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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

  • Jonathan Golledge
    Correspondence
    Corresponding author. Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, 4811, Australia.
    Affiliations
    Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia

    The Department of Vascular and Endovascular Surgery, The Townsville University Hospital, Townsville, Queensland, Australia

    The Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland, Australia
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  • Ramesh Velu
    Affiliations
    The Department of Vascular and Endovascular Surgery, The Townsville University Hospital, Townsville, Queensland, Australia
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  • Frank Quigley
    Affiliations
    The Mater Hospital, Townsville, Queensland, Australia
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  • Jason Jenkins
    Affiliations
    Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
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  • Tejas P. Singh
    Affiliations
    Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia

    The Department of Vascular and Endovascular Surgery, The Townsville University Hospital, Townsville, Queensland, Australia
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Published:November 02, 2021DOI:https://doi.org/10.1016/j.ejvs.2021.09.011

      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.

      Keywords

      Abdominal aortic diameter has been associated with the risk of adverse events in healthy individuals; however, its predictive ability in patients with established vascular disease is unknown. This prospective observational study found that larger abdominal aortic diameter, size index, and height index were independently associated with an increased risk of major adverse cardiovascular events, peripheral artery surgery, abdominal aortic aneurysm (AAA) events, and all cause mortality over a median follow up of approximately 4.6 years. Abdominal aortic size index significantly improved the classification of risk of peripheral artery surgery, AAA events, and all cause mortality over clinical risk factors alone.

      Introduction

      Abdominal aortic ultrasound imaging is performed in many high income countries to screen for an abdominal aortic aneurysm (AAA).
      • Chaikof E.L.
      • Dalman R.L.
      • Eskandari M.K.
      • Jackson B.M.
      • Lee W.A.
      • Mansour M.A.
      • et al.
      The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic aneurysm.
      ,
      • Wanhainen A.
      • Verzini F.
      • Van Herzeele I.
      • Allaire E.
      • Bown M.
      • Cohnert T.
      • et al.
      Editor's Choice - European Society for Vascular Surgery (ESVS) 2019 Clinical Practice Guidelines on the Management of Abdominal Aorto-iliac Artery Aneurysms.
      While abdominal aortic imaging is performed to identify large AAAs requiring elective surgical repair, aortic size, both in the aneurysmal
      Mortality results for randomised controlled trial of early elective surgery or ultrasonographic surveillance for small abdominal aortic aneurysms. The UK Small Aneurysm Trial Participants.
      ,
      • Forsdahl S.H.
      • Solberg S.
      • Singh K.
      • Jacobsen B.K.
      Abdominal aortic aneurysms, or a relatively large diameter of non-aneurysmal aortas, increase total and cardiovascular mortality: the Tromso study.
      and non-aneurysmal
      • Forsdahl S.H.
      • Solberg S.
      • Singh K.
      • Jacobsen B.K.
      Abdominal aortic aneurysms, or a relatively large diameter of non-aneurysmal aortas, increase total and cardiovascular mortality: the Tromso study.
      • Freiberg M.S.
      • Arnold A.M.
      • Newman A.B.
      • Edwards M.S.
      • Kraemer K.L.
      • Kuller L.H.
      Abdominal aortic aneurysms, increasing infrarenal aortic diameter, and risk of total mortality and incident cardiovascular disease events: 10-year follow-up data from the Cardiovascular Health Study.
      • Norman P.
      • Le M.
      • Pearce C.
      • Jamrozik K.
      Infrarenal aortic diameter predicts all-cause mortality.
      range, can provide valuable information about the mortality risk.
      • Norman P.E.
      • Muller J.
      • Golledge J.
      The cardiovascular and prognostic significance of the infrarenal aortic diameter.
      Abdominal aortic diameter larger than the normal range has been associated with an increased risk of both cardiovascular and all cause mortality in these healthy populations.
      • Norman P.E.
      • Muller J.
      • Golledge J.
      The cardiovascular and prognostic significance of the infrarenal aortic diameter.
      Some studies have suggested a J shaped relationship between mortality and abdominal aortic diameter, with small aortic diameter, as well as large aortic diameter, associated with an increased mortality risk
      • Norman P.
      • Le M.
      • Pearce C.
      • Jamrozik K.
      Infrarenal aortic diameter predicts all-cause mortality.
      and coronary heart disease prevalence,
      • Jones G.T.
      • Drinkwater B.
      • Blake-Barlow A.
      • Hill G.B.
      • Williams M.J.A.
      • Krysa J.
      • et al.
      Both small and large infrarenal aortic size is associated with an increased prevalence of ischaemic heart disease.
      compared with a diameter in the normal range. As a result, abdominal aortic diameter has been suggested as a valuable measure of the risk of major adverse cardiovascular events (MACE), which can be used to help with decisions about the need for primary prevention medical therapies.
      • Norman P.E.
      • Muller J.
      • Golledge J.
      The cardiovascular and prognostic significance of the infrarenal aortic diameter.
      The maximum diameter of the ascending aorta, usually reported relative to body surface area (defined as aortic size index) or height (aortic height index), has also been associated with the risk of major adverse events.
      • Qazi S.
      • Massaro J.M.
      • Chuang M.L.
      • D'Agostino R.B.
      • Sr .,
      • Hoffmann U.
      • O'Donnell C.J.
      Increased aortic diameters on multidetector computed tomographic scan are independent predictors of incident adverse cardiovascular events: the Framingham Heart Study.
      • Zafar M.A.
      • Li Y.
      • Rizzo J.A.
      • Charilaou P.
      • Saeyeldin A.
      • Velasquez C.A.
      • et al.
      Height alone, rather than body surface area, suffices for risk estimation in ascending aortic aneurysm.
      • Davies R.R.
      • Gallo A.
      • Coady M.A.
      • Tellides G.
      • Botta D.M.
      • Burke B.
      • et al.
      Novel measurement of relative aortic size predicts rupture of thoracic aortic aneurysms.
      Aortic size index has also recently been proposed as a better measure of relative abdominal aortic size.
      • Jones G.T.
      • Drinkwater B.
      • Blake-Barlow A.
      • Hill G.B.
      • Williams M.J.A.
      • Krysa J.
      • et al.
      Both small and large infrarenal aortic size is associated with an increased prevalence of ischaemic heart disease.
      ,
      • Jones G.T.
      • Sandiford P.
      • Hill G.B.
      • Williams M.J.A.
      • Khashram M.
      • Tilyard M.W.
      • et al.
      Correcting for body surface area identifies the true prevalence of abdominal aortic aneurysm in screened women.
      However, no previous study has compared the associations of abdominal aortic diameter, size index, and height index with the incidence of major adverse events. Abdominal aortic imaging is commonly performed in patients referred to vascular surgeons for the management of aortic and peripheral occlusive and aneurysmal disease (APOAD). It is unclear if abdominal aortic size in these heterogeneous groups of patients with established vascular disease, all of whom have a higher risk of events than healthy community populations, is predictive of major adverse events. If abdominal aortic size is also predictive of adverse events in patients with established vascular disease it may be useful in risk stratifying them to assist in decisions about the intensity of medical management. 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 to vascular specialists for treatment of various types of APOAD.

