You are here

Article Text

Article menu
Cardiac risk factors and prevention
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. 1 Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
    2. 2 Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
    3. 3 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
    4. 4 Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands
    5. 5 Faculty of Population Health Sciences, University College London Institute of Cardiovascular Science, London, United Kingdom
    6. 6 Health 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}umcutrecht.nl

    Abstract

    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

    https://doi.org/10.1136/heartjnl-2019-316088

    Statistics from Altmetric.com

      Request Permissions

      If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

      Introduction

      Patients with symptomatic cardiovascular disease are at high risk for recurrent major adverse cardiovascular events (MACE). Major adverse limb events (MALE), including amputations and peripheral revascularisations, lead to significant morbidity1–3 but are rarely reported as (primary) outcome in trials and cohorts. Patients with peripheral artery disease (PAD) are at especially high risk of these events, having a threefold increase in incident MACE4 and over tenfold increase in MALE incidence.5 Hypercholesterolaemia is associated with a 20% higher risk of PAD in the general population,6 and 1 mmol/L reduction of low-density lipoprotein cholesterol (LDL-c) leads to a 22% decrease in MACE incidence.7 Lipid-lowering with a statin in patients with PAD is associated with an 18% reduction of adverse limb outcomes.8 The FOURIER trial showed that by lowering LDL-c with PCSK9 monoclonal antibody, the risk of MALE is lowered by 42% in comparison with placebo.5 Non-high-density lipoprotein cholesterol (non-HDL-c) includes both LDL-c and remnant cholesterol and has a stronger association with cardiovascular outcomes in comparison with LDL-c.9 Hypertension is associated with an increased risk of PAD and MALE in the general population.10 11 In patients with PAD, however, it has been suggested that lowering blood pressure below a critical level may worsen PAD symptoms and progression by decreasing peripheral perfusion.12 Smoking is one of the most important risk factors for PAD and is attributable to more than half of the prevalence of PAD.13 14 Also, smoking cessation increases the amputation-free survival in patients with PAD (HR 0.43, 95% CI 0.22 to 0.86).15

      The aims of the current study were to determine the incidence of MALE and MALE/MACE in patients with symptomatic vascular disease, to assess to what extent non-HDL-c, systolic blood pressure (SBP) and smoking increase the risk of MALE and MALE/MACE, and to quantify the population attributable fractions (PAF) of these risk factors.

      Methods

      Patients were from the Utrecht Cardiovascular Cohort - Second Manifestations of ARTerial disease (UCC-SMART), a single-centre, ongoing prospective cohort study in Utrecht, the Netherlands. A detailed description of the study protocol has been described previously.16 Study patients are newly referred patients to the University Medical Center Utrecht with atherosclerotic disease or increased risk for atherosclerotic disease and were included between January 1996 and March 2017 (online supplementary figure 1). From this cohort, we included all patients with symptomatic PAD, coronary artery disease (CAD), cerebrovascular disease (CVD) and/or abdominal aortic aneurysm (AAA). PAD was defined as a symptomatic and documented obstruction of distal arteries of the leg (ankle-brachial index ≤0.90), a revascularisation procedure of the leg (percutaneous transluminal angioplasty or bypass surgery) or a prior amputation. CAD was defined as a clinical diagnosis of angina pectoris, myocardial infarction, cardiac arrest or coronary revascularisation; CVD was defined as a clinical diagnosis of a transient ischaemic attack or ischaemic or haemorrhagic stroke; and AAA was defined as a history of abdominal aortic surgery or an abdominal aortic anteroposterior diameter of ≥3 cm at baseline. Written informed consent was obtained from all patients.

      Supplemental material

      Data collection

      After inclusion, all baseline characteristics were determined using a standardised screening protocol consisting of questionnaires, physical examination, laboratory testing, ankle-brachial index, and abdominal aortic and carotid ultrasound. Non-HDL-c was defined as total cholesterol minus HDL-c and was measured from fasting venous blood samples. LDL-c was calculated using the Friedewald formula. Office SBP was measured in sitting position twice in both arms, and the highest mean of the measurements on one arm was used. Smoking and the amount of pack-years were self-reported. Diabetes mellitus (DM) at baseline was either self-reported DM type 1 or 2 or a fasting glucose of >7.0 mmol/L at baseline. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula. Medication use was self-reported.

