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.

A Systematic Review and Meta-Analysis of the Incidence and Risk Factors for Major Adverse Cardiovascular Events in Patients with Unrepaired Abdominal Aortic Aneurysms.

Major adverse cardiovascular events (MACE), including myocardial infarction (MI), stroke and cardiovascular death, cause substantial morbidity and mortality. This review assessed the incidence rate of MACE and the association with modifiable risk factors (diabetes, hypertension) and medication use (aspirin, statins) in patients with unrepaired abdominal aortic aneurysm (AAA). Electronic databases were searched systematically for observational studies reporting the incidence of MI, stroke or cardiovascular death in patients with unrepaired AAAs. The primary outcome was cardiovascular death reported as an incidence rate (events per 100 person-years (PY)). Fourteen studies, including 69,579 participants with a mean follow-up time of 5.4 years, were included. Meta-analysis revealed the overall incidence of cardiovascular death, MI and stroke of 2.31 per 100 PY (95% CI, 1.63-3.26; I2 = 98%), 1.65 per 100 PY (95% CI, 1.01-2.69, I2 = 88%) and 0.89 per 100 PY (95% CI, 0.53-1.48, I2 = 87.0%), respectively. The mean rates of statin and aspirin prescriptions were 58.1% and 53.5%, respectively. In conclusion, there is a substantial incidence of MACE in patients with unrepaired AAA, but the prescription of preventative medication is suboptimal. Greater emphasis should be placed on secondary prevention in this population.

Risk Factors for Hospital Re-admission for Diabetes Related Foot Disease: A Prospective Cohort Study.

OBJECTIVE: Diabetes related foot disease (DFD) is a common reason for admission to hospital, but the predictive factors for repeat admission are poorly defined. The primary aim of this study was to identify rates and predictive factors for DFD related hospital re-admission. METHODS: Patients admitted to hospital for treatment of DFD at a single regional centre were recruited prospectively between January 2020 and December 2020. Participants were followed for 12 months to evaluate the primary outcome of hospital re-admission. The relationship between predictive factors and re-admission were examined using non-parametric statistical tests and Cox proportional hazard analyses. RESULTS: The median age of the 190 participants was 64.9 (standard deviation 13.3) years and 68.4% were male. Forty-one participants (21.6%) identified themselves as Aboriginal or Torres Strait Islander people. One hundred participants (52.6%) were re-admitted to hospital at least once over 12 months. The commonest reason for re-admission was for treatment of foot infection (84.0% of first re-admission). Absent pedal pulses (unadjusted hazard ratio [HR] 1.90; 95% confidence interval [CI] 1.26 - 2.85), loss of protective sensation (LOPS) (unadjusted HR 1.98; 95% CI 1.08 - 3.62), and male sex (unadjusted HR 1.62; 95% CI 1.03 - 2.54) increased the risk of re-admission. After risk adjustment, only absence of pedal pulses (HR 1.92, 95% CI 1.27 - 2.91) and LOPS (HR 2.02, 95% CI 1.09 - 3.74) significantly increased the risk of re-admission. CONCLUSION: Over 50% of patients admitted to hospital for treatment of DFD are re-admitted within one year. Patients with absent pedal pulses and those with LOPS are twice as likely to be re-admitted.

Cohort Study Examining the Presentation, Distribution, and Outcomes of Peripheral Artery Disease in Aboriginal, Torres Strait Islander, and Non-Indigenous Australians.

