Rates of Stroke in Patients With Different Presentations of Carotid Artery Stenosis.

OBJECTIVE: Carotid artery stenosis may present without the classical symptoms of transient ischaemic attack or stroke but the rates of stroke for these presentations is unknown. The aim of this study was to examine the rates of stroke in patients with different presentations of carotid artery stenosis. METHODS: A multicentre prospective cohort study was conducted across three Australian vascular centres with low rates of surgical treatment of patients without transient ischaemic attack or stroke. Patients with a 50 - 99% carotid artery stenosis presenting with non-focal symptoms (e.g., dizziness or syncope; n = 47), prior contralateral carotid endarterectomy (n = 71), prior ipsilateral symptoms more than six months earlier (n = 82), and no symptoms (n = 304) were recruited. The primary outcome was ipsilateral ischaemic stroke. Secondary outcomes were any ischaemic stroke and cardiovascular death. Data were analysed using Cox proportional hazard and Kaplan-Meier analyses. RESULTS: Between 2002 and 2020, 504 patients were enrolled (mean age 71 years, 30% women) and followed for a median of 5.1 years (interquartile range 2.5, 8.8; 2 981 person years). Approximately 82% were prescribed antiplatelet therapy, 84% were receiving at least one antihypertensive drug, and 76% were prescribed a statin at entry. After five years the incidence of ipsilateral stroke was 6.5% (95% confidence interval [CI] 4.3 - 9.5). There were no statistically significant differences in the annual rate of ipsilateral stroke among people with non-focal symptoms (2.1%; 95% CI 0.8 - 5.7), prior contralateral carotid endarterectomy (0.2%; 0.03 - 1.6) or ipsilateral symptoms > 6 months prior (1.0%; 0.4 - 2.5) compared with those with no symptoms (1.2%; 0.7 - 1.8; p = .19). There were no statistically significant differences in secondary outcomes across groups. CONCLUSION: This cohort study showed no large differences in stroke rates among people with different presentations of carotid artery stenosis.

Genetic Predisposition to Diabetes and Abdominal Aortic Aneurysm: A Two Stage Mendelian Randomisation Study.

OBJECTIVE: Observational studies demonstrate an inverse association between type II diabetes and abdominal aortic aneurysm (AAA) for reasons that are unclear. The aim of this study was to clarify the causal association between type II diabetes predisposition and AAA using Mendelian randomisation. METHODS: Effect estimates for single nucleotide polymorphisms (SNPs) associated with diabetes were obtained from the DIAbetes Meta-ANalysis of Trans-Ethnic association studies (DIAMANTE) consortium to construct a genetic instrumental variable. Corresponding effect estimates for associations of these SNPs with AAA were obtained from the International Aneurysm Consortium comprising six separate AAA genomewide association studies (4 972 cases and 99 858 controls). Mendelian randomisation estimates were calculated using inverse variance, weighted median, and MR-Egger methods, and compared against recently published observational estimates. RESULTS: A genetic risk score was constructed from 206 SNPs associated with diabetes. All three Mendelian randomisation models showed no effect of genetic liability to diabetes and risk of AAA (inverse variance: odds ratio 1.04 per unit higher log odds, 95% 0.98 - 1.11, p = .19; MR-Egger slope p = .33; weighted median p = .50). Results were similar after excluding the TCF7L2 locus (inverse variance p = .075). Findings from the Mendelian randomisation analysis differed from previous observational reports of an inverse association (pdif < .001). CONCLUSION: Lifelong genetic predisposition to diabetes does not appear to protect against AAA. These findings differ from traditional epidemiological studies showing an inverse association between diabetes and AAA, for reasons that remain unclear.

Development and Internal Validation of a Risk Score to Detect Asymptomatic Carotid Stenosis.