      The primary outcome of this study was the incidence of MALE, a composite outcome consisting of a lower limb revascularisation (vascular intervention or thrombolysis) and major amputation (at the level of the ankle or more proximal). Minor amputations were not regarded as MALE in accordance with prior studies.2 17 The incidence of MACE was assessed to serve as a comparison with MALE. MACE was a composite outcome consisting of non-fatal myocardial infarction, non-fatal stroke or vascular death. MALE/MACE was a composite outcome consisting of either MALE or MACE. Patients received biannual questionnaires to evaluate possible endpoints. Whenever a possible event was reported, hospital discharge letters, general practitioner letters, and results of relevant laboratory and radiology examinations were collected, and the endpoint was verified by three independent experienced physicians from the UCC-SMART endpoint committee. Interventions already planned at inclusion in the UCC-SMART cohort were not regarded endpoints.

      Data analyses

      Because complete case analysis may lead to loss of statistical power and possible bias,18 values of determinants or possible confounders were imputed by single regression imputation. Missing data were <1.0%, except for C reactive protein (CRP) (n=224, 2.8%). Follow-up was defined as time from inclusion until MALE event, death, loss to follow-up (n=543, 6.7%) or until March 2017. Cox proportional hazard models were fitted to determine the effect of the risk factors on the risk of MALE, MACE or MALE/MACE. The presence of PAD at baseline was an effect modifier in the relation between the risk of MALE and non-HDL-c (p for interaction <0.01), SBP (p for interaction 0.01) and smoking (p for interaction <0.01). All models were stratified on the presence of PAD at baseline. Using restricted cubic splines, there was no evidence for a non-linear relation between SBP and the incidence of MALE (p for non-linearity 0.28), MACE (p for non-linearity 0.06) and MALE/MACE (p for non-linearity 0.16). There was no evidence for violations of the proportional hazard assumption, assessed visually on plotted Schoenfeld residuals.

      Potential confounders were selected prior to the analysis based on causal diagrams. To adjust for potential confounding factors, the model investigating the relation between non-HDL-c and MALE and MACE occurrence was adjusted for age, sex, DM, SBP, smoking, statin use and eGFR. The presence of DM was no effect modifier for the relation between non-HDL-c and the occurrence of MALE (p for interaction 0.63). In the relation between SBP and the risk of MALE and MACE, the following possible confounders were added to the models: age, sex, non-HDL-c, smoking, DM, body mass index (BMI) and CRP. The relation between smoking and the risk of MALE and MACE was adjusted for the following possible confounders: age, sex, SBP, DM, BMI, non-HDL-c and eGFR. A dose–response relationship was assessed on the relation between smoking and the incidence of MALE and MACE for the following categories: 0–20 pack-years, 21–40 pack-years or >40 pack-years.

      PAF was quantified for all three relationships and was defined as the proportion of cases that could be prevented if the risk factor would be completely removed from the population. PAF was based on Cox models adjusted for confounding factors using the R package ‘AF’ (V.0.1.4).19 In order to calculate PAF, non-HDL-c was dichotomised at below or above 2.6 mmol/L, for SBP a cut-off at 140 mm Hg was used, and smoking was analysed as current smoking versus never or former smoking.

      All analyses were performed with R statistic programming (V.3.4.1; R Foundation for Statistical Computing, Vienna, Austria).

      Sensitivity analyses

      A sensitivity analysis was performed in which minor amputations were included in the definition of MALE. Because previous studies found a non-linear relation between SBP and the risk of MACE with a nadir around 140 mm Hg,20 21 a separate analysis was done in which only people with a blood pressure of more than 140 mm Hg were included. Also, further exploratory Cox models were fitted for all relations in which atherosclerotic disease location, number of atherosclerotic disease locations, haemoglobin A1c, aspirin, alcohol, eGFR and different classes of antihypertensive drugs were added to the models. In order to assess the impact of competing risks, the analyses were repeated with Fine and Gray competing risk models.