      Methods

      Study design and participants

      The study was designed as part of an ongoing prospective cohort investigation that began in 2002 and aimed to identify risk factors associated with the outcome of peripheral vascular disease.
      • Golledge J.
      • Rowbotham S.
      • Velu R.
      • Quigley F.
      • Jenkins J.
      • Bourke M.
      • et al.
      Association of serum lipoprotein (a) with the requirement for a peripheral artery operation and the incidence of major adverse cardiovascular events in people with peripheral artery disease.
      • Singh T.P.
      • Moxon J.V.
      • Healy G.N.
      • Cadet-James Y.
      • Golledge J.
      Presentation and outcomes of indigenous Australians with peripheral artery disease.
      • Singh T.P.
      • Wong S.
      • Quigley F.
      • Jenkins J.
      • Golledge J.
      Association of gout with major adverse cardiovascular events and all-cause mortality in patients with peripheral artery disease.
      To be eligible for the current study participants had to have a diagnosis of an APOAD and be recruited from the outpatient vascular services at The Townsville University Hospital, the Mater Hospital Townsville, or The Royal Brisbane and Women’s Hospital in Queensland, Australia, between February 2002 and November 2020 and have attended at least one follow up review. Participants presenting with any of the following APOADs were eligible: (1) visceral artery disease (defined as ≥ 50% stenosis or occlusion of one or more renal or mesenteric arteries); (2) carotid artery stenosis (defined as ≥ 50% stenosis or occlusion of at least one carotid artery associated with or without focal neurological symptoms, such as stroke, transient ischaemic attack, or amaurosis fugax);
      • Palamuthusingam D.
      • Quigley F.
      • Golledge J.
      Implications of the finding of no significant carotid stenosis based on data from a regional Australian vascular unit.
      (3) intermittent claudication (defined as leg pain on exertion relieved by rest associated with lower limb artery ≥ 50% stenosis or occlusion);
      • Nastasi D.R.
      • Moxon J.V.
      • Norman R.
      • Trollope A.F.
      • Rowbotham S.
      • Quigley F.
      • et al.
      The cost-effectiveness of intensive low-density lipoprotein cholesterol lowering in people with peripheral artery disease.
      (4) aneurysm of the aorta or peripheral arteries (AAA was defined as maximum abdominal aortic diameter ≥ 30 mm)
      • Wanhainen A.
      • Verzini F.
      • Van Herzeele I.
      • Allaire E.
      • Bown M.
      • Cohnert T.
      • et al.
      Editor's Choice - European Society for Vascular Surgery (ESVS) 2019 Clinical Practice Guidelines on the Management of Abdominal Aorto-iliac Artery Aneurysms.
      – iliac artery aneurysm was defined by common or internal iliac artery diameters ≥ 15 and ≥ 8 mm, respectively,
      • Wanhainen A.
      • Verzini F.
      • Van Herzeele I.
      • Allaire E.
      • Bown M.
      • Cohnert T.
      • et al.
      Editor's Choice - European Society for Vascular Surgery (ESVS) 2019 Clinical Practice Guidelines on the Management of Abdominal Aorto-iliac Artery Aneurysms.
      femoral artery aneurysm was defined by a common femoral or superficial femoral artery diameter of ≥ 15 mm, and popliteal artery aneurysm was defined as popliteal artery diameter ≥ 9 mm;
      • Magee R.
      • Quigley F.
      • McCann M.
      • Buttner P.
      • Golledge J.
      Growth and risk factors for expansion of dilated popliteal arteries.
      (5) chronic limb threatening ischaemia (CLTI; rest pain, ischaemic ulceration, or gangrene secondary to peripheral artery disease, defined by the absence of lower limb pulses, an ankle brachial pressure index < 0.9 and/or significant stenosis (≥ 50%) or occlusion of lower limb arteries).
      • Nastasi D.R.
      • Moxon J.V.
      • Norman R.
      • Trollope A.F.
      • Rowbotham S.
      • Quigley F.
      • et al.
      The cost-effectiveness of intensive low-density lipoprotein cholesterol lowering in people with peripheral artery disease.
      The APOAD was diagnosed by a Royal Australasian College of Surgeons accredited vascular surgeon based on symptoms, clinical examination, and investigations, as previously described.
      • Golledge J.
      • Rowbotham S.
      • Velu R.
      • Quigley F.
      • Jenkins J.
      • Bourke M.
      • et al.
      Association of serum lipoprotein (a) with the requirement for a peripheral artery operation and the incidence of major adverse cardiovascular events in people with peripheral artery disease.
      • Singh T.P.
      • Moxon J.V.
      • Healy G.N.
      • Cadet-James Y.
      • Golledge J.
      Presentation and outcomes of indigenous Australians with peripheral artery disease.
      • Singh T.P.
      • Wong S.
      • Quigley F.
      • Jenkins J.
      • Golledge J.
      Association of gout with major adverse cardiovascular events and all-cause mortality in patients with peripheral artery disease.
      ,
      • Nastasi D.R.
      • Moxon J.V.
      • Norman R.
      • Trollope A.F.
      • Rowbotham S.
      • Quigley F.
      • et al.
      The cost-effectiveness of intensive low-density lipoprotein cholesterol lowering in people with peripheral artery disease.
      Written informed consent was obtained from all participants upon entry into the study. The study was performed in accordance with the Declaration of Helsinki, and ethical approval was granted from the relevant institutional ethics committees (HREC/13/QTHS/125 and HREC/14/QTHS/203).

