BACKGROUND AND PURPOSE—Age-related changes in the cerebrovasculature, including blood–brain barrier (BBB) disruption, are emerging as potential risks for diverse neurological conditions. Because the ...accumulation of senescent cells in tissues is increasingly recognized as a critical step leading to age-related organ dysfunction, we evaluated whether senescent vascular cells are associated with compromised BBB integrity.
METHODS—Effects of vascular cell senescence on tight junction and barrier integrity were studied using an in vitro BBB model, composed of endothelial cells, pericytes, and astrocytes. In addition, tight junction coverage in microvessels and BBB integrity in BubR1 hypomorphic (BubR1) mice, which display senescence cell-dependent phenotypes, were examined.
RESULTS—When an in vitro BBB model was constructed with senescent endothelial cells and pericytes, tight junction structure and barrier integrity (evaluated by transendothelial electric resistance and tracer efflux assay using sodium fluorescein and Evans blue-albumin were significantly impaired. Endothelial cells and pericytes from BubR1 mice had increased senescent-associated β-galactosidase activity and p16 expression, demonstrating an exacerbation of senescence. The coverage by tight junction proteins in the cortical microvessels were reduced in BubR1 mice, consistent with a compromised BBB integrity from permeability assays. Importantly, the coverage of microvessels by end-feet of aquaporin 4–immunoreactive astrocytes was not altered in the cortex of the BubR1 mice.
CONCLUSIONS—Our results indicate that accumulation of senescent vascular cells is associated with compromised BBB integrity, providing insights into the mechanism of BBB disruption related to biological aging.
The aim of the current Valve Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI)clinical endpoints to make ...them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand the understanding of patient risk stratification and case selection.
A recent study confirmed that VARC definitions have already been incorporated into clinical and research practice and represent a new standard for consistency in reporting clinical outcomes of patients with symptomatic severe aortic stenosis (AS) undergoing TAVI. However, as the clinical experience with this technology has matured and expanded, certain definitions have become unsuitable or ambiguous.
Two in-person meetings (held in September 2011 in Washington, DC, USA, and in February 2012 in Rotterdam, the Netherlands) involving VARC study group members, independent experts (including surgeons, interventional and non-interventional cardiologists, imaging specialists, neurologists, geriatric specialists, and clinical trialists), the US Food and Drug Administration (FDA), and industry representatives, provided much of the substantive discussion from which this VARC-2 consensus manuscript was derived. This document provides an overview of risk assessment and patient stratification that need to be considered for accurate patient inclusion in studies. Working groups were assigned to define the following clinical endpoints: mortality, stroke, myocardial infarction, bleeding complications, acute kidney injury, vascular complications, conduction disturbances and arrhythmias, and a miscellaneous category including relevant complications not previously categorized. Furthermore, comprehensive echocardiographic recommendations are provided for the evaluation of prosthetic valve (dys)function. Definitions for the quality of life assessments are also reported. These endpoints formed the basis for several recommended composite endpoints.
This VARC-2 document has provided further standardization of endpoint definitions for studies evaluating the use of TAVI, which will lead to improved comparability and interpretability of the study results, supplying an increasingly growing body of evidence with respect to TAVI and/or surgical aortic valve replacement. This initiative and document can furthermore be used as a model during current endeavours of applying definitions to other transcatheter valve therapies (for example, mitral valve repair).