      Results

      Baseline characteristics

      A total of 8139 patients were included, with a total follow-up of 66 359 person-years (median follow-up 7.8 years, IQR 4.0–11.8 years). The baseline characteristics of the included patients are presented in table 1. The mean age was 60.0±10.3 years, and 74% of the patients were male, 61% had a history of CAD, 30% of CVD, 18% of PAD and 9% of AAA. The baseline characteristics across quartiles of non-HDL-c, SBP and smoking status are presented in online supplementary tables 1-3.

      View this table:
      Table 1

      Patient characteristics according to vascular disease location

      Prescription frequencies of guideline medications increased over the years in the UCC-SMART cohort. In the first 10 years of inclusion (1996–2006), 54% of the patients were prescribed a statin and 24% an ACE inhibitor, which increased to 80% statin use and 37% use after 2006. Patients with CAD were more often prescribed statins (82%) than patients with PAD (49%), CVD (58%) or AAA (51%).

      Incidence rates of MALE and MACE

      A total of 577 first MALE were observed, of which 48 were major amputations, 311 surgical interventions and 218 revascularisations (incidence rate 8.7 per 1000 person-years; figure 1A). In patients with PAD at baseline, 376 first MALE occurred (incidence rate 29.9 per 1000 person-years). In patients with a history of CAD but without PAD, the MALE incidence rate was 3.8 per 1000 person-years. For CVD, the MALE incidence rate was 4.1 per 1000 person-years, and for AAA this incidence rate was 9.3 per 1000 person-years. The incidence rates were highest in patients with PAD+DM (44.6 per 1000 person-years) and PAD+polyvascular disease (36.1 per 1000 person-years).

      Figure 1
      Figure 1

      (A) MALE-free, (B) MACE-free and (C) MALE/MACE-free survival according to vascular disease location at baseline. Kaplan-Meier curves according to atherosclerotic disease location. Patients in CAD, CVD and AAA groups do not have PAD at baseline. AAA, abdominal aortic aneurysm; CAD, coronary artery disease; CVD, cerebrovascular disease; MACE, major adverse cardiovascular events; MALE, major adverse limb events; PAD, peripheral artery disease.

      A total of 1568 MACE were observed (incidence rate 24.0 per 1000 person-years; figure 1B). The incidence rate of MACE was 31.3 per 1000 in patients with PAD. In patients without PAD, the incidence rates were 21.8 per 1000 in patients with CAD, 24.3 per 1000 in patients with CVD and 47.4 per 1000 person-years in patients with AAA. The combined endpoint MALE/MACE was observed 1933 times (incidence rate 29.1 per 1000 person-years; figure 1C), and the incidence rates per 1000 person-years were 57.3 for PAD, 23.1 for CAD, 25.4 for CVD and 50.6 for AAA.

      Relation between non-HDL-c, SBP and smoking and occurrence of MALE, MACE and MALE/MACE

      There was no significant relation between non-HDL-c and the occurrence of MALE, MACE or MALE/MACE in patients with PAD (figure 2A). In patients with CAD/CVD/AAA but without PAD, the risk of all outcomes was higher with higher non-HDL-c.

      Figure 2
      Figure 2

      Relation between non-HDL-c and SBP and the risk of MALE, MACE and MALE/MACE according to vascular disease location. This figure shows the hazard rates for the risk of MALE, MACE and MALE/MACE per mmol/L increase in non-HDL-c (A) and per 10 mm Hg increase in SBP (B). (A) Adjusted for age, sex, SBP, DM, smoking and eGFR. (B) Adjusted for age, sex, non-HDL-c, smoking, DM, BMI and CRP. AAA, abdominal aortic aneurysm; BMI, body mass index; CAD, coronary artery disease; CRP, C reactive protein; CVD, cerebrovascular disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; MACE, major adverse cardiovascular events; MALE, major adverse limb events; non-HDL-c, non-high-density lipoprotein cholesterol; PAD, peripheral artery disease; SBP, systolic blood pressure.

      There was a positive relation between SBP and the occurrence of MALE, MACE and MALE/MACE in patients with PAD (figure 2B). In patients with CAD/CVD/AAA but without PAD, the occurrence of MALE and MALE/MACE was positively related to SBP. SBP had no significant effect on MACE.