      Risk factors and medications

      Clinical characteristics collected included age, sex, diabetes, hypertension, smoking, coronary heart disease (CHD), stroke and currently prescribed medications.
      • Golledge J.
      • Cronin O.
      • Iyer V.
      • Bradshaw B.
      • Moxon J.V.
      • Cunningham M.A.
      Body mass index is inversely associated with mortality in patients with peripheral vascular disease.
      Smoking classification was based on smoking history and defined as current smoker (smoked within the last month), previous smoker, or never smoked. Hypertension, diabetes, and stroke were defined by documented history or medical treatment for these conditions. CHD was defined by a history of myocardial infarction (MI), angina, or coronary revascularisation. Prescriptions of aspirin, other antiplatelet drugs, warfarin, or novel oral anticoagulants were recorded and defined as receipt of an antithrombotic drug. Prescription of statins was also recorded. All medication prescriptions were obtained from medical records at the time of recruitment. Body mass index was measured as described previously.
      • Golledge J.
      • Cronin O.
      • Iyer V.
      • Bradshaw B.
      • Moxon J.V.
      • Cunningham M.A.
      Body mass index is inversely associated with mortality in patients with peripheral vascular disease.

      Aortic size assessment

      Maximum anterior to posterior and transverse infrarenal aortic diameters were measured by experienced sonographers using ultrasound machines employed in the vascular laboratories at each site using a standard protocol, as described previously.
      • Ferguson C.D.
      • Clancy P.
      • Bourke B.
      • Walker P.J.
      • Dear A.
      • Buckenham T.
      • et al.
      Association of statin prescription with small abdominal aortic aneurysm progression.
      ,
      • Golledge J.
      • Moxon J.
      • Pinchbeck J.
      • Anderson G.
      • Rowbotham S.
      • Jenkins J.
      • et al.
      Association between metformin prescription and growth rates of abdominal aortic aneurysms.
      Aortic diameter was measured from outer wall to outer wall of the artery in the orthogonal plane.
      • Ferguson C.D.
      • Clancy P.
      • Bourke B.
      • Walker P.J.
      • Dear A.
      • Buckenham T.
      • et al.
      Association of statin prescription with small abdominal aortic aneurysm progression.
      ,
      • Matthews E.O.
      • Pinchbeck J.
      • Elmore K.
      • Jones R.E.
      • Moxon J.V.
      • Golledge J.
      The reproducibility of measuring maximum abdominal aortic aneurysm diameter from ultrasound images.
      The reproducibility of aortic diameter measurements was assessed in each vascular laboratory, with interobserver reproducibility coefficients being < 4 mm as previously reported.
      • Ferguson C.D.
      • Clancy P.
      • Bourke B.
      • Walker P.J.
      • Dear A.
      • Buckenham T.
      • et al.
      Association of statin prescription with small abdominal aortic aneurysm progression.
      • Golledge J.
      • Moxon J.
      • Pinchbeck J.
      • Anderson G.
      • Rowbotham S.
      • Jenkins J.
      • et al.
      Association between metformin prescription and growth rates of abdominal aortic aneurysms.
      • Matthews E.O.
      • Pinchbeck J.
      • Elmore K.
      • Jones R.E.
      • Moxon J.V.
      • Golledge J.
      The reproducibility of measuring maximum abdominal aortic aneurysm diameter from ultrasound images.
      Body surface area was estimated according to the formula proposed by Mosteller.
      • Mosteller R.D.
      Simplified calculation of body-surface area.
      Aortic size index was calculated by dividing maximum aortic diameter (cm) by body surface area (m2), and aortic height index by dividing maximum aortic diameter (cm) by height (m) as described previously.
      • Zafar M.A.
      • Li Y.
      • Rizzo J.A.
      • Charilaou P.
      • Saeyeldin A.
      • Velasquez C.A.
      • et al.
      Height alone, rather than body surface area, suffices for risk estimation in ascending aortic aneurysm.
      ,
      • Davies R.R.
      • Gallo A.
      • Coady M.A.
      • Tellides G.
      • Botta D.M.
      • Burke B.
      • et al.
      Novel measurement of relative aortic size predicts rupture of thoracic aortic aneurysms.