OBJECTIVE: Asymptomatic carotid stenosis (ACS) is associated with an increased risk of ischaemic stroke and myocardial infarction. Risk scores have been developed to detect individuals at high risk of ACS, thereby enabling targeted screening, but previous external validation showed scope for refinement of prediction by adding additional predictors. The aim of this study was to develop a novel risk score in a large contemporary screened population. METHODS: A prediction model was developed for moderate (≥50%) and severe (≥70%) ACS using data from 596 469 individuals who attended screening clinics. Variables that predicted the presence of ≥50% and ≥70% ACS independently were determined using multivariable logistic regression. Internal validation was performed using bootstrapping techniques. Discrimination was assessed using area under the receiver operating characteristic curves (AUROCs) and agreement between predicted and observed cases using calibration plots. RESULTS: Predictors of ≥50% and ≥70% ACS were age, sex, current smoking, diabetes mellitus, prior stroke/transient ischaemic attack, coronary artery disease, peripheral arterial disease, blood pressure, and blood lipids. Models discriminated between participants with and without ACS reliably, with an AUROC of 0.78 (95% confidence interval [CI] 0.77-0.78) for ≥ 50% ACS and 0.82 (95% CI 0.81-0.82) for ≥ 70% ACS. The number needed to screen in the highest decile of predicted risk to detect one case with ≥50% ACS was 13 and that of ≥70% ACS was 58. Targeted screening of the highest decile identified 41% of cases with ≥50% ACS and 51% with ≥70% ACS. CONCLUSION: The novel risk model predicted the prevalence of ACS reliably and performed better than previous models. Targeted screening among the highest decile of predicted risk identified around 40% of all cases with ≥50% ACS. Initiation or intensification of cardiovascular risk management in detected cases might help to reduce both carotid related ischaemic strokes and myocardial infarctions.

Associations of Perioperative Variables With the 30-Day Risk of Stroke or Death in Carotid Endarterectomy for Symptomatic Carotid Stenosis.

Background and Purpose- This analysis was performed to assess the association between perioperative and clinical variables and the 30-day risk of stroke or death after carotid endarterectomy for symptomatic carotid stenosis. Methods- Individual patient-level data from the 5 largest randomized controlled carotid trials were pooled in the Carotid Stenosis Trialists' Collaboration database. A total of 4181 patients who received carotid endarterectomy for symptomatic stenosis per protocol were included. Determinants of outcome included carotid endarterectomy technique, type of anesthesia, intraoperative neurophysiological monitoring, shunting, antiplatelet medication, and clinical variables. Stroke or death within 30 days after carotid endarterectomy was the primary outcome. Adjusted risk ratios (aRRs) were estimated in multilevel multivariable analyses using a Poisson regression model. Results- Mean age was 69.5±9.2 years (70.7% men). The 30-day stroke or death rate was 4.3%. In the multivariable regression analysis, local anesthesia was associated with a lower primary outcome rate (versus general anesthesia; aRR, 0.70 [95% CI, 0.50-0.99]). Shunting (aRR, 1.43 [95% CI, 1.05-1.95]), a contralateral high-grade carotid stenosis or occlusion (aRR, 1.58 [95% CI, 1.02-2.47]), and a more severe neurological deficit (mRS, 3-5 versus 0-2: aRR, 2.51 [95% CI, 1.30-4.83]) were associated with higher primary outcome rates. None of the other characteristics were significantly associated with the perioperative stroke or death risk. Conclusions- The current results indicate lower perioperative stroke or death rates in patients operated upon under local anesthesia, whereas a more severe neurological deficit and a contralateral high-grade carotid stenosis or occlusion were identified as potential risk factors. Despite a possible selection bias and patients not having been randomized, these findings might be useful to guide surgeons and anesthetists when treating patients with symptomatic carotid disease.

Editor's Choice - Metformin Prescription is Associated with a Reduction in the Combined Incidence of Surgical Repair and Rupture Related Mortality in Patients with Abdominal Aortic Aneurysm.