      In patients with PAD, former and current smoking increased the risk of MALE insignificantly (figure 3). In these patients, both former and current smoking were associated with an increased risk of MACE and MALE/MACE. In patients with CAD/CVD/AAA but without PAD, former and current smoking increased the risk of MALE, MACE and MALE/MACE.

      Figure 3
      Figure 3

      Relation between smoking and the risk of MALE, MACE and MALE/MACE according to vascular disease location. The figure shows the HR of current smoking versus never smoking for MALE, MACE and MALE/MACE. HRs for former smoking are displayed in online supplementary figure 1. Models were adjusted for age, sex, systolic blood pressure, non-high-density lipoprotein cholesterol, diabetes mellitus, body mass index and estimated glomerular filtration rate. AAA, abdominal aortic aneurysm; CAD, coronary artery disease; CVD, cerebrovascular disease; MACE, major adverse cardiovascular events; MALE, major adverse limb events; PAD, peripheral artery disease; SBP, systolic blood pressure.

      A dose–response effect was observed in the relation between smoking and MALE. In comparison with smokers with <20 pack-years, the risk was increased for 21–40 pack-years (HR 1.45, 95% CI 1.18 to 1.78) and >40 pack-years (HR 2.18, 95% CI 1.54 to 2.38). A similar effect was observed for MACE (HR 1.10, 95% CI 9.97 to 1.10 for 21–40 pack-years; HR 1.25, 95% CI 1.09 to 1.45 for >40 pack-years) and MALE/MACE (HR 1.19, 95% CI 1.07 to 1.34 for 21–40 pack-years; HR 1.41, 95% CI 1.25 to 1.61 for >40 pack-years).

      Population attributable fraction

      The PAF of incident MALE in patients with PAD was 5% (95% CI 0 to 31) for non-HDL-c, 9% (95% CI 0 to 19) for SBP and 7% (95% CI 0 to 16) for smoking. In patients with CAD/CVD/AAA, this was 0% (95% CI 0 to 27) for non-HDL-c, 18% (95% CI 5 to 31) for SBP and 28% (95% CI 18 to 36) for smoking (figure 4).

      Figure 4
      Figure 4

      The population attributable fractions of MALE and MACE for elevated non-HDL-c, elevated SBP and smoking This figure shows the population attributable fractions of incident MALE and MACE attributable to non-HDL-c (>2.6 mmol/L), SBP (>140mmHg) and current smoking ±95% confidence intervals for patients with (A) PAD and (B) CAD/CVD/AAA. The PAF is the proportion of cases that could be prevented if the risk factor would be completely removed from the population. PAD, peripheral artery disease; CAD, coronary artery disease; CVD, cerebrovascular disease; AAA, abdominal aortic aneurysm; MALE, Major Adverse Limb Events; MACE, Major Adverse Cardiovascular Events; non-HDL-C, non-high-density lipoprotein cholesterol; SBP, systolic blood pressure.

      Sensitivity analyses

      Including minor amputations in the MALE endpoint resulted in 15 additional MALE events, and repeating the analyses with this definition of MALE did not meaningfully change the relations between risk factors and risk of MALE. The effect of non-HDL-c, SBP and smoking on the risk of MALE was similar in the highest risk groups, PAD+DM or PAD+polyvascular disease (online supplementary table 4), except for current smoking in patients with PAD+DM. In this group current smoking led to a non-significant lower risk of MALE. Inclusion of only patients with an SBP of ≥140 mm Hg led to a stronger relation between SBP and risk of MACE in patients with PAD (HR 1.16, 95% CI 1.07 to 1.25), but did not change the estimate in patients with CAD/CVD/AAA. There was no effect on the risk of MALE in both groups. Further adjustment for additional possible confounders did not change the estimates meaningfully. The competing risk-adjusted analysis showed similar results as the main analysis (online supplementary table 5).

      Discussion

      In the present study it is shown that the incidence of MALE and MALE/MACE differs according to vascular disease location. The highest incidence of MALE was observed in patients with PAD, and in these patients the incidence of MALE was higher than of MACE. In patients with CAD/CVD/AAA, higher non-HDL-c, higher SBP and smoking were associated with an increased risk of MALE, and the effect of smoking and SBP on the incidence of MALE was much stronger than on the incidence of MACE.