      Definition and assessment of outcomes

      Participants were offered follow up three months after their initial outpatient visit and then annually as the standard care. Outcome data were recorded during clinical reviews on prospectively defined case report forms. Hospital charts and electronic records were also reviewed by a vascular specialist. Outcome data were also obtained from linked hospital admission records from the Queensland Hospital Admitted Patient Data Collection, which is regularly audited to minimise inaccuracies.
      • Golledge J.
      • Rowbotham S.
      • Velu R.
      • Quigley F.
      • Jenkins J.
      • Bourke M.
      • et al.
      Association of serum lipoprotein (a) with the requirement for a peripheral artery operation and the incidence of major adverse cardiovascular events in people with peripheral artery disease.
      • Singh T.P.
      • Moxon J.V.
      • Healy G.N.
      • Cadet-James Y.
      • Golledge J.
      Presentation and outcomes of indigenous Australians with peripheral artery disease.
      • Singh T.P.
      • Wong S.
      • Quigley F.
      • Jenkins J.
      • Golledge J.
      Association of gout with major adverse cardiovascular events and all-cause mortality in patients with peripheral artery disease.
      ,
      • Nastasi D.R.
      • Moxon J.V.
      • Norman R.
      • Trollope A.F.
      • Rowbotham S.
      • Quigley F.
      • et al.
      The cost-effectiveness of intensive low-density lipoprotein cholesterol lowering in people with peripheral artery disease.
      The primary outcome was the first occurrence of a MACE, defined as including MI, stroke, or cardiovascular death. The secondary outcomes included peripheral artery surgical operations, AAA events, and all cause mortality. Peripheral artery surgical operations were defined to include both open surgical and endovascular lower limb peripheral revascularisations, carotid artery revascularisation, AAA, and other aneurysm repairs.
      • Golledge J.
      • Moxon J.V.
      • Rowbotham S.
      • Pinchbeck J.
      • Yip L.
      • Velu R.
      • et al.
      Risk of major amputation in patients with intermittent claudication undergoing early revascularization.
      • Morris D.R.
      • Singh T.P.
      • Moxon J.V.
      • Smith A.
      • Stewart F.
      • Jones R.E.
      • et al.
      Assessment and validation of a novel angiographic scoring system for peripheral artery disease.
      • Morris D.R.
      • Skalina T.A.
      • Singh T.P.
      • Moxon J.V.
      • Golledge J.
      Association of computed tomographic leg muscle characteristics with lower limb and cardiovascular events in patients with peripheral artery disease.
      AAA events were defined to include AAA rupture or requirement for AAA repair.
      • Golledge J.
      • Morris D.R.
      • Pinchbeck J.
      • Rowbotham S.
      • Jenkins J.
      • Bourke M.
      • et al.
      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.
      Decisions about requirement for operative interventions were at the discretion of the treating consultant surgeon but were in line with current international guidelines,
      • Wanhainen A.
      • Verzini F.
      • Van Herzeele I.
      • Allaire E.
      • Bown M.
      • Cohnert T.
      • et al.
      Editor's Choice - European Society for Vascular Surgery (ESVS) 2019 Clinical Practice Guidelines on the Management of Abdominal Aorto-iliac Artery Aneurysms.
      ,
      • Golledge J.
      • Morris D.R.
      • Pinchbeck J.
      • Rowbotham S.
      • Jenkins J.
      • Bourke M.
      • et al.
      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.
      ,
      • Aboyans V.
      • Ricco J.B.
      • Bartelink M.E.L.
      • Bjorck M.
      • Brodmann M.
      • Cohnert T.
      • et al.
      Editor's Choice - 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS).
      including lifestyle limiting intermittent claudication failing to respond to conservative therapy, symptomatic or large asymptomatic AAA, and CLTI.
      • Golledge J.
      • Moxon J.V.
      • Rowbotham S.
      • Pinchbeck J.
      • Yip L.
      • Velu R.
      • et al.
      Risk of major amputation in patients with intermittent claudication undergoing early revascularization.

      Sample size

      The aim was to have adequate power to test the hypothesis that abdominal aortic size was associated with MACE. Previous studies suggest that approximately 20% of people with APOADs have a MACE during short term follow up.
      • Singh T.P.
      • Moxon J.V.
      • Healy G.N.
      • Cadet-James Y.
      • Golledge J.
      Presentation and outcomes of indigenous Australians with peripheral artery disease.
      ,
      • Singh T.P.
      • Wong S.
      • Quigley F.
      • Jenkins J.
      • Golledge J.
      Association of gout with major adverse cardiovascular events and all-cause mortality in patients with peripheral artery disease.
      ,
      • Nastasi D.R.
      • Moxon J.V.
      • Norman R.
      • Trollope A.F.
      • Rowbotham S.
      • Quigley F.
      • et al.
      The cost-effectiveness of intensive low-density lipoprotein cholesterol lowering in people with peripheral artery disease.
      Monte-Carlo simulations suggest that a multivariable regression model is powered sufficiently when 10 outcome events per degree of freedom of the predictor variables are observed.
      • Peduzzi P.
      • Concato J.
      • Kemper E.
      • Holford T.R.
      • Feinstein A.R.
      A simulation study of the number of events per variable in logistic regression analysis.
      Conservatively, assuming an incidence of MACE of 10% and planning to adjust for age, sex, presenting problem (five options), current smoking, diabetes, hypertension, CHD, stroke, and statin and antithrombotic drug prescriptions in the regression models, it was estimated that a sample size of at least 1 500 participants would be required to have adequate power to test the main hypothesis.

      Data analysis

      Data were analysed using SPSS version 25 (IBM, Armonk, NY, USA) and Stata v16.1 (StataCorp, College Station, TX, USA). Continuous data were not normally distributed, as confirmed using the Shapiro–Wilk test, and were presented as median and interquartile range (IQR) and compared between groups using the Kruskal–Wallis test. The distribution of categorical variables between groups was compared using Pearson’s chi square test. Kaplan–Meier curves with log rank test were used to compare the proportion of participants having outcome events. Cox proportional hazard analyses assessed the association between aortic size and outcome events adjusted for age, sex, presenting problem, current smoking, diabetes, hypertension, CHD, stroke, and statin and antithrombotic prescriptions. Results were presented as hazard ratios (HRs) and 95% confidence intervals (CIs). The ability of different aortic size measures to predict outcome events was examined by calculating the net reclassification index (NRI).
      • Golledge J.
      • Ewels C.
      • Muller R.
      • Walker P.J.
      Association of chronic kidney disease categories defined with different formulae with major adverse events in patients with peripheral vascular disease.
      NRI was used to assess whether the addition of the different measures of aortic size to a model incorporating traditional risk factors significantly improved the ability to predict adverse events. A sensitivity analysis was performed to test whether the main findings were similar when participants with more urgent presentations (i.e., AAA measuring ≥ 55 mm, symptomatic carotid artery disease, or CLTI) were excluded. Analyses restricted to male and female participants were also performed. A p value < .05 was considered significant for all of these analyses.