OBJECTIVES: Currently there is no drug therapy for abdominal aortic aneurysm (AAA) and most previous investigations have focused on imaging rather than clinical outcomes. The aim of this study was to assess whether AAA related clinical events were lower in patients prescribed metformin. METHODS: This was a prospective cohort observational study performed in three cities in Australia, which was designed to study risk factors for clinical events not simply to focus on metformin. Patients with an asymptomatic unrepaired AAA of any diameter ≥30 mm were recruited from hospital outpatient clinics and surveillance programs run at four centres. The main outcome was the requirement for AAA repair or AAA related mortality (AAA events). The association between metformin prescription and AAA events was assessed using Kaplan-Meier analysis and Cox proportional hazard analysis. RESULTS: Patients (1,080) with a mean (SD) initial AAA diameter of 46.1 (11.3) mm were followed for a mean (SD) of 2.5 (3.1) years until an AAA event (n = 454), death (n = 176), loss to follow up (n = 128), or completion of current follow up (n = 322). Patients with diabetes who were prescribed metformin (adjusted HR 0.63, 95% CI 0.44-0.93), but not patients with diabetes who were not prescribed metformin (adjusted HR 1.15, 95% CI 0.83-1.59), had a lower incidence of AAA events compared with those without diabetes. Findings were similar in sensitivity analyses restricted to patients with an initial AAA diameter ≤50 mm and patients with a minimum follow up of six months before an AAA event. CONCLUSIONS: These findings suggest that clinically important AAA events may be reduced in patients with diabetes who are prescribed metformin, but not those with diabetes receiving other treatments. A randomised controlled trial is needed to definitively test whether metformin reduces AAA related clinical events in patients with small AAAs who do not have diabetes.

Systematic Review and Meta-analysis of Clinical Trials Examining the Benefit of Exercise Programmes Using Nordic Walking in Patients With Peripheral Artery Disease.

OBJECTIVES: An exercise programme is part of the initial management of peripheral artery disease (PAD). Nordic walking uses poles and a core-focused walking technique to reduce the load on the legs, which may have advantages as an exercise programme for PAD. This systematic review examined the benefit of a Nordic walking programme for treating PAD compared with other programmes. METHODS: A systematic approach was used to identify clinical trials comparing Nordic walking and control programmes in PAD patients. For inclusion, studies had to report maximum walking distance (MWD) measured with a treadmill test or corridor walking test both at entry and follow up. Study quality was appraised using the Cochrane collaboration tool for assessing risk of bias. An inverse variance weighted meta-analysis was performed to compare improvements in MWD. RESULTS: Five independent trials involving 294 patients were identified. In three trials, supervised Nordic walking programmes were compared with supervised standard walking. One trial compared a home based Nordic walking programme with a similar standard walking programme. One trial compared a partly supervised Nordic walking programme with best medical management. Meta-analysis of all data suggested that MWD improvements were similar for patients treated by Nordic and standard walking programmes (standardised mean difference, SMD = 1.31, 95% CI -1.28 to 3.91; p = .322). Findings for completely supervised programmes were similar to the primary analysis (SMD = -0.79, 95% CI -2.81 to 1.24; p = .446) while those from partially supervised or home based programmes favoured Nordic walking (SMD = 4.46, 95% CI 3.39, 5.53; p < .001), mainly due to results from one home based trial. CONCLUSIONS: This systematic review suggests no benefit of Nordic over standard walking as supervised exercise for PAD. Favourable results were reported for one home based Nordic walking programme. A larger trial is needed to assess whether this finding can be replicated or not.

Efficacy of Telmisartan to Slow Growth of Small Abdominal Aortic Aneurysms: A Randomized Clinical Trial.