      In previously published studies, it was shown that lipid-lowering therapy resulted in a reduction in amputations or limb events in patients with PAD.8 22 23 In the FOURIER trial, a 42% reduction in MALE incidence was shown after treatment with a PCSK9 inhibitor in comparison with placebo.5 In contrast to the current study, non-urgent revascularisations were not included in the MALE endpoint of the FOURIER trial. In FOURIER’s secondary endpoint consisting of all peripheral revascularisations, no difference was observed, indicating non-HDL-c may not be associated with non-urgent revascularisations. Therefore, inclusion of non-urgent revascularisations in the current study may have weakened the observed relation between non-HDL-c and the incidence of MALE.

      The positive relation between SBP and risk of MALE as observed in this study is consistent with earlier studies in patients in the general population or with PAD.10 11 24 25 The results from the current study show that SBP also increases the risk of MALE in patients with vascular disease at other locations and that this effect is stronger than on the incidence of MACE. These estimates did not change when only patients with SBP of ≥140 mm Hg were analysed to account for a potential J-shaped relationship.

      Current smoking is a strong risk factor for incident MALE and PAD, which is consistent with previously published results.15 26 The results from the current study show that this effect is very strong in patients with CAD/CVD/AAA and that the effect of smoking on the incidence of MALE is stronger than on the incidence of MACE. Previous studies reported a dose-dependent relation between smoking and the incidence and prevalence of PAD,13 26 27 while the results from the current study show that a similar effect also applies to incident MALE.

      The effects of non-HDL-c, SBP and smoking on the incidence of MALE were smaller in patients with PAD in comparison with patients with CAD/CVD/AAA. These differences could be partially explained by a difference in pathophysiology. In patients without PAD, MALE may primarily be a result of generalised progression of atherosclerosis, whereas recurrent MALE might also occur due to restenosis or thrombosis of a peripheral artery stent or bypass in patients with PAD. However, it is also possible that these differences are due to selection on the index event. This can be understood by viewing the onset of PAD as the sum of the effect of multiple causal factors. If one very strong causal factor, for example smoking, is already present, less effect of the other factors is required for the onset of disease. Subsequently comparing the smokers and non-smokers who have already developed PAD leads to the smokers having a relatively healthy risk profile in comparison with the non-smokers in both measured and non-measured factors, which cannot be completely corrected for.28

      Because the FOURIER study found similar relative effect sizes on the incidence of MALE in patients with PAD as in patients with vascular disease at other locations from lipid-lowering,5 it is likely that the actual effect is closer towards the estimate of the CAD/CVD/AAA group.

      The results from the current study contribute to the evidence that the modifiable risk factors for MACE also increase the risk of MALE in patients with symptomatic vascular disease, including patients with pre-existing PAD. In comparison with MACE, the fraction of MALE that can be attributed to the modifiable risk factors SBP and smoking is even larger. This implies that improved risk factor management in patients with symptomatic atherosclerotic disease could prevent many cases of incident MALE, apart from the benefit on reduction of MACE risk. In light of the high incidence, the numbers needed to treat are expected to be low. The morbidity associated with MALE can be very high and a large fraction is attributable due to treatable risk factors. Inclusion of those events in (primary) composite outcomes of intervention studies as MALE/MACE could therefore better reflect the effect of an intervention on the total disease burden due to atherosclerotic disease.

      The strengths of this prospective cohort study include the large number of patients with symptomatic atherosclerotic disease with long and complete follow-up, resulting in a high number of MALE and MACE. Also, the generalisability of the results is high as the UCC-SMART cohort resembles a referred patient population with vascular disease. A possible limitation is the fact that baseline characteristics were only recorded at the start of the study and may have changed in the duration of the follow-up. Furthermore, the results in patients with PAD may have been affected by selection on the index event and are therefore expected to be closer to the results in the CAD/CVD/AAA group.