      Results

      Relationship between abdominal aortic size quartiles and risk factors at recruitment

      A total of 1 752 participants presenting with visceral artery disease (n = 85, 4.8%), carotid artery disease (n = 162, 9.2%), aortic or peripheral aneurysm (n = 1 038, 59.2%), intermittent claudication (n = 332, 18.9%), and CLTI (n = 135, 7.7%) were included. Table 1, Table 2 show the relationship between abdominal aortic diameter and size index quartiles and risk factors and medications recorded at the time of recruitment. Older age, male sex, current smoking, CHD, and previous stroke were significantly more common, while diabetes was significantly less common, in participants in higher compared with lower quartiles of aortic diameter and size indices (Table 1, Table 2).
      Table 1Risk factors and medications recorded at recruitment in relation to aortic diameter in 1 752 participants with various types of aortic and peripheral occlusive and aneurysmal disease
      Risk factorAortic diameter – mmp value
      <22.0 (n = 411)22.0–35.9 (n = 450)36.0–47.4 (n = 452)≥ 47.5 (n = 439)
      Age – y65.9 (59.0–72.4)70.7 (64.4–75.7)74.0 (69.0–79.3)73.5 (67.5–78.3)<.001
      Body mass index – kg/m227.0 (23.7–30.6)28.2 (24.3–31.6)27.6 (24.4–30.9)26.9 (24.3– 30.4).092
      Body surface area1.86 (1.72–2.05)2.00 (1.83–2.14)1.98 (1.82–2.15)1.99 (1.80–2.14)<.001
      Male sex245 (59.6)377 (83.8)367 (81.2)372 (84.7)<.001
      Presentation<.001
      Consider all categories of presentation or smoking distribution between groups.
       Visceral artery disease59 (14.4)25 (5.6)1 (0.2)0 (0)
       Carotid artery disease57 (13.9)82 (18.2)13 (2.9)10 (2.3)
       Aortic and peripheral aneurysm17 (4.1)184 (40.9)417 (92.3)420 (95.7)
       Intermittent claudication209 (50.9)117 (26.0)4 (0.9)2 (0.5)
       CLTI69 (16.8)42 (9.3)17 (3.8)7 (1.6)
       Diabetes134 (32.6)139 (30.9)110 (24.3)72 (16.4)<.001
       Hypertension285 (69.3)346 (76.9)344 (76.1)327 (74.5).054
      Smoking<.001
      Consider all categories of presentation or smoking distribution between groups.
       Current124 (30.2)137 (30.4)109 (24.1)130 (29.6)
       Former190 (46.2)248 (55.1)285 (63.1)257 (58.5)
       Never97 (23.6)65 (14.4)58 (12.8)52 (11.9)
      Previous stroke27 (6.6)63 (14.0)47 (10.4)37 (8.4).002
      Coronary heart disease165 (40.1)225 (50.0)213 (47.1)233 (53.1).001
      Statin248 (60.3)293 (65.1)312 (69.0)283 (64.5).067
      Antithrombotic drugs298 (72.5)352 (78.2)322 (71.2)309 (70.4).036
      Data are presented as n (%) or median (interquartile range). CLTI = chronic limb threatening ischaemia.
      Consider all categories of presentation or smoking distribution between groups.
      Table 2Risk factors and medications recorded at recruitment in relation to aortic size index in 1 752 participants with various types of aortic and peripheral occlusive and aneurysmal disease
      Risk factorAortic size index – cm/m2p value
      <1.134 (n = 437)1.134–1.805 (n = 439)1.806–2.402 (n = 438)≥ 2.403 (n = 438)
      Age – y64.5 (58.3–71.2)71.0 (65.9– 76.0)73.6 (69.0–78.6)74.4 (68.0–79.3)<.001
      Body mass index – kg/m228.7 (25.7–32.9)27.5 (24.1–31.0)27.8 (24.6– 31.0)25.6 (22.9–28.4)<.001
      Body surface area2.00 (1.80– 2.17)1.98 (1.80– 2.15)2.00 (1.84–2.15)1.88 (1.72–2.04)<.001
      Male sex299 (68.4)360 (82.0)373 (85.2)329 (75.1)<.001
      Presentation<.001
      Consider all categories of presentation or smoking distribution between groups.
       Visceral artery disease60 (13.7)24 (5.5)1 (0.2)0
       Carotid artery disease68 (15.6)66 (15.0)17 (3.9)11 (2.5)
       Aortic and peripheral aneurysm19 (4.3)201 (45.8)401 (91.6)417 (95.2)
       Intermittent claudication216 (49.4)108 (24.6)5 (1.1)3 (0.7)
       CLTI74 (16.9)40 (9.1)14 (3.2)7 (1.6)
       Diabetes166 (38.0)128 (29.2)96 (21.9)65 (14.8)<.001
       Hypertension320 (73.2)324 (73.8)332 (75.8)326 (74.4).84
      Smoking<.001
      Consider all categories of presentation or smoking distribution between groups.
       Current125 (28.6)134 (30.5)96 (21.9)145 (33.1)
       Former220 (50.3)238 (54.2)287 (65.5)235 (53.6)
       Never92 (21.1)67 (15.3)55 (12.6)58 (13.2)
      Previous stroke29 (6.6)66 (15.0)40 (9.1)39 (8.9)<.001
      Coronary heart disease179 (41.0)214 (48.7)213 (48.6)230 (52.5).006
      Statin268 (61.3)284 (64.7)304 (69.4)280 (63.9).088
      Antithrombotic drugs321 (73.5)331 (75.4)321 (73.3)308 (70.3).40
      Data are presented as n (%) or median (interquartile range). CLTI = chronic limb threatening ischaemia.
      Consider all categories of presentation or smoking distribution between groups.

