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Original research
Cardiovascular risk factors and the risk of major adverse limb events in patients with symptomatic cardiovascular disease
  1. Steven H J Hageman1,
  2. Gert Jan de Borst2,
  3. Johannes A N Dorresteijn1,
  4. Michiel L Bots3,
  5. Jan Westerink1,
  6. Folkert W Asselbergs4,5,6,
  7. Frank L J Visseren1
  8. on behalf of the UCC-SMART Study Group
    1. 1Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
    2. 2Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
    3. 3Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
    4. 4Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands
    5. 5Faculty of Population Health Sciences, University College London Institute of Cardiovascular Science, London, United Kingdom
    6. 6Health Data Research UK and Institute of Health Informatics, University College London, London, United Kingdom
    1. Correspondence to Dr Frank L J Visseren, Department of Vascular Medicine, University Medical Center Utrecht, Utrecht 3508, The Netherlands; F.L.J.Visseren{at}


    Aim To determine the relationship between non-high-density lipoprotein cholesterol (non-HDL-c), systolic blood pressure (SBP) and smoking and the risk of major adverse limb events (MALE) and the combination with major adverse cardiovascular events (MALE/MACE) in patients with symptomatic vascular disease.

    Methods Patients with symptomatic vascular disease from the Utrecht Cardiovascular Cohort - Secondary Manifestations of ARTerial disease (1996–2017) study were included. The effects of non-HDL-c, SBP and smoking on the risk of MALE were analysed with Cox proportional hazard models stratified for presence of peripheral artery disease (PAD). MALE was defined as major amputation, peripheral revascularisation or thrombolysis in the lower limb.

    Results In 8139 patients (median follow-up 7.8 years, IQR 4.0–11.8), 577 MALE (8.7 per 1000 person-years) and 1933 MALE/MACE were observed (29.1 per 1000 person-years). In patients with PAD there was no relation between non-HDL-c and MALE, and in patients with coronary artery disease (CAD), cerebrovascular disease (CVD) or abdominal aortic aneurysm (AAA) the risk of MALE was higher per 1 mmol/L non-HDL-c (HR 1.14, 95% CI 1.01 to 1.29). Per 10 mm Hg SBP, the risk of MALE was higher in patients with PAD (HR 1.06, 95% CI 1.01 to 1.12) and in patients with CVD/CAD/AAA (HR 1.15, 95% CI 1.08 to 1.22). The risk of MALE was higher in smokers with PAD (HR 1.45, 95% CI 0.97 to 2.14) and CAD/CVD/AAA (HR 7.08, 95% CI 3.99 to 12.57).

    Conclusions The risk of MALE and MALE/MACE in patients with symptomatic vascular disease differs according to vascular disease location and is associated with non-HDL-c, SBP and smoking. These findings confirm the importance of MALE as an outcome and underline the importance of risk factor management in patients with vascular disease.

    • peripheral vascular disease
    • smoking cessation
    • Lipoproteins and hyperlipidaemia
    • hypertension
    • cardiac risk factors and prevention

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    • Collaborators FW Asselbergs and HM Nathoe, Department of Cardiology; GJ de Borst, Department of Vascular Surgery; ML Bots and MI Geerlings, Julius Centre for Health Sciences and Primary Care; MH Emmelot, Department of Geriatrics; PA de Jong and T Leiner, Department of Radiology; AT Lely, Department of Obstetrics and Gynaecology; NP van der Kaaij, Department of Cardiothoracic Surgery; LJ Kappelle and YM Ruigrok, Department of Neurology; MC Verhaar, Department of Nephrology; and FLJ Visseren (chair) and J Westerink, Department of Vascular Medicine, University Medical Centre Utrecht and Utrecht University.

    • Contributors All authors have made significant contribution to this work and have approved the manuscript.

    • Funding The UCC-SMART study was financially supported by a grant from the University Medical Centre Utrecht.

    • Disclaimer The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

    • Competing interests FWA is supported by UCL Hospitals NIHR Biomedical Research Centre. The other authors report no conflicts of interest.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Patient consent for publication Not required.

    • Ethics approval The study was approved by the local medical ethics committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available upon reasonable request. UCC-SMART cohort, UMC Utrecht.

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