      In conclusion, the incidence of MALE in patients with clinical manifestation of vascular disease differs according to vascular disease location and is associated with non-HDL-c, SBP and smoking. A large fraction of incident MALE is attributable to modifiable risk factors. These findings confirm the importance of MALE as an outcome and underline the importance of classic risk factor management in patients with vascular disease to prevent not only MACE, but also disabling MALE.

      Key messages

      What is already known on this subject?

      • Patients with symptomatic cardiovascular disease are not only at risk for recurrent major adverse cardiovascular events (MACE), but also for major adverse limb events (MALE).

      • These events may lead to significant morbidity but are only rarely reported as (primary) outcome in trials and cohorts.

      • Classic risk factors for MACE may also increase the risk of MALE.

      What might this study add?

      • The incidence of MALE and MALE/MACE in patients with symptomatic vascular disease differs according to vascular disease location, varying from 3.8 per 1000 person-years in patients with coronary artery disease (CAD) up to 29.9 per 1000 person-years in patients with peripheral artery disease.

      • In patients with CAD, cerebrovascular disease or abdominal aortic aneurysm, the risk of MALE is higher in patients with higher non-high-density lipoprotein cholesterol (HR 1.14 per 1 mmol/L increase, 95% CI 1.01 to 1.29), systolic blood pressure (HR 1.06 per 10 mm Hg increase, 95% CI 1.01 to 1.12) and in smokers (HR 1.15, 95% CI 1.08 to 1.22).

      • In order to guide preventive measures, the population attributable fractions were quantified for these modifiable risk factors, which show that a large fraction of incident MALE is attributable to systolic blood pressure and smoking.

      How might this impact on clinical practice?

      • These findings confirm the importance of MALE as an outcome and underline the importance of classic risk factor management in patients with vascular disease to prevent not only MACE, but also disabling MALE.

      Acknowledgments

      We gratefully acknowledge the contribution of the research nurses, R van Petersen (data manager) and B van Dinther (study manager), and the members of the Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease Study Group (UCC-SMART Study Group).