      Association of abdominal aortic size with outcome events

      Participants were followed for a median of 4.6 years (IQR 2.0 – 8.0). During this period 235 (13.4%), 112 (6.4%), 394 (22.5%), 98 (5.6%), 482 (27.5%), and 16 (0.9%) participants had at least one MI, stroke, lower limb peripheral revascularisation, carotid artery revascularisation, AAA repair, and AAA rupture, respectively. There were 639 (36.5%) deaths of which 349 were due to cardiovascular causes. Larger aortic diameter, size index, and height index were significantly associated with a greater risk of all outcome events in both unadjusted and adjusted analyses (see Figure 1, Figure 2, Figure 3; Table 3).
      Figure 1
      Figure 1Cumulative Kaplan–Meier estimates of the freedom from (A) major adverse cardiovascular event (MACE); (B) peripheral artery surgery; (C) abdominal aortic aneurysm (AAA) events; and (D) all cause mortality according to quartile of abdominal aortic diameter.
      Figure 2
      Figure 2Cumulative Kaplan–Meier estimates of the freedom from (A) major adverse cardiovascular event (MACE); (B) peripheral artery surgery; (C) abdominal artery aneurysm (AAA) events; and (D) all cause mortality according to quartile of abdominal aortic size index.
      Figure 3
      Figure 3Cumulative Kaplan–Meier estimates of the freedom from (A) major adverse cardiovascular event (MACE); (B) peripheral artery surgery; (C) abdominal aortic aneurysm (AAA) events; and (D) all cause mortality according to quartile of abdominal aortic height index.
      Table 3Association between aortic size measurement and major adverse events during the follow up of 1 752 participants with various types of aortic and peripheral occlusive and aneurysmal disease
      EventAortic diameterAortic size indexAortic height index
      UnadjustedAdjustedUnadjustedAdjustedUnadjustedAdjusted
      HR (95% CI)p valueHR (95% CI)p valueHR (95% CI)p valueHR (95% CI)p valueHR (95% CI)p valueHR (95% CI)p value
      Major adverse cardiovascular events
      1.12 (1.04–1.21).0041.17 (1.05–1.31).0061.19 (1.10–1.29)<.0011.28 (1.14–1.42)<.0011.14 (1.06–1.23).0011.19 (1.07–1.34).002
      Any peripheral artery surgical procedure
      1.75 (1.64–1.87)<.0012.05 (1.90–2.22)<.0011.70 (1.59–1.82)<.0012.07 (1.91–2.25)<.0011.73 (1.62–1.86)<.0012.05 (1.90–2.22)<.001
      AAA event
      3.32 (3.11–3.55)<.0013.01 (2.77–3.26)<.0013.37 (3.13–3.62)<.0013.04 (2.78–3.32)<.0013.41 (3.18–3.66)<.0012.98 (2.75–3.24)<.001
      All cause mortality
      1.18 (1.10–1.26)<.0011.20 (1.08–1.32)<.0011.27 (1.19–1.36)<.0011.28 (1.16–1.41)<.0011.20 (1.12–1.28)<.0011.20 (1.09–1.32)<.001
      Analyses adjusted for age, sex, presentation, diabetes, hypertension, coronary heart disease, previous stroke, current smoking, statin, and antithrombotic prescriptions. The aortic size measurements were reported relative to an increase of approximately one standard deviation (aortic diameter 15.8 mm; aortic size index 0.833 cm/m2; aortic height index 0.917 cm/m). HR = hazard ratio; CI = confidence interval; AAA = abdominal aortic aneurysm.

      Ability of abdominal aortic size to predict outcome events

      Based on the NRI, none of the aortic size measures significantly added to the ability of clinical risk factors alone to classify the risk of MACE (Table 4). In contrast, all three aortic size measures significantly improved the classification of risk of peripheral artery surgery and AAA events (Table 4). Only aortic size index, but not aortic diameter or aortic height index, significantly improved the classification of all cause mortality risk (NRI 0.11, 95% CI 0.02 – 0.21; p = .023).
      Table 4Discrimination and reclassification of 1 752 participants with various types of aortic and peripheral occlusive and aneurysmal disease for different major adverse outcomes using aortic diameter, aortic size index, and aortic height index
      ModelsNet reclassification index (95% CI)p value
      Major adverse cardiovascular events
       Clinical risk factors only
       Clinical risk factors + aortic diameter–0.02 (–0.12–0.08).65
       Clinical risk factors + aortic size index0.02 (–0.08–0.12).69
       Clinical risk factors + aortic height index–0.05 (–0.15–0.06).81
      Requirement for peripheral artery surgery
       Clinical risk factors only
       Clinical risk factors + aortic diameter0.54 (0.45–0.64)<.001
       Clinical risk factors + aortic size index0.54 (0.44–0.63)<.001
       Clinical risk factors + aortic height index0.53 (0.43–0.62)<.001
      Abdominal aortic aneurysm events
       Clinical risk factors only
       Clinical risk factors + aortic diameter1.46 (1.35–1.56)<.001
       Clinical risk factors + aortic size index1.37 (1.27–1.47)<.001
       Clinical risk factors + aortic height index1.47 (1.36–1.57)<.001
      All cause mortality
       Clinical risk factors only
       Clinical risk factors + aortic diameter0.03 (–0.07–0.13).57
       Clinical risk factors + aortic size index0.11 (0.02–0.21).023
       Clinical risk factors + aortic height index0.04 (–0.06–0.14).40
      Clinical risk factors includes age, sex, presentation, diabetes, hypertension, coronary heart disease, previous stroke, current smoking, statin, and antithrombotic prescriptions.

      Sensitivity analyses

      In analyses restricted to participants with non-urgent presentations, larger aortic diameter, size index, and height index were significantly associated with a greater risk of all outcome events in both unadjusted and adjusted analyses with the exception of aortic diameter and the risk of MACE (Supplementary Table 1). Based on NRI, aortic diameter and aortic height index, but not aortic size index, significantly added to the ability of clinical risk factors alone to classify the risk of MACE (Supplementary Table 2). All three aortic size measures significantly improved the classification of risk of peripheral artery surgery and AAA events (Supplementary Table 2). None of the aortic size measures significantly improved the classification of all cause mortality risk (Supplementary Table 2).
      In analyses restricted to male participants, larger aortic size index, but not aortic diameter or aortic height index, was significantly associated with a greater risk of MACE in adjusted analyses (Supplementary Table 3). Larger aortic diameter, size index, and height index were significantly associated with a greater risk of all other outcome events in both unadjusted and adjusted analyses (Supplementary Table 3). In female participants, larger aortic diameter, size index and height index were significantly associated with a greater risk of all outcome events in both unadjusted and adjusted analyses (Supplementary Table 4). All three aortic size measures significantly improved the classification of risk of peripheral artery surgery and AAA events in both male and female participants (Supplementary Table 5). Aortic size index and height index significantly improved the classification of risk of all cause mortality over clinical risk factors alone only in female participants (Supplementary Table 5).