IMPORTANCE: Carotid endarterectomy and carotid artery stenting are the leading approaches to revascularization for carotid stenosis, yet contemporary data on trends in rates and outcomes are limited. ...OBJECTIVE: To describe US national trends in performance and outcomes of carotid endarterectomy and stenting among Medicare beneficiaries from 1999 to 2014. DESIGN, SETTING, AND PARTICIPANTS: Serial cross-sectional analysis of Medicare fee-for-service beneficiaries aged 65 years or older from 1999 to 2014 using the Medicare Inpatient and Denominator files. Spatial mixed models adjusted for age, sex, and race were fit to calculate county-specific risk-standardized revascularization rates. Mixed models were fit to assess trends in outcomes after adjustment for demographics, comorbidities, and symptomatic status. EXPOSURES: Carotid endarterectomy and carotid artery stenting. MAIN OUTCOMES AND MEASURES: Revascularization rates per 100 000 beneficiary-years of fee-for-service enrollment, in-hospital mortality, 30-day stroke or death, 30-day stroke, myocardial infarction, or death, 30-day all-cause mortality, and 1-year stroke. RESULTS: During the study, 937 111 unique patients underwent carotid endarterectomy (mean age, 75.8 years; 43% women) and 231 077 underwent carotid artery stenting (mean age, 75.4 years; 49% women). There were 81 306 patients who underwent endarterectomy in 1999 and 36 325 in 2014; national rates per 100 000 beneficiary-years decreased from 298 in 1999-2000 to 128 in 2013-2014 (P < .001). The number of patients who underwent stenting ranged from 10 416 in 1999 to 22 865 in 2006 (an increase per 100 000 beneficiary-years from 40 in 1999-2000 to 75 in 2005-2006; P < .001); by 2014, there were 10 208 patients who underwent stenting and the rate decreased to 38 per 100 000 beneficiary-years (P < .001). Outcomes improved over time despite increases in vascular risk factors (eg, hypertension prevalence increased from 67% to 81% among patients who underwent endarterectomy and from 61% to 70% among patients who underwent stenting) and the proportion of symptomatic patients (all P < .001). There were adjusted annual decreases in 30-day ischemic stroke or death of 2.90% (95% CI, 2.63% to 3.18%) among patients who underwent endarterectomy and 1.13% (95% CI, 0.71% to 1.54%) among patients who underwent stenting; an absolute decrease from 1999 to 2014 was observed for endarterectomy (1.4%; 95% CI, 1.2% to 1.5%) but not stenting (−0.1%; 95% CI, −0.5% to 0.4%). Rates for 1-year ischemic stroke decreased after endarterectomy (absolute decrease, 3.5% 95% CI, 3.2% to 3.7%; adjusted annual decrease, 2.17% 95% CI, 2.00% to 2.34%) and stenting (absolute decrease, 1.6% 95% CI, 1.2% to 2.1%; adjusted annual decrease, 1.86% 95% CI, 1.45%-2.26%). Additional improvements were noted for in-hospital mortality, 30-day stroke, myocardial infarction, or death, and 30-day all-cause mortality as well as within demographic subgroups. CONCLUSIONS AND RELEVANCE: Among fee-for-service Medicare beneficiaries, the performance of carotid endarterectomy declined from 1999 to 2014, whereas the performance of carotid artery stenting increased until 2006 and then declined from 2007 to 2014. Outcomes improved despite increases in vascular risk factors.
Objectives The aim of the current Valve Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI) clinical ...endpoints to make them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand the understanding of patient risk stratification and case selection. Background A recent study confirmed that VARC definitions have already been incorporated into clinical and research practice and represent a new standard for consistency in reporting clinical outcomes of patients with symptomatic severe aortic stenosis (AS) undergoing TAVI. However, as the clinical experience with this technology has matured and expanded, certain definitions have become unsuitable or ambiguous. Methods and Results Two in-person meetings (held in September 2011 in Washington, DC, and in February 2012 in Rotterdam, The Netherlands) involving VARC study group members, independent experts (including surgeons, interventional and noninterventional cardiologists, imaging specialists, neurologists, geriatric specialists, and clinical trialists), the US Food and Drug Administration (FDA), and industry representatives, provided much of the substantive discussion from which this VARC-2 consensus manuscript was derived. This document provides an overview of risk assessment and patient stratification that need to be considered for accurate patient inclusion in studies. Working groups were assigned to define the following clinical endpoints: mortality, stroke, myocardial infarction, bleeding complications, acute kidney injury, vascular complications, conduction disturbances and arrhythmias, and a miscellaneous category including relevant complications not previously categorized. Furthermore, comprehensive echocardiographic recommendations are provided for the evaluation of prosthetic valve (dys)function. Definitions for the quality of life assessments are also reported. These endpoints formed the basis for several recommended composite endpoints. Conclusions This VARC-2 document has provided further standardization of endpoint definitions for studies evaluating the use of TAVI, which will lead to improved comparability and interpretability of the study results, supplying an increasingly growing body of evidence with respect to TAVI and/or surgical aortic valve replacement. This initiative and document can furthermore be used as a model during current endeavors of applying definitions to other transcatheter valve therapies (for example, mitral valve repair).