OBJECTIVE: This retrospective cohort study investigated the anatomical distribution, severity, and outcome of peripheral artery disease (PAD) in Aboriginal and Torres Strait Islanders compared with non-indigenous Australians. METHODS: The distribution, severity, and outcome of PAD were assessed using a validated angiographic scoring system and review of medical records in a cohort of Aboriginal and Torres Strait Islander and non-indigenous Australians. The relationship between ethnicity and PAD severity, distribution, and outcome were examined using non-parametric statistical tests, Kaplan-Meier and Cox proportional hazard analyses. RESULTS: Seventy-three Aboriginal and Torres Strait Islanders and 242 non-indigenous Australians were included and followed for a median of 6.7 [IQR 2.7, 9.3] years. Aboriginal and Torres Strait Islander patients were more likely to present with symptoms of chronic limb threatening ischaemia (81% vs. 25%; p < .001), had greater median [IQR] angiographic scores for the symptomatic limb (7 [5, 10] vs. 4 [2, 7]) and tibial arteries (5 [2, 6] vs. 2 [0, 4]) and had higher risk of major amputation (HR 6.1, 95% CI 3.6 - 10.5; p < .001) and major adverse cardiovascular events (HR 1.5, 95% CI 1.0 - 2.3; p = .036) but not for revascularisation (HR 0.8, 95% CI 0.5 - 1.3; p = .37) compared with non-indigenous Australians. The associations with major amputation and major adverse cardiovascular events were no longer statistically significant when adjusted for limb angiographic score. CONCLUSION: Compared with non-indigenous patients, Aboriginal and Torres Strait Islander Australians had more severe tibial artery disease and a higher risk of major amputation and major adverse cardiovascular events.

Association between aortic peak wall stress and rupture index with abdominal aortic aneurysm-related events.

OBJECTIVE: The aim of this study was to assess whether aortic peak wall stress (PWS) and peak wall rupture index (PWRI) were associated with the risk of abdominal aortic aneurysm (AAA) rupture or repair (defined as AAA events) among participants with small AAAs. METHODS: PWS and PWRI were estimated from computed tomography angiography (CTA) scans of 210 participants with small AAAs (≥ 30 and ≤ 50 mm) prospectively recruited between 2002 and 2016 from two existing databases. Participants were followed for a median of 2.0 (inter-quartile range 1.9, 2.8) years to record the incidence of AAA events. The associations between PWS and PWRI with AAA events were assessed using Cox proportional hazard analyses. The ability of PWS and PWRI to reclassify the risk of AAA events compared to the initial AAA diameter was examined using net reclassification index (NRI) and classification and regression tree (CART) analysis. RESULTS: After adjusting for other risk factors, one standard deviation increase in PWS (hazard ratio, HR, 1.56, 95% confidence intervals, CI 1.19, 2.06; p = 0.001) and PWRI (HR 1.74, 95% CI 1.29, 2.34; p < 0.001) were associated with significantly higher risks of AAA events. In the CART analysis, PWRI was identified as the best single predictor of AAA events at a cut-off value of > 0.562. PWRI, but not PWS, significantly improved the classification of risk of AAA events compared to the initial AAA diameter alone. CONCLUSION: PWS and PWRI predicted the risk of AAA events but only PWRI significantly improved the risk stratification compared to aortic diameter alone. KEY POINTS: • Aortic diameter is an imperfect measure of abdominal aortic aneurysm (AAA) rupture risk. • This observational study of 210 participants found that peak wall stress (PWS) and peak wall rupture index (PWRI) predicted the risk of aortic rupture or AAA repair. • PWRI, but not PWS, significantly improved the risk stratification for AAA events compared to aortic diameter alone.

The predictive value of four serum biomarkers for major adverse events in patients with small abdominal aortic aneurysm.

BACKGROUND: The primary aim of this study was to test which of a group of four inflammation and thrombosis biomarkers were independently predictive of major adverse cardiovascular events (MACE) in patients with small abdominal aortic aneurysm (AAA). METHODS: A total of 471 participants with a 30- to 54-mm AAA had serum C-reactive protein (CRP), fibrinogen, neutrophil-lymphocyte ratio (NLR), and homocysteine measured. The primary outcome was MACE, which was defined as the first occurrence of myocardial infarction, stroke, or cardiovascular death. The association of biomarkers with events was assessed using Kaplan-Meier and Cox proportional hazard analyses. The net improvement in risk of event categorization with addition of a biomarker to clinical risk factors alone was assessed using net reclassification index. RESULTS: Participants were followed for a median of 2.4 years (interquartile range, 0.8-5.4 years), and 102 (21.7%) had a MACE. The incidence of MACE was 13.2% in participants with CRP >3.0 mg/L, compared with 10.1% in those with CRP ≤3.0 mg/L at 2.5 years (P = .047). After adjusting for other risk factors, higher CRP was associated with a significantly higher risk of MACE (hazard ratio, 1.19; 95% confidence interval, 1.05-1.35). None of the other biomarkers were associated with the risk of MACE. According to the net reclassification index, CRP significantly improved the risk classification of MACE compared with clinical risk factors alone. CONCLUSIONS: CRP can assist in classification of risk of MACE for patients with small AAA.