      Discussion

      The current study found that larger abdominal aortic diameter, size index, and height index were associated with increased risks of MACE, peripheral artery surgery, AAA events, and all cause mortality over a median follow up of approximately five years in a large number of participants with a variety of APOAD presentations. These associations were independent of traditional risk factors. All three abdominal aortic size measures significantly improved the classification of risk of peripheral artery surgery and AAA events over use of clinical risk factors alone. Only abdominal aortic size index significantly improved the classification of risk of all cause mortality over clinical risk factors alone. Findings were broadly similar when restricted to participants with non-urgent presentations and men and women. The findings demonstrate the value of measuring abdominal aortic size in patients referred to specialist vascular services.
      Previous studies have demonstrated the independent association of large abdominal aortic diameter with increased risk of death in community populations screened for AAA.
      • Forsdahl S.H.
      • Solberg S.
      • Singh K.
      • Jacobsen B.K.
      Abdominal aortic aneurysms, or a relatively large diameter of non-aneurysmal aortas, increase total and cardiovascular mortality: the Tromso study.
      ,
      • Norman P.
      • Le M.
      • Pearce C.
      • Jamrozik K.
      Infrarenal aortic diameter predicts all-cause mortality.
      ,
      • Norman P.E.
      • Muller J.
      • Golledge J.
      The cardiovascular and prognostic significance of the infrarenal aortic diameter.
      Larger abdominal aortic diameter has also been associated with an increased risk of all cause mortality in patients with AAA.
      Mortality results for randomised controlled trial of early elective surgery or ultrasonographic surveillance for small abdominal aortic aneurysms. The UK Small Aneurysm Trial Participants.
      ,
      • Norman P.E.
      • Muller J.
      • Golledge J.
      The cardiovascular and prognostic significance of the infrarenal aortic diameter.
      The novel findings of the current study are firstly that the association between large abdominal aortic diameter and increased mortality risk is also present in populations with established vascular disease, including patients with occlusive artery disease. Approximately 40% of the participants in the current study had occlusive rather than aneurysmal disease. Furthermore, abdominal aortic size in these participants was independently associated with the risk of not only death, but also MACE, peripheral artery surgery, and AAA events. The findings highlight that patients with larger abdominal aortic diameter in the non-aneurysmal, as well as aneurysmal range, referred to vascular services might benefit from intensive medical management to prevent cardiovascular events such as MI, stroke, requirement for surgery, and death.
      The current study also provides novel information on the ability of abdominal aortic size and height index in reclassifying the risk of adverse events. Abdominal aortic size significantly improved the classification of risk of peripheral artery surgery and AAA events over clinical risk factors alone. Only abdominal aortic size index significantly improved the classification of all cause mortality risk. This suggests that aortic size index, rather than abdominal aortic diameter or abdominal aortic height index, may be most useful for classifying the risk of adverse events. The findings need to be validated in other cohorts.
      A number of limitations of the current study should be acknowledged. The study was designed to include a heterogeneous group of patients referred for management of different APOADs. The findings may not be generalisable to other cohorts of more homogenous presentations of peripheral artery disease. The current study is an observational investigation and while the associations presented were adjusted for other key cardiovascular risk factors it is impossible to exclude residual confounding.
      In conclusion, this study shows that larger abdominal aortic diameter, size index and height index are all independently associated with an increased risk of MACE, peripheral artery surgery, AAA events and all cause mortality in patients with established vascular disease.

      Funding

      This study was supported by funding from the National Health and Medical Research Council ( 1063476 and 1180736 ) and the Queensland Government (Australia).

      Conflicts of interest

      None.

      Acknowledgements

      Jonathan Golledge holds a Practitioner Fellowship from the National Health and Medical Research Council (1117061) and a Senior Clinical Research Fellowship from the Queensland Government. TPS holds a Junior Doctor Research Fellowship from the Queensland Government.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