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Background Early administration of intravenous recombinant tissue plasminogen activator (rt-PA) after ischaemic stroke improves outcome. Previous analysis of combined data from individual ...patients suggested potential benefit beyond 3 h from stroke onset. We re-examined the effect of time to treatment with intravenous rt-PA (alteplase) on therapeutic benefit and clinical risk by adding recent trial data to the analysis. Methods We added data from ECASS III (821 patients) and EPITHET (100 patients) to a pool of common data elements from six other trials of alteplase for acute stroke (2775 patients). We used multivariate logistic regression to assess the relation of stroke onset to start of treatment (OTT) with treatment on favourable 3-month outcome (defined as modified Rankin score 0–1), mortality, and occurrence and outcome of clinically relevant parenchymal haemorrhage. The presence of an arterial occlusion was inferred from the patient's symptoms and absence of haemorrhage or other causes of ischaemic stroke. Vascular imaging was not a requirement in the trials. All patients with confirmed OTT within 360 min were included in the analysis. Findings Treatment was started within 360 min of stroke onset in 3670 patients randomly allocated to alteplase (n=1850) or to placebo (n=1820). Odds of a favourable 3-month outcome increased as OTT decreased (p=0·0269) and no benefit of alteplase treatment was seen after around 270 min. Adjusted odds of a favourable 3-month outcome were 2·55 (95% CI 1·44–4·52) for 0–90 min, 1·64 (1·12–2·40) for 91–180 min, 1·34 (1·06–1·68) for 181–270 min, and 1·22 (0·92–1·61) for 271–360 min in favour of the alteplase group. Large parenchymal haemorrhage was seen in 96 (5·2%) of 1850 patients assigned to alteplase and 18 (1·0%) of 1820 controls, with no clear relation to OTT (p=0·4140). Adjusted odds of mortality increased with OTT (p=0·0444) and were 0·78 (0·41–1·48) for 0–90 min, 1·13 (0·70–1·82) for 91–180 min, 1·22 (0·87–1·71) for 181–270 min, and 1·49 (1·00–2·21) for 271–360 min. Interpretation Patients with ischaemic stroke selected by clinical symptoms and CT benefit from intravenous alteplase when treated up to 4·5 h. To increase benefit to a maximum, every effort should be taken to shorten delay in initiation of treatment. Beyond 4·5 h, risk might outweigh benefit. Funding None.
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Summary Background In the randomised Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), the primary endpoint did not differ between carotid artery stenting and carotid ...endarterectomy in patients with symptomatic and asymptomatic stenosis. A prespecified secondary aim was to examine differences by sex. Methods Patients who were asymptomatic or had had a stroke or transient ischaemic attack within 180 days before random allocation were enrolled in CREST at 117 clinical centres in the USA and Canada. The primary outcome was the composite of stroke, myocardial infarction, or death during the periprocedural period or ipsilateral stroke within 4 years. We used standard survival methods including Kaplan-Meier survival curves and sex-by-treatment interaction term to assess the relation between patient factors and risk of reaching the primary outcome. Analyses were by intention to treat. CREST is registered with ClinicalTrials.gov , NCT00004732. Findings Between Dec 21, 2000, and July 18, 2008, 2502 patients were randomly assigned to carotid endarterectomy (n=1240) or carotid artery stenting (n=1262), 872 (34·9%) of whom were women. Rates of the primary endpoint for carotid artery stenting compared with carotid endarterectomy were 6·2% versus 6·8% in men (hazard ratio HR 0·99, 95% CI 0·66–1·46) and 8·9% versus 6·7% in women (1·35, 0·82–2·23). There was no significant interaction in the primary endpoint between sexes (interaction p=0·34). Periprocedural events occurred in 35 (4·3%) of 807 men assigned to carotid artery stenting compared with 40 (4·9%) of 823 assigned to carotid endarterectomy (HR 0·90, 95% CI 0·57–1·41) and 31 (6·8%) of 455 women assigned to carotid artery stenting compared with 16 (3·8%) of 417 assigned to carotid endarterectomy (1·84, 1·01–3·37; interaction p=0·064). Interpretation Periprocedural risk of events seems to be higher in women who have carotid artery stenting than those who have carotid endarterectomy whereas there is little difference in men. Additional data are needed to confirm whether this differential risk should be taken into account in decisions for treatment of carotid disease in women. Funding National Institute of Neurological Disorders and Stroke and Abbott Vascular Solutions (formerly Guidant).
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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 . . .