Importance: Currently there is no drug therapy for abdominal aortic aneurysm (AAA). Objective: To test the efficacy of the angiotensin receptor blocker telmisartan in slowing AAA growth in the Telmisartan in the Management of Abdominal Aortic Aneurysm (TEDY) trial. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled trial recruited participants between September 6, 2011, and October 5, 2016, to evaluate the efficacy of telmisartan treatment in patients with AAA. Participants with 35- to 49-mm AAAs recruited from Australia, the Netherlands, and the US were randomized 1:1 to receive telmisartan, 40 mg, or identical placebo. Analyses were conducted according to intention-to-treat principles. Final follow-up was conducted on October 11, 2018, and data analysis was performed between June and November 2019. Intervention: Telmisartan, 40 mg, or identical placebo. Main Outcomes and Measures: The primary outcome of the difference in AAA growth, assessed on core imaging laboratory-read ultrasonographic scanning, was tested with linear mixed-effects models. Other outcomes included effects on blood pressure, computed tomographic (CT)-measured AAA diameter and volume, time to AAA-related events (AAA repair or mortality due to AAA rupture), and health-related quality of life. Results: Of 300 intended participants, 210 were enrolled and randomized to receive telmisartan (n = 107) or placebo (n = 103). Of patients included in the intention-to-treat analysis (telmisartan: n = 106, placebo: n = 101), 183 were men (88%); mean (SD) age was 73.5 (7.9) years. At 1 year, participants receiving telmisartan had mean lower systolic (8.9; 95% CI, 4.1-13.8 mm Hg; P < .001) and diastolic (7.0; 4.3-9.8 mm Hg; P < .001) blood pressure levels compared with participants receiving placebo. A total of 188 participants (91%) received at least 2 ultrasonographic scans and 133 participants (64%) had at least 2 CT scans. There was no significant difference in ultrasonographic-assessed AAA growth rates among those assigned telmisartan (1.68 mm/y) or placebo (1.78 mm/y): mean difference, -0.11 mm/y (95% CI, -0.60 to 0.38 mm/y; P = .66). Telmisartan had no significant effects on AAA growth assessed by CT-measured AAA diameter (mean difference, -0.01 mm/y; 95% CI, -0.02 to 0.01 mm/y; P = .23) or volume (mean difference, -0.02 cm3/y; 95% CI, -0.04 to 0.00 cm3/y; P = .11), AAA-related events (relative risk, 1.35; 95% CI, 0.54-3.35; P = .52), or health-related quality of life (mean difference in physical component score at 24 months, 0.4; 95% CI, 0.4-0.4; P = .80). Hypotensive symptoms (eg, syncope) were twice as common among participants receiving telmisartan compared with placebo (28 [26%] vs 13 [13%]; P = .02), but overall adverse event rates were otherwise similar for both groups. Conclusions and Relevance: This underpowered study did not show a treatment effect for telmisartan on small AAA growth. Future trials will need to ensure adequate sample size and duration of follow-up. Trial Registrations: anzctr.org.au Identifier: ACTRN12611000931976; ClinicalTrials.gov Identifier: NCT01683084.

Sex-Specific Associations of Vascular Risk Factors With Abdominal Aortic Aneurysm: Findings From 1.5 Million Women and 0.8 Million Men in the United States and United Kingdom.

Background Large studies are required for reliable estimates of important risk factors for abdominal aortic aneurysm (AAA). This could guide targeted AAA screening programs, particularly in subgroups like women who are currently excluded from such programs. Method and Results In a cross-sectional study, 1.5 million women and 0.8 million men without known vascular disease attended commercial screening clinics in the United Kingdom or United States from 2008 to 2013. Measurements of vascular risk factors were related to AAA using logistic regression with correction for regression dilution bias. Screening detected 12 729 new AAA cases (0.6%). Compared with never smoking, current smoking was associated with 15 times the risk of AAA among women (risk ratio 15.0, 95% CI 13.2-17.0) and 7 times among men (7.3, 6.4-8.2). In women aged <75 years, the risk of AAA was nearly 30 times greater in current smokers (26.4, 20.3-34.2). In every age group, the prevalence of AAA in female smokers was greater than in male never-smokers. Positive log-linear associations with AAA for women and men were also observed for usual body mass index, usual systolic blood pressure, height, usual low-density lipoprotein cholesterol, and usual triglycerides. Conclusions Log-linear increases in the risks of AAA with traditional vascular risk factors should be considered when evaluating populations that may be at-risk for the development of AAA, and when considering potential treatments. However, at any given age, female smokers are at higher risk of AAA than male never-smokers, and a policy of screening male never-smokers but not higher-risk female smokers is questionable.

Validation of Risk Prediction Models to Detect Asymptomatic Carotid Stenosis.

Background Significant asymptomatic carotid stenosis (ACS) is associated with higher risk of strokes. While the prevalence of moderate and severe ACS is low in the general population, prediction models may allow identification of individuals at increased risk, thereby enabling targeted screening. We identified established prediction models for ACS and externally validated them in a large screening population. Methods and Results Prediction models for prevalent cases with ≥50% ACS were identified in a systematic review (975 studies reviewed and 6 prediction models identified [3 for moderate and 3 for severe ACS]) and then validated using data from 596 469 individuals who attended commercial vascular screening clinics in the United States and United Kingdom. We assessed discrimination and calibration. In the validation cohort, 11 178 (1.87%) participants had ≥50% ACS and 2033 (0.34%) had ≥70% ACS. The best model included age, sex, smoking, hypertension, hypercholesterolemia, diabetes mellitus, vascular and cerebrovascular disease, measured blood pressure, and blood lipids. The area under the receiver operating characteristic curve for this model was 0.75 (95% CI, 0.74-0.75) for ≥50% ACS and 0.78 (95% CI, 0.77-0.79) for ≥70% ACS. The prevalence of ≥50% ACS in the highest decile of risk was 6.51%, and 1.42% for ≥70% ACS. Targeted screening of the 10% highest risk identified 35% of cases with ≥50% ACS and 42% of cases with ≥70% ACS. Conclusions Individuals at high risk of significant ACS can be selected reliably using a prediction model. The best-performing prediction models identified over one third of all cases by targeted screening of individuals in the highest decile of risk only.

Association of Computed Tomographic Leg Muscle Characteristics With Lower Limb and Cardiovascular Events in Patients With Peripheral Artery Disease.

Background Poor lower extremity physical performance is an independent predictor of unfavorable outcome in patients with peripheral artery disease ( PAD ); however, few studies have assessed muscle characteristics on imaging directly. Method and Results A novel 3-dimensional semi-automated protocol was developed to estimate leg muscle volume and density (mean attenuation) from computed tomography images. Patients with PAD who underwent a lower extremity computed tomography scan at a tertiary vascular surgery center were included, and were followed up using hospital records and linked data as part of a retrospective cohort study. The primary outcomes were lower limb events (major amputation or peripheral revascularization) and cardiovascular events (myocardial infarction, stroke, or cardiovascular death). Two hundred and twenty-three patients with PAD were included (median age 69.0 years; 73% men) and followed for a median of 4.9 [2.6-7.0] years. During this time there were 99 index lower limb events and 97 cardiovascular events. Low leg muscle density was associated with increased risk of lower limb (rate ratio 1.41 [1.11-1.80] per SD reduction) and cardiovascular events (rate ratio 1.60 [1.29-1.99] per SD reduction). Low muscle density remained an independent predictor of cardiovascular (but not lower limb) events, after adjusting for age, sex, traditional cardiovascular risk factors, and angiographic PAD severity (rate ratio 1.39 [1.09-1.77] per lower SD ). In contrast, leg muscle volume was not associated with outcomes after adjusting for risk factors and PAD severity. Conclusions Low leg muscle density, but not volume, is a strong, independent predictor of major cardiovascular events among people with PAD . Further research is needed to understand the mechanisms underlying these associations.

Evidence-Based Carotid Interventions for Stroke Prevention: State-of-the-art Review.

Carotid artery stenosis is responsible for between 10-20% of all ischaemic strokes. Interventions, such as carotid endarterectomy and carotid stenting, effectively reduce the risk of stroke in selected individuals. This review describes the history of carotid interventions, and summarises reliable evidence on the safety and efficacy of these interventions gained from large randomised clinical trials.Early trials comparing carotid endarterectomy to medical therapy alone in symptomatic patients, and asymptomatic patients, demonstrated that endarterectomy halved the risk of stroke and perioperative death in these two unique populations. The absolute risk reduction was smaller in the asymptomatic carotid trials, consistent with their lower absolute stroke risk. More recent trials in symptomatic patients, suggest that carotid stenting has similar long term durability to carotid endarterectomy, but possibly has higher procedural hazards dominated by non-disabling strokes. The Asymptomatic Carotid Surgery Trial-2, along with individual patient data meta-analysis of all asymptomatic trials, will provide reliable evidence for the choice of intervention in asymptomatic patients in whom a decision has been made for carotid revascularisation. Given improvements in effective cardiovascular medical therapy, in particular lipid-lowering medications, there is renewed uncertainty as to whether carotid interventions still provide meaningful net reductions in stroke risk in asymptomatic populations. Four large trials in Europe and the US are currently underway, and are expected to report long-term results in the next decade.It is essential that surgeons, interventionalists, and physicians continue to randomise large numbers of patients from around the world to clarify current uncertainty around the management of asymptomatic carotid stenosis.

A Systematic Review and Meta-Analysis of Circulating Biomarkers Associated with Failure of Arteriovenous Fistulae for Haemodialysis.

BACKGROUND: Arteriovenous fistula (AVF) failure is a significant cause of morbidity and expense in patients on maintenance haemodialysis (HD). Circulating biomarkers could be valuable in detecting patients at risk of AVF failure and may identify targets to improve AVF outcome. Currently there is little consensus on the relationship between circulating biomarkers and AVF failure. The aim of this systematic review was to identify circulating biomarkers associated with AVF failure. METHODS: Studies evaluating the association between circulating biomarkers and the presence or risk of AVF failure were systematically identified from the MEDLINE, EMBASE and Cochrane Library databases. No restrictions on the type of study were imposed. Concentrations of circulating biomarkers of routine HD patients with and without AVF failure were recorded and meta-analyses were performed on biomarkers that were assessed in three or more studies with a composite population of at least 100 participants. Biomarker concentrations were synthesized into inverse-variance random-effects models to calculate standardized mean differences (SMD) and 95% confidence intervals (CI). RESULTS: Thirteen studies comprising a combined population of 1512 participants were included after screening 2835 unique abstracts. These studies collectively investigated 48 biomarkers, predominantly circulating molecules which were assessed as part of routine clinical care. Meta-analysis was performed on twelve eligible biomarkers. No significant association between any of the assessed biomarkers and AVF failure was observed. CONCLUSION: This paper is the first systematic review of biomarkers associated with AVF failure. Our results suggest that blood markers currently assessed do not identify an at-risk AVF. Further, rigorously designed studies assessing biological plausible biomarkers are needed to clarify whether assessment of circulating markers can be of any clinical value. PROSPERO registration number CRD42016033845.

The association between plasma matrix metalloproteinase-9 concentration and endoleak after endovascular aortic aneurysm repair: a meta-analysis.

BACKGROUND: The most common complication after endovascular aneurysm repair (EVAR) is continued perfusion of the aneurysmal sac, known as endoleak. Assessment of markers released from the aneurysm wall into the circulation has been suggested as a possible alternative for detecting endoleaks. The aim of this meta-analysis was to examine if circulating concentrations of matrix metalloproteinase (MMP)-9 were higher in patients with endoleak after EVAR. METHODS: A systematic search of the MEDLINE, EMBASE, Scopus, Web of Science and Cochrane Library Databases was conducted. Studies reporting circulating MMP-9 concentrations in patients who did and did not have endoleaks after EVAR that met inclusion and exclusion criteria were included. A meta-analysis using a random effects model was performed to assess the association between circulating concentrations of MMP-9 and endoleak. Sensitivity analyses were performed using the one-study remove approach. Study quality was assessed using a quality assessment tool. RESULTS: Prior to EVAR, plasma concentrations of MMP-9 were similar in patients that did and did not subsequently develop an endoleak (Standardised mean difference: -0.13; 95% confidence interval, -0.63 to 0.37, p=0.60). 1 month after EVAR, plasma concentrations of MMP-9 were non-significantly higher in patients that had an endoleak (Standardized mean difference: 0.56; 95% CI -0.02 to 1.15, p=0.06). 3 months after EVAR, plasma concentrations of MMP-9 were higher in patients that had an endoleak (Standardised mean difference: 1.42; 95% confidence interval, 0.48-2.36, p<0.003). CONCLUSIONS: This meta-analysis suggests that plasma MMP-9 concentrations measured 3 months after EVAR are higher in patients that have an endoleak. It remains to be established whether plasma MMP-9 testing is sufficiently accurate for use as a surveillance test for endoleak after EVAR.

The association of circulating 25-hydroxyvitamin D concentration with peripheral arterial disease: A meta-analysis of observational studies.

BACKGROUND AND AIMS: The association of vitamin D deficiency with cardiovascular disease is controversial. The present meta-analysis was performed to examine if circulating levels of 25-hydroxyvitamin D [25(OH)D] were lower in patients with peripheral artery disease (PAD) when compared to non-PAD controls. METHODS: A comprehensive database search was conducted in Web of science, Scopus, PubMed, EMBASE and The Cochrane Library to identify observational studies reporting 25(OH)D concentrations in PAD patients and non-PAD participants. Data extraction and study quality assessments were conducted independently. A random-effects model was used to meta-analyse extracted data and generate standardized mean differences (SMDs) in circulating 25(OH)D levels between PAD patients and non-PAD controls. Subgroup analyses were conducted focussing on patients presenting with intermittent claudication (IC) and critical limb ischaemia (CLI). RESULTS: Six case-control studies assessing 6418 individuals fulfilled the inclusion criteria. Two studies were considered to be of moderate methodological quality and four were considered to be of high quality. A meta-analysis of data from 1217 PAD patients and 5201 non-PAD participants showed that circulating 25(OH)D concentrations were lower in PAD patients compared with non-PAD participants (SMD = -0.32, 95% CI: -0.58, -0.05; P = 0.02). Subgroup analyses showed that 25(OH)D levels were significantly lower among PAD patients with CLI, but not IC, when compared to non-PAD controls (SMD = -1.29, 95% CI: -1.66, -0.91; P < 0.001 and SMD = -0.01, 95% CI: -0.15, 0.13; P=0.88, respectively). CONCLUSIONS: This meta-analysis suggests that low levels of circulating 25(OH)D are associated with PAD presence, particularly in patients presenting with CLI. These data suggest the possibility that vitamin D insufficiency may contribute to the development of more advanced PAD although this remains to be confirmed.

TElmisartan in the management of abDominal aortic aneurYsm (TEDY): The study protocol for a randomized controlled trial.

BACKGROUND: Experimental studies suggest that angiotensin II plays a central role in the pathogenesis of abdominal aortic aneurysm. This trial aims to evaluate the efficacy of the angiotensin receptor blocker telmisartan in limiting the progression of abdominal aortic aneurysm. METHODS/DESIGN: Telmisartan in the management of abdominal aortic aneurysm (TEDY) is a multicentre, parallel-design, randomised, double-blind, placebo-controlled trial with an intention-to-treat analysis. We aim to randomly assign 300 participants with small abdominal aortic aneurysm to either 40 mg of telmisartan or identical placebo and follow patients over 2 years. The primary endpoint will be abdominal aortic aneurysm growth as measured by 1) maximum infra-renal aortic volume on computed tomographic angiography, 2) maximum orthogonal diameter on computed tomographic angiography, and 3) maximum diameter on ultrasound. Secondary endpoints include change in resting brachial blood pressure, abdominal aortic aneurysm biomarker profile and health-related quality of life. TEDY is an international collaboration conducted from major vascular centres in Australia, the United States and the Netherlands. DISCUSSION: Currently, no medication has been convincingly demonstrated to limit abdominal aortic aneurysm progression. TEDY will examine the potential of a promising treatment strategy for patients with small abdominal aortic aneurysms. TRIAL REGISTRATION: Australian and Leiden study centres: Australian New Zealand Clinical Trials Registry ACTRN12611000931976 , registered on 30 August 2011; Stanford study centre: clinicaltrials.gov NCT01683084 , registered on 5 September 2012.