      References

      1. ↵
        2. Mahoney EM ,
        3. Wang K ,
        4. Keo HH , et al
        . Vascular hospitalization rates and costs in patients with peripheral artery disease in the United States. Circ Cardiovasc Qual Outcomes 2010;3:642–51.doi:10.1161/CIRCOUTCOMES.109.930735
        OpenUrlAbstract/FREE Full Text
      2. ↵
        2. Anand SS ,
        3. Caron F ,
        4. Eikelboom JW , et al
        . Major Adverse Limb Events and Mortality in Patients With Peripheral Artery Disease: The COMPASS Trial. J Am Coll Cardiol 2018;71:2306–15.doi:10.1016/j.jacc.2018.03.008
        OpenUrlFREE Full Text
      3. ↵
        2. Duval S ,
        3. Keo HH ,
        4. Oldenburg NC , et al
        . The impact of prolonged lower limb ischemia on amputation, mortality, and functional status: the friends registry. Am Heart J 2014;168:577–87.doi:10.1016/j.ahj.2014.06.013
        OpenUrlCrossRefPubMedWeb of Science
      4. ↵
        2. Aboyans V ,
        3. Desormais I ,
        4. Lacroix P , et al
        . The general prognosis of patients with peripheral arterial disease differs according to the disease localization. J Am Coll Cardiol 2010;55:898–903.doi:10.1016/j.jacc.2009.09.055
        OpenUrlFREE Full Text
      5. ↵
        2. Bonaca MP ,
        3. Nault P ,
        4. Giugliano RP , et al
        . Low-Density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease. Circulation 2018;137:338–50.doi:10.1161/CIRCULATIONAHA.117.032235
        OpenUrlAbstract/FREE Full Text
      6. ↵
        2. Fowkes FGR ,
        3. Rudan D ,
        4. Rudan I , et al
        . Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013;382:1329–40.doi:10.1016/S0140-6736(13)61249-0
        OpenUrlCrossRefPubMedWeb of Science
      7. ↵
        2. Baigent C ,
        3. Blackwell L ,
        4. Emberson J , et al
        . Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–81.doi:10.1016/S0140-6736(10)61350-5
        OpenUrlCrossRefPubMedWeb of Science
      8. ↵
        2. Kumbhani DJ ,
        3. Steg PG ,
        4. Cannon CP , et al
        . Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: insights from the reach registry. Eur Heart J 2014;35:2864–72.doi:10.1093/eurheartj/ehu080
        OpenUrlCrossRefPubMedWeb of Science
      9. ↵
        2. Boekholdt SM ,
        3. Arsenault BJ ,
        4. Mora S , et al
        . Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA 2012;307:1302–9.doi:10.1001/jama.2012.366
        OpenUrlCrossRefPubMedWeb of Science
      10. ↵
        2. Emdin CA ,
        3. Anderson SG ,
        4. Callender T , et al
        . Usual blood pressure, peripheral arterial disease, and vascular risk: cohort study of 4.2 million adults. BMJ 2015;351:h4865.doi:10.1136/bmj.h4865
        OpenUrlAbstract/FREE Full Text
      11. ↵
        2. Itoga NK ,
        3. Tawfik DS ,
        4. Lee CK , et al
        . Association of blood pressure measurements with peripheral artery disease events. Circulation 2018;138:1805–14.doi:10.1161/CIRCULATIONAHA.118.033348
        OpenUrlPubMed
      12. ↵
        2. Lane DA ,
        3. Lip GY
        . Treatment of hypertension in peripheral arterial disease. Cochrane Database Syst Rev 2013:10–13.
      13. ↵
        2. Willigendael EM ,
        3. Teijink JAW ,
        4. Bartelink M-L , et al
        . Influence of smoking on incidence and prevalence of peripheral arterial disease. J Vasc Surg 2004;40:1158–65.doi:10.1016/j.jvs.2004.08.049
        OpenUrlCrossRefPubMedWeb of Science
      14. ↵
        2. Lu JT ,
        3. Creager MA
        . The relationship of cigarette smoking to peripheral arterial disease. Rev Cardiovasc Med 2004;5:189–93.
        OpenUrlPubMed
      15. ↵
        2. Armstrong EJ ,
        3. Wu J ,
        4. Singh GD , et al
        . Smoking cessation is associated with decreased mortality and improved amputation-free survival among patients with symptomatic peripheral artery disease. J Vasc Surg 2014;60:1565–71.doi:10.1016/j.jvs.2014.08.064
        OpenUrlCrossRefPubMed
      16. ↵
        2. Simons PC ,
        3. Algra A ,
        4. van de Laak MF , et al
        . Second manifestations of arterial disease (smart) study: rationale and design. Eur J Epidemiol 1999;15:773–81.doi:10.1023/A:1007621514757
        OpenUrlCrossRefPubMedWeb of Science
      17. ↵
        2. Sabatine MS ,
        3. Giugliano RP ,
        4. Keech AC , et al
        . Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22.doi:10.1056/NEJMoa1615664
        OpenUrlCrossRefPubMed
      18. ↵
        2. Donders ART ,
        3. van der Heijden GJMG ,
        4. Stijnen T , et al
        . Review: a gentle introduction to imputation of missing values. J Clin Epidemiol 2006;59:1087–91.doi:10.1016/j.jclinepi.2006.01.014
        OpenUrlCrossRefPubMedWeb of Science
      19. ↵
        2. Sjölander A ,
        3. Vansteelandt S
        . Doubly robust estimation of attributable fractions in survival analysis. Stat Methods Med Res 2017;26:948–69.doi:10.1177/0962280214564003
        OpenUrl
      20. ↵
        2. Dorresteijn JAN ,
        3. van der Graaf Y ,
        4. Spiering W , et al
        . Relation between blood pressure and vascular events and mortality in patients with manifest vascular disease: J-curve revisited. Hypertension 2012;59:14–21.doi:10.1161/HYPERTENSIONAHA.111.179143
        OpenUrlCrossRef
      21. ↵
        2. Bangalore S ,
        3. Messerli FH ,
        4. Wun C-C , et al
        . J-curve revisited: an analysis of blood pressure and cardiovascular events in the treating to new targets (TnT) trial. Eur Heart J 2010;31:2897–908.doi:10.1093/eurheartj/ehq328
        OpenUrlCrossRefPubMed
      22. ↵
        2. Arