less difficulty with driving, eating/swallowing, neck pain, and headaches but more difficulty with walking and leg pain (all p < 0.05). However, by 1 year, there were no differences in any HRQOL measure between CAS and CEA. In the exploratory analyses, periprocedural stroke was associated with poorer 1-year HRQOL across all SF-36 domains, but periprocedural MI or cranial nerve palsy were not.
Among patients undergoing carotid revascularization, CAS is associated with better HRQOL during the early recovery period as compared with CEA-particularly with regard to physical limitations and pain-but these differences diminish over time and are not evident after 1 year. Although CAS and CEA are associated with similar overall HRQOL at 1 year, event-specific analyses confirm that stroke has a greater and more sustained impact on HRQOL than MI. (Carotid Revascularization Endarterectomy versus Stenting Trial CREST; NCT00004732)
Tenecteplase for thrombolysis in a 4.5-to-24-hour window did not improve disability outcomes at 90 days in patients with ischemic stroke who had been chosen on the basis of imaging. Most patients had ...endovascular thrombectomy.
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