The association of genetic variants of matrix metalloproteinases with abdominal aortic aneurysm: a systematic review and meta-analysis.

CONTEXT: Aberrant matrix turnover is believed to play a key role in the pathogenesis of abdominal aortic aneurysm (AAA). Matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitor of metalloproteinases; TIMPs) are important enzymes in the control of extracellular matrix remodelling. OBJECTIVE: The aim of this study was to investigate if single nucleotide polymorphisms (SNPs) within MMP and TIMP gene families are associated with the presence of AAA. DATA SOURCES: We performed a search of MEDLINE and EMBASE databases on the 21st November 2012. STUDY SELECTION: Case-control studies assessing the association of at least one SNP in a MMP or TIMP gene with AAA were included. DATA EXTRACTION: Data were independently extracted by two reviewers. A random effects model was used to calculate combined odds ratios for commonly investigated SNPs according to dominant, recessive and additive inheritance. RESULTS: Thirteen studies examining 58 SNPs within 10 different MMP and TIMP genes were identified. Eight SNPs were assessed in at least 3 studies (combined sample size ranging from 141- 2191 AAA cases and 340-2013 controls) and included in a meta-analysis. Results on 1258 cases and 1406 controls for MMP3 rs3025058 showed an association with AAA presence; best described by a dominant pattern of inheritance (OR=1.48 95%CI 1.23 - 1.78, p=3.95×10-5). No associations with AAA were identified for other SNPs assessed in this study including rs1799750 (MMP1), rs3918242 (MMP9), rs486055 (MMP10), rs2276109 (MMP12), rs2252070 (MMP13), rs4898 (TIMP1) or rs9619311 (TIMP3). CONCLUSION: A common SNP within the MMP3 promoter region, previously suggested to increase MMP3 expression, appears to be a moderate risk factor for AAA.

Association of lower extremity performance with cardiovascular and all-cause mortality in patients with peripheral artery disease: a systematic review and meta-analysis.

BACKGROUND: Peripheral artery disease (PAD) is associated with impaired mobility and a high rate of mortality. The aim of this systematic review was to investigate whether reduced lower extremity performance was associated with an increased incidence of cardiovascular and all-cause mortality in people with PAD. METHODS AND RESULTS: A systematic search of the MEDLINE, EMBASE, SCOPUS, Web of Science, and Cochrane Library databases was conducted. Studies assessing the association between measures of lower extremity performance and cardiovascular or all-cause mortality in PAD patients were included. A meta-analysis was conducted combining data from commonly assessed performance tests. The 10 identified studies assessed lower extremity performance by strength tests, treadmill walking performance, 6-minute walk, walking velocity, and walking impairment questionnaire (WIQ). A meta-analysis revealed that shorter maximum walking distance was associated with increased 5-year cardiovascular (unadjusted RR=2.54, 95% CI 1.86 to 3.47, P<10(-5), n=1577, fixed effects) and all-cause mortality (unadjusted RR=2.23 95% CI 1.85 to 2.69, P<10(-5), n=1710, fixed effects). Slower 4-metre walking velocity, a lower WIQ stair-climbing score, and poor hip extension, knee flexion, and plantar flexion strength were also associated with increased mortality. No significant associations were found for hip flexion strength, WIQ distance score, or WIQ speed score with mortality. CONCLUSIONS: A number of lower extremity performance measures are prognostic markers for mortality in PAD and may be useful clinical tools for identifying patients at higher risk of death. Further studies are needed to determine whether interventions that improve measures of lower extremity performance reduce mortality.