Association of Oral Anticoagulation Prescription with Clinical Events in Patients with an Asymptomatic Unrepaired Abdominal Aortic Aneurysm.

BACKGROUND: Most abdominal aortic aneurysms (AAA) have large volumes of intraluminal thrombus which has been implicated in promoting the risk of major adverse events. The aim of this study was to examine the association of therapeutic anticoagulation with AAA-related events and major adverse cardiovascular events (MACE) in patients with an unrepaired AAA. METHODS: Patients with an asymptomatic unrepaired AAA were recruited from four sites in Australia. The primary outcome was the combined incidence of AAA repair or AAA rupture-related mortality (AAA-related events). The main secondary outcome was MACE (the combined incidence of myocardial infarction, stroke, or cardiovascular death). The associations of anticoagulation with these outcomes were assessed using Cox proportional hazard analyses (reporting hazard ratio, HR, and 95% confidence intervals, CI) to adjust for other risk factors. RESULTS: A total of 1161 patients were followed for a mean (standard deviation) of 4.9 (4.0) years. Of them, 536 (46.2%) patients had a least one AAA-related event and 319 (27.5%) at least one MACE. In the sample, 98 (8.4%) patients were receiving long-term therapeutic anticoagulation using warfarin (84), apixaban (7), rivaroxaban (6), or dabigatran (1). Prescription of an anticoagulant was associated with a reduced risk of an AAA-related event (adjusted HR 0.61; 95% CI 0.42, 0.90, p = 0.013), but not MACE (HR 1.16; 95% CI 0.78, 1.72, p = 0.476). CONCLUSIONS: These findings suggest that AAA-related events but not MACE may be reduced in patients prescribed an anticoagulant medication. Due to the inherent biases of observational studies, a randomized controlled trial is needed to assess whether anticoagulation reduces the risk of AAA-related events.

Effect of Telmisartan on the Peak Wall Stress and Peak Wall Rupture Index of Small Abdominal Aortic Aneurysms: An Exploratory Analysis of the TEDY Trial.

OBJECTIVE: This study was an unplanned exploratory analysis of a subset of participants from the Telmisartan in the Management of Abdominal Aortic Aneurysm (TEDY) trial. It aimed to assess the efficacy of the angiotensin 1 receptor blocker telmisartan in reducing abdominal aortic aneurysm (AAA) peak wall stress (PWS) and peak wall rupture index (PWRI) among individuals with small AAAs. METHODS: Participants with AAAs measuring 35 - 49 mm in maximum diameter were randomised to receive telmisartan 40 mg or identical placebo in the TEDY trial. Participants who had computed tomography angiography performed at entry and at least one other time point during the trial (12 or 24 months) were included in the current study. Orthogonal AAA diameter, PWS, and PWRI were measured using previously validated methods. The annual change in PWS and PWRI from baseline was compared between participants allocated telmisartan or placebo using linear mixed effects models. These models were either unadjusted or adjusted for risk factors that were different in the groups at entry (p < .100) or systolic blood pressure (SBP) at one year. RESULTS: Of the 207 participants recruited to TEDY, 124 were eligible for inclusion in this study. This study included 65 and 59 participants from the telmisartan and placebo groups, respectively. The PWS and PWRI were not significantly different in the two groups at baseline. Participants allocated telmisartan had a slower annual increase in PWS (-4.19; 95% CI -8.24, -0.14 kPa/year; p = .043) and PWRI (-0.014; 95% CI -0.026, -0.001; p = .032) compared with those allocated placebo after adjusting for risk factors. After adjustment for SBP at one year, telmisartan did not significantly reduce annual increases in PWS or PWRI. CONCLUSION: The findings of this study suggest that telmisartan limits the rate of increase in PWS and PWRI of small AAAs by reducing blood pressure.