Summary Background Age was reported to be an effect-modifier in four randomised controlled trials comparing carotid artery stenting (CAS) and carotid endarterectomy (CEA), with better CEA outcomes ...than CAS outcomes noted in the more elderly patients. We aimed to describe the association of age with treatment differences in symptomatic patients and provide age-specific estimates of the risk of stroke and death within narrow (5 year) age groups. Methods In this meta-analysis, we analysed individual patient-level data from four randomised controlled trials within the Carotid Stenosis Trialists' Collaboration (CSTC) involving patients with symptomatic carotid stenosis. We included only trials that randomly assigned patients to CAS or CEA and only patients with symptomatic stenosis. We assessed rates of stroke or death in 5-year age groups in the periprocedural period (between randomisation and 120 days) and ipsilateral stroke during long-term follow-up for patients assigned to CAS or CEA. We also assessed differences between CAS and CEA. All analyses were done on an intention-to-treat basis. Findings Collectively, 4754 patients were randomly assigned to either CEA or CAS treatment in the four studies. 433 events occurred over a median follow-up of 2·7 years. For patients assigned to CAS, the periprocedural hazard ratio (HR) for stroke and death in patients aged 65–69 years compared with patients younger than 60 years was 2·16 (95% CI 1·13–4·13), with HRs of roughly 4·0 for patients aged 70 years or older. We noted no evidence of an increased periprocedural risk by age group in the CEA group (p=0·34). These changes underpinned a CAS-versus CEA periprocedural HR of 1·61 (95% CI 0·90–2·88) for patients aged 65–69 years and an HR of 2·09 (1·32–3·32) for patients aged 70–74 years. Age was not associated with the postprocedural stroke risk either within treatment group (p≥0·09 for CAS and 0·83 for CEA), or between treatment groups (p=0·84). Interpretation In these RCTs, CEA was clearly superior to CAS in patients aged 70–74 years and older. The difference in older patients was almost wholly attributable to increasing periprocedural stroke risk in patients treated with CAS. Age had little effect on CEA periprocedural risk or on postprocedural risk after either procedure. Funding None.
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Objective Carotid endarterectomy (CEA) is usually performed under general anesthesia (GA), although some advocate regional anesthesia (RA) to reduce hemodynamic instability and allow neurologic ...monitoring and selective shunting. RA does not reduce risk of periprocedural stroke or death, although some series show a reduction in myocardial infarction (MI). We investigated the association of anesthesia type and periprocedural MI among patients receiving GA or RA for CEA and patients undergoing carotid artery stenting (CAS) in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). Methods Between 2000 and 2008, 1151 patients underwent CEA (anesthetic type available for 1149 patients), and 1123 patients underwent CAS ≤30 days of randomization in CREST. CEA patients were categorized by anesthetic type (GA vs RA). CREST defined protocol MI as chest pain or electrocardiogram change plus biomarker evidence of MI, and total MI was defined as protocol MI plus biomarker-positive (+)-only MI. The incidence of protocol MI and total MI in patients undergoing CEA under GA and RA were compared with those undergoing CAS. Other study end points were similarly compared. Differences in baseline characteristics and periprocedural events were evaluated among the three groups. Logistic regression, adjusting for age and symptomatic status, was used to assess group differences. Results The three groups had similar demographic risk factors, except for prevalence of symptomatic carotid stenosis, which was lowest in the CEA-RA group ( P = .03). Of the 111 patients in the CEA-RA group, no protocol MIs occurred and only two biomarker+-only MIs, for an overall incidence of 1.8%, similar to the 1.7% overall incidence in patients undergoing CAS. In contrast, the combined incidence of protocol and biomarker+-only MIs in the 1038 patients in the CEA-GA group was significantly higher at 3.4% ( P = .04), twice the risk of protocol MI and biomarker+-only MI compared with those undergoing CAS (odds ratio OR, 2.01; 95% confidence interval CI, 1.14-3.54). Direct comparison of the MI incidence between CEA-RA and CEA-GA showed no statistical difference. Patients undergoing CEA-GA had lower odds of a periprocedural stroke (OR, 0.48; 95% CI, 0.28-0.79) and stroke or death (OR, 0.46; 95% CI, 0.27-0.76) compared with those undergoing CAS but were not significantly different from those undergoing CEA-RA. Conclusions Patients in CREST undergoing CEA-RA had a similar risk of periprocedural MI as those undergoing CAS, whereas the risk for CEA-GA was twice that compared with patients undergoing CAS. Nevertheless, because periprocedural MI is one of the few variables favoring CAS over CEA and has been associated with decreased long-term survival, RA should be seriously considered for patients undergoing CEA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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