      References

        • Chaikof E.L.
        • Dalman R.L.
        • Eskandari M.K.
        • Jackson B.M.
        • Lee W.A.
        • Mansour M.A.
        • et al.
        The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic aneurysm.
        J Vasc Surg. 2018; 67: 2-77
        • Wanhainen A.
        • Verzini F.
        • Van Herzeele I.
        • Allaire E.
        • Bown M.
        • Cohnert T.
        • et al.
        Editor's Choice - European Society for Vascular Surgery (ESVS) 2019 Clinical Practice Guidelines on the Management of Abdominal Aorto-iliac Artery Aneurysms.
        Eur J Vasc Endovasc Surg. 2019; 57: 8-93
      1. Mortality results for randomised controlled trial of early elective surgery or ultrasonographic surveillance for small abdominal aortic aneurysms. The UK Small Aneurysm Trial Participants.
        Lancet. 1998; 352: 1649-1655
        • Forsdahl S.H.
        • Solberg S.
        • Singh K.
        • Jacobsen B.K.
        Abdominal aortic aneurysms, or a relatively large diameter of non-aneurysmal aortas, increase total and cardiovascular mortality: the Tromso study.
        Int J Epidemiol. 2010; 39: 225-232
        • Freiberg M.S.
        • Arnold A.M.
        • Newman A.B.
        • Edwards M.S.
        • Kraemer K.L.
        • Kuller L.H.
        Abdominal aortic aneurysms, increasing infrarenal aortic diameter, and risk of total mortality and incident cardiovascular disease events: 10-year follow-up data from the Cardiovascular Health Study.
        Circulation. 2008; 117: 1010-1017
        • Norman P.
        • Le M.
        • Pearce C.
        • Jamrozik K.
        Infrarenal aortic diameter predicts all-cause mortality.
        Arterioscler Thromb Vasc Biol. 2004; 24: 1278-1282
        • Norman P.E.
        • Muller J.
        • Golledge J.
        The cardiovascular and prognostic significance of the infrarenal aortic diameter.
        J Vasc Surg. 2011; 54: 1817-1820
        • Jones G.T.
        • Drinkwater B.
        • Blake-Barlow A.
        • Hill G.B.
        • Williams M.J.A.
        • Krysa J.
        • et al.
        Both small and large infrarenal aortic size is associated with an increased prevalence of ischaemic heart disease.
        Eur J Vasc Endovasc Surg. 2020; 60: 594-601
        • Qazi S.
        • Massaro J.M.
        • Chuang M.L.
        • D'Agostino R.B.
        • Sr .,
        • Hoffmann U.
        • O'Donnell C.J.
        Increased aortic diameters on multidetector computed tomographic scan are independent predictors of incident adverse cardiovascular events: the Framingham Heart Study.
        Circ Cardiovasc Imaging. 2017; 10e006776
        • Zafar M.A.
        • Li Y.
        • Rizzo J.A.
        • Charilaou P.
        • Saeyeldin A.
        • Velasquez C.A.
        • et al.
        Height alone, rather than body surface area, suffices for risk estimation in ascending aortic aneurysm.
        J Thorac Cardiovasc Surg. 2018; 155: 1938-1950
        • Davies R.R.
        • Gallo A.
        • Coady M.A.
        • Tellides G.
        • Botta D.M.
        • Burke B.
        • et al.
        Novel measurement of relative aortic size predicts rupture of thoracic aortic aneurysms.
        Ann Thorac Surg. 2006; 81: 169-177
        • Jones G.T.
        • Sandiford P.
        • Hill G.B.
        • Williams M.J.A.
        • Khashram M.
        • Tilyard M.W.
        • et al.
        Correcting for body surface area identifies the true prevalence of abdominal aortic aneurysm in screened women.
        Eur J Vasc Endovasc Surg. 2019; 57: 221-228
        • Golledge J.
        • Rowbotham S.
        • Velu R.
        • Quigley F.
        • Jenkins J.
        • Bourke M.
        • et al.
        Association of serum lipoprotein (a) with the requirement for a peripheral artery operation and the incidence of major adverse cardiovascular events in people with peripheral artery disease.
        J Am Heart Assoc. 2020; 9e015355
        • Singh T.P.
        • Moxon J.V.
        • Healy G.N.
        • Cadet-James Y.
        • Golledge J.
        Presentation and outcomes of indigenous Australians with peripheral artery disease.
        BMC Cardiovasc Disord. 2018; 18: 94
        • Singh T.P.
        • Wong S.
        • Quigley F.
        • Jenkins J.
        • Golledge J.
        Association of gout with major adverse cardiovascular events and all-cause mortality in patients with peripheral artery disease.
        Atherosclerosis. 2020; 312: 23-27
        • Palamuthusingam D.
        • Quigley F.
        • Golledge J.
        Implications of the finding of no significant carotid stenosis based on data from a regional Australian vascular unit.
        Ann Vasc Surg. 2011; 25: 1050-1056
        • Nastasi D.R.
        • Moxon J.V.
        • Norman R.
        • Trollope A.F.
        • Rowbotham S.
        • Quigley F.
        • et al.
        The cost-effectiveness of intensive low-density lipoprotein cholesterol lowering in people with peripheral artery disease.
        J Vasc Surg. 2021; 73: 1396-1403
        • Magee R.
        • Quigley F.
        • McCann M.
        • Buttner P.
        • Golledge J.
        Growth and risk factors for expansion of dilated popliteal arteries.
        Eur J Vasc Endovasc Surg. 2010; 39: 606-611
        • Golledge J.
        • Cronin O.
        • Iyer V.
        • Bradshaw B.
        • Moxon J.V.
        • Cunningham M.A.
        Body mass index is inversely associated with mortality in patients with peripheral vascular disease.
        Atherosclerosis. 2013; 229: 549-555
        • Ferguson C.D.
        • Clancy P.
        • Bourke B.
        • Walker P.J.
        • Dear A.
        • Buckenham T.
        • et al.
        Association of statin prescription with small abdominal aortic aneurysm progression.
        Am Heart J. 2010; 159: 307-313
        • Golledge J.
        • Moxon J.
        • Pinchbeck J.
        • Anderson G.
        • Rowbotham S.
        • Jenkins J.
        • et al.
        Association between metformin prescription and growth rates of abdominal aortic aneurysms.
        Br J Surg. 2017; 104: 1486-1493
        • Matthews E.O.
        • Pinchbeck J.
        • Elmore K.
        • Jones R.E.
        • Moxon J.V.
        • Golledge J.
        The reproducibility of measuring maximum abdominal aortic aneurysm diameter from ultrasound images.
        Ultrasound J. 2021; 13: 13
        • Mosteller R.D.
        Simplified calculation of body-surface area.
        N Engl J Med. 1987; 317: 1098
        • Golledge J.
        • Moxon J.V.
        • Rowbotham S.
        • Pinchbeck J.
        • Yip L.
        • Velu R.
        • et al.
        Risk of major amputation in patients with intermittent claudication undergoing early revascularization.
        Br J Surg. 2018; 105: 699-708
        • Morris D.R.
        • Singh T.P.
        • Moxon J.V.
        • Smith A.
        • Stewart F.
        • Jones R.E.
        • et al.
        Assessment and validation of a novel angiographic scoring system for peripheral artery disease.
        Br J Surg. 2017; 104: 544-554
        • Morris D.R.
        • Skalina T.A.
        • Singh T.P.
        • Moxon J.V.
        • Golledge J.
        Association of computed tomographic leg muscle characteristics with lower limb and cardiovascular events in patients with peripheral artery disease.
        J Am Heart Assoc. 2018; 7e009943
        • Golledge J.
        • Morris D.R.
        • Pinchbeck J.
        • Rowbotham S.
        • Jenkins J.
        • Bourke M.
        • et al.
        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.
        Eur J Vasc Endovasc Surg. 2019; 57: 94-101
        • Aboyans V.
        • Ricco J.B.
        • Bartelink M.E.L.
        • Bjorck M.
        • Brodmann M.
        • Cohnert T.
        • et al.
        Editor's Choice - 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS).
        Eur J Vasc Endovasc Surg. 2018; 55: 305-368
        • Peduzzi P.
        • Concato J.
        • Kemper E.
        • Holford T.R.
        • Feinstein A.R.
        A simulation study of the number of events per variable in logistic regression analysis.
        J Clin Epidemiol. 1996; 49: 1373-1379
        • Golledge J.
        • Ewels C.
        • Muller R.
        • Walker P.J.
        Association of chronic kidney disease categories defined with different formulae with major adverse events in patients with peripheral vascular disease.
        Atherosclerosis. 2014; 232: 289-297

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