Athero-occlusive Disease Appears to be Associated with Slower Abdominal Aortic Aneurysm Growth: An Exploratory Analysis of the TEDY Trial.

OBJECTIVE: The role of atherosclerosis in abdominal aortic aneurysm (AAA) pathogenesis is controversial. The aim of this study was to compare AAA growth in patients who did and did not have concurrent athero-occlusive disease (AOD). METHODS: Patients with an AAA measuring 35 - 49 mm in maximum diameter were recruited as part of the TElmisartan in the management of abdominal aortic aneurysm (TEDY) trial. TEDY participants who had infrarenal aortic volume and orthogonal diameter assessed by computed tomography at entry and at least one other time point during the trial (12 and/or 24 months) were included. AOD was defined by prior diagnoses of coronary heart disease, stroke, or peripheral arterial disease or an ankle brachial pressure index < 0.90. The increase in AAA volume and diameter from entry for participants who did and did not have AOD was assessed using linear mixed effects models; 131 of the 210 participants recruited to TEDY were included. RESULTS: In an unadjusted analysis, the mean (95% confidence interval) annual increases in AAA volume and diameter for participants with AOD were 3.26 (0.82 - 5.70) cm3 and 0.70 (0.19 - 1.22) mm slower than those without AOD, p = .008 and .007 respectively. The association between AOD and significantly slower AAA growth was maintained after adjusting for risk factors and medications, significantly unequally distributed between participants with and without an AOD diagnosis. CONCLUSION: In an exploratory analysis of a selective cohort from the TEDY trial, AOD was associated with slower AAA growth. Validation of these findings in other cohorts is needed.

Association of chronic venous disease with major adverse cardiovascular events.

OBJECTIVE: The aim of the present study was to examine whether severe chronic venous disease (CVD) is associated with a greater risk of major adverse cardiovascular events (MACE) compared with mild CVD. METHODS: Participants with CVD were prospectively recruited from outpatient vascular departments at two hospitals in North Queensland, Australia. CVD severity was ascertained by vascular specialists using the CEAP (clinical, etiologic, anatomic, pathophysiologic) classification. MACE, defined as myocardial infarction, stroke, or cardiovascular death, were identified from the outpatient follow-up and linked medical records. Kaplan-Meier and Cox proportional hazard analyses were used to examine the association of CVD severity with the occurrence of MACE. A subanalysis was performed in which participants with CEAP C5 and C6 (severe CVD) were compared with those with CEAP C2 to C4 (mild CVD). RESULTS: A total of 774 participants were included and followed up for a median of 3.09 years (interquartile range, 1.09-8.14 years). The participants with C6 CVD (n = 69) had a threefold greater risk of MACE (hazard ratio, 3.03; 95% confidence interval, 1.02-9.03; P = .046) compared with those with C2 CVD (n = 326) after adjusting for other risk factors. Participants with severe CVD had an increased risk of MACE compared with those with mild CVD (adjusted hazard ratio, 2.37; 95% confidence interval, 1.12-5.04; P = .024). CONCLUSIONS: Individuals with severe CVD have an increased risk of MACE compared with those with mild CVD, independently of traditional risk factors. Further research is required to clarify the cause of the excess risk.

Cohort Study Examining the Association of Immunosuppressant Drug Prescription With Major Adverse Cardiovascular and Limb Events in Patients With Peripheral Artery Disease.

AIM: Immune activation is strongly implicated in atherosclerotic plaque instability, however, the effect of immunosuppressant drugs on cardiovascular events in patients with peripheral artery disease (PAD) is not known. The aim of this study was to assess whether prescription of one or more immune suppressant drugs was associated with a lower risk of major adverse cardiovascular (MACE; i.e. myocardial infarction, stroke or cardiovascular events) or limb events (MALE; i.e. major amputation or requirement for peripheral revascularization) in patients with PAD. METHODS: A total of 1506 participants with intermittent claudication (n = 872) or chronic limb threatening ischemia (CLTI; n = 634) of whom 53 (3.5%) were prescribed one or more immunosuppressant drugs (prednisolone 41; methotrexate 17; leflunomide 5; hydroxychloroquine 3; azathioprine 2; tocilizumab 2; mycophenolate 1; sulfasalazine 1; adalimumab 1) were recruited from 3 Australian hospitals. Participants were followed for a median of 3.9 (inter-quartile range 1.2, 7.3) years. The association of immunosuppressant drug prescription with MACE or MALE was examined using Cox proportional hazard analyses. RESULTS: After adjusting for other risk factors, prescription of an immunosuppressant drug was associated with a significantly greater risk of MACE (Hazard ratio, HR, 1.83, 95% confidence intervals, CI, 1.11, 3.01; P = 0.017) but not MALE (HR 1.32, 95% CI 0.90, 1.92; P = 0.153). In a sub-analysis restricted to participants with CLTI findings were similar: MACE (HR 2.44, 95% CI 1.32, 4.51; P = 0.005); MALE (HR 1.38, 95% CI 0.87, 2.19; P = 0.175); major amputation (HR 1.37, 95% CI 0.49, 3.86; P = 0.547). CONCLUSIONS: This cohort study suggested that immunosuppressant drug therapy is associated with a greater risk of MACE amongst patients with PAD.

Cohort Study Examining the Prevalence and Relationship with Outcome of Standard Modifiable Risk Factors in Patients with Peripheral Artery Occlusive and Aneurysmal Disease.

OBJECTIVE: The aim was to examine the presentation and outcome of patients with peripheral artery occlusive and aneurysmal disease (POAD) in relation to standard modifiable cardiovascular risk factors (SMuRFs; i.e., hypertension, diabetes, hypercholesterolaemia, and smoking). METHODS: A total of 2 129 participants with POAD were recruited from three vascular clinics in Queensland, Australia. SMuRFs were defined using established criteria. Participants were followed via outpatient appointments and linked data to record the primary outcome event of major adverse cardiovascular events (MACE). The association between SMuRFs and MACE was assessed using Cox proportional hazard analysis. Subanalyses examined the association of individual SMuRFs with MACE and assessed findings separately in participants with occlusive and aneurysmal disease. RESULTS: At recruitment 71 (3.3%), 551 (25.9%), 977 (45.9%), 471 (22.1%), and 59 (2.8%) participants had zero, one, two, three, and four SMuRFs. During a median follow up of 2.6 (interquartile range 0.4, 6.2) years, the risk of MACE was progressively higher with the increasing numbers of SMuRFs (adjusted hazard ratio [HR] 95% confidence interval [CI] 4.09, 1.29 - 12.91; 4.28, 1.37 - 13.41; 5.82, 1.84 - 18.39; and 9.42, 2.77 - 32.08; for one, two, three, or four SMuRFs, respectively) by comparison with those who were SMuRF-less at recruitment. Participants with occlusive disease were significantly more likely to have a greater number of SMuRFs than those with aneurysmal disease. In a subanalysis, there was a significantly higher risk of MACE with three or four SMuRFs in participants presenting with either occlusive or aneurysmal disease compared with those who were SMuRF-less. Hypertension, diabetes, and smoking but not hypercholesterolaemia were independently associated with increased risk of MACE. CONCLUSION: Very few patients presenting with POAD had no SMuRFs. There was a progressive increase in the risk of MACE in relation to the number of SMuRFs identified at entry.

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.

Editor's Choice - Cohort Study Examining the Association Between Abdominal Aortic Size and Major Adverse Cardiovascular Events in Patients with Aortic and Peripheral Occlusive and Aneurysmal Disease.

OBJECTIVE: The aim of this study was to examine whether there were independent associations between abdominal aortic diameter, size index, and height index and the risk of major adverse events in patients referred for treatment of various types of aortic and peripheral occlusive and aneurysmal disease (APOAD). METHODS: In total, 1 752 participants with a variety of APOADs were prospectively recruited between 2002 and 2020 and had a maximum abdominal aortic diameter, aortic size index (aortic diameter relative to body surface area), and aortic height index (aortic diameter relative to height) measured by ultrasound at recruitment. Participants were followed for a median of 4.6 years (interquartile range 2.0 - 8.0 years) to record outcome events, including major adverse cardiovascular events (MACE), peripheral artery surgery, abdominal aortic aneurysm (AAA) events (rupture or repair), and all cause mortality. The association between aortic size and events was assessed using Cox proportional hazard analysis. The ability of aortic size to improve risk of events classification was assessed using the net reclassification index (NRI). RESULTS: After adjusting for other risk factors, larger aortic diameter was associated with an increased risk of MACE (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.05 - 1.31), requirement for peripheral artery surgery (HR 2.05, 95% CI 1.90 - 2.22), AAA events (HR 3.01, 95% CI 2.77 - 3.26), and all cause mortality (HR 1.20, 95% CI 1.08 - 1.32). Findings were similar for aortic size and aortic height indices. According to the NRI, all three aortic size measures significantly improved classification of risk of peripheral artery surgery and AAA events but not MACE. Aortic size index, but not aortic diameter or aortic height index, significantly improved the classification of all cause mortality risk. CONCLUSION: Larger abdominal aortic diameter, size index, and height index are all independently associated with an increased risk of major adverse events in patients with established vascular disease.

Editor's Choice - Association Between Metformin Prescription and Abdominal Aortic Aneurysm Growth and Clinical Events: a Systematic Review and Meta-Analysis.

OBJECTIVE: A meta-analysis of the association between metformin prescription and abdominal aortic aneurysm (AAA) growth and events (rupture or surgical repair) was performed. METHODS: Open source databases were searched for observational studies reporting the association between metformin prescription and AAA growth or events. Meta-analyses were performed using random effects models. The risk of bias of included studies was assessed using a quality assessment tool developed in a previous systematic review. Sensitivity analyses restricted to people with diabetes, leave one out analyses, and an individual patient risk factor adjusted sub-analysis were performed. Funnel plots assessed reporting bias. RESULTS: Eight studies comprising 153 553 patients were included, of whom 35 240 were and 118 313 were not prescribed metformin. Pooled weighted mean (± standard deviation) AAA growth was significantly reduced in patients prescribed metformin (0.9 ± 0.4 mm/year) compared with those not receiving the medication (1.8 ± 0.4 mm/year; weighted mean difference [WMD] 0.8 mm/year, 95% confidence interval [CI] 0.5 - 1.1; p < .001; I2 = 89%). Leave one out analysis suggested that the significance of findings did not change after removal of individual studies. A sub-analysis within people with diabetes suggested that metformin reduced AAA growth (WMD 0.7 mm/year, 95% CI 0.3 - 1.0). Metformin prescription was associated with a reduced risk of AAA events (risk ratio 0.6, 95% CI 0.4 - 0.9, p = .028). Three, four, and one studies had low, moderate, and high risk of bias, respectively. Individual patient data analysis suggested that metformin prescription slowed annual AAA growth by 0.5 mm/year (95% CI 0.2 - 0.7). The GRADE summary suggested that the certainty of evidence that metformin limited AAA growth and prevented AAA events was very low. CONCLUSION: Observational studies suggest that metformin prescription is associated with a clinically important significant reduction in both growth and clinically relevant events in people with AAA. These findings support the need for randomised trials to examine the benefit of metformin.

Systematic review and Meta-Analysis of Mendelian randomisation analyses of Abdominal aortic aneurysms.

INTRODUCTION: Mendelian randomisation (MR) has been suggested to be able to overcome biases of observational studies, but no meta-analysis is available on MR studies on abdominal aortic aneurysm (AAA). This systematic review and Meta-analysis examined the evidence of causal risk factors for AAA identified in MR studies. METHODS: Publicly available databases were systematically searched for MR studies that reported any causal risk factors for AAA diagnosis. Meta-analyses were performed using random effect models and reported as odds ratio (OR) and 95% confidence intervals (CI). Study quality was assessed using a modified version of Strengthening the Reporting of Mendelian Randomisation Studies (STROBE-MR) guidelines. RESULTS: Sixteen MR studies involving 34,050 patients with AAA and 2,205,894 controls were included. Meta-analyses suggested that one standard deviation increase in high density lipoprotein (HDL) significantly reduced (OR: 0.66, 95% CI: 0.61, 0.72) and one standard deviation increase in low density lipoprotein (LDL) significantly increased the risk (OR: 1.68, 95%, CI: 1.55, 1.82) of AAA. One standard deviation increase in triglycerides did not significantly increase the risk of AAA (OR: 1.21, 95% CI: 0.86, 1.71). Quality assessment suggested that ten and five studies were of low and moderate risk of bias respectively, with one study considered as high risk of bias. CONCLUSION: This meta-analysis suggests LDL and HDL are positive and negative casual risk factors for AAA.

Major amputation rates and outcomes for Aboriginal and Torres Strait Islander and non-Indigenous people in North Queensland Australia between 2000 and 2015.

BACKGROUND: This study estimated the incidence of major amputation for people in North Queensland, Australia, examined changes in amputation rates over time and investigated survival after major amputation. METHODS: This was a retrospective study of patients who underwent a major amputation above the ankle between 2000 and 2015. Major amputation rates and incidence rate ratios (IRR) were calculated using census data to define the at-risk population. Associations between risk factors and calendar year with major amputation were assessed using quasipoisson regression. Kaplan-Meier survival and Cox-proportional hazard analyses estimated the incidence of and risk factors for all-cause mortality. RESULTS: The annual incidence of major amputation was estimated to be greater in Aboriginal and Torres Strait Islanders than non-Indigenous people (IRR 2.75, 95 % CI 1.92 to 3.84). After adjusting for population growth, the annual incidence of major amputations did not change significantly over time for either groups. Aboriginal and Torres Strait Islander people were at greater risk of all-cause mortality after major amputation compared to non-Indigenous people, although this association was not significant after adjusting for other risk factors (hazard ratio 1.24, 95 % CI 0.82 to 1.90). CONCLUSIONS: The incidence of major amputation in North Queensland has not reduced over time, indicating the need for better preventative treatments, particularly in Aboriginal and Torres Strait Islander people.

Systematic review of genome-wide association studies of abdominal aortic aneurysm.

BACKGROUND AND AIMS: Abdominal aortic aneurysm (AAA) is an important cause of death worldwide and has an estimated heritability between 70 and 77%. Genome-wide association studies (GWAS) are an established way to discover genetic risk variants. The aim of this study was to systematically review the findings and quality of previous AAA GWAS. METHODS: The Medline, PubMed, Web of Science and relevant genetic databases were searched to identify previous AAA GWAS. A framework was developed to grade the methodological quality of the GWAS. Data from included studies were extracted to assess methods and findings. RESULTS: Eight case-control studies were included. Thirty-three of the 38 total single nucleotide polymorphisms (SNPs) previously reported were associated with AAA diagnosis at genome-wide significance (p < 5.0 × 10-8). The CDKN2B antisense RNA-1 gene had the most significant association with AAA diagnosis (p = 6.94 × 10-29 and p = 1.54 × 10-33 for rs4007642 and rs10757274 respectively). Age, sex and smoking history were not reported for the complete cohort in any of the included studies, although five of the eight studies adjusted or matched for at least two confounding variables. All included studies had important design limitations including lack of sample size estimation, inconsistent case and control ascertainment and limited phenotyping of the AAAs. AAA growth was assessed in one GWAS, however, no significant associations with the reported SNPs were found. CONCLUSIONS: This systematic review identified 33 SNPs associated with AAA diagnosis at genome-wide significance previously validated in multiple cohorts. The association between SNPs and AAA growth was not adequately examined. Previous GWAS have a number of design limitations.

Systematic Review and Meta-Analysis of Peak Wall Stress and Peak Wall Rupture Index in Ruptured and Asymptomatic Intact Abdominal Aortic Aneurysms.

Background Prior studies have suggested aortic peak wall stress (PWS) and peak wall rupture index (PWRI) can estimate the rupture risk of an abdominal aortic aneurysm (AAA), but whether these measurements have independent predictive ability over assessing AAA diameter alone is unclear. The aim of this systematic review was to compare PWS and PWRI in participants with ruptured and asymptomatic intact AAAs of similar diameter. Methods and Results Web of Science, Scopus, Medline, and The Cochrane Library were systematically searched to identify studies assessing PWS and PWRI in ruptured and asymptomatic intact AAAs of similar diameter. Random-effects meta-analyses were performed using inverse variance-weighted methods. Leave-one-out sensitivity analyses were conducted to assess the robustness of findings. Risk of bias was assessed using a modification of the Newcastle-Ottawa scale and standard quality assessment criteria for evaluating primary research papers. Seven case-control studies involving 309 participants were included. Meta-analyses suggested that PWRI (standardized mean difference, 0.42; 95% CI, 0.14-0.70; P=0.004) but not PWS (standardized mean difference, 0.13; 95% CI, -0.18 to 0.44; P=0.418) was greater in ruptured than intact AAAs. Sensitivity analyses suggested that the findings were not dependent on the inclusion of any single study. The included studies were assessed to have a medium to high risk of bias. Conclusions Based on limited evidence, this study suggested that PWRI, but not PWS, is greater in ruptured than asymptomatic intact AAAs of similar maximum aortic diameter.

Effect of blood pressure lowering drugs and antibiotics on abdominal aortic aneurysm growth: a systematic review and meta-analysis.

OBJECTIVE: There is currently no medical treatment proven to limit abdominal aortic aneurysm (AAA) progression. The aim of this systematic review and meta-analysis was to pool data from previous randomised controlled trials assessing the efficacy of blood pressure-lowering and antibiotic medications in limiting AAA growth and AAA-related events, that is, rupture or repair. METHODS: A systematic literature search was performed to identify randomised controlled trials that examined the efficacy of blood pressure-lowering medications or antibiotics in reducing AAA growth and AAA-related events. AAA growth (mm/year) was measured by ultrasound or computed tomography imaging. Meta-analyses were performed using random effects models. A subanalysis was conducted including trials that investigated tetracycline or macrolide antibiotics. RESULTS: Ten randomised controlled trials including 2045 participants with an asymptomatic AAA were included. Follow-up was between 18 and 63 months. Neither blood pressure-lowering medications (mean growth±SD 2.0±2.4 vs 2.3±2.7 mm/year; standardised mean difference (SMD) -0.07, 95% CI -0.19 to 0.06; p=0.288) or antibiotics (mean growth±SD 2.6±2.1 vs 2.6±2.5 mm/year; SMD -0.11, 95% CI -0.38 to 0.16; p=0.418) reduced AAA growth or AAA-related events (blood pressure-lowering medications: 92 vs 95 events; risk ratio (RR) 0.86, 95% CI 0.66 to 1.11; p=0.244; and antibiotics: 69 vs 73 events; RR 0.93, 95% CI 0.69 to 1.25; p=0.614). The subanalysis of antibiotics showed similar results. CONCLUSIONS: This meta-analysis suggests that neither blood pressure-lowering medications or antibiotics limit growth or clinically relevant events in people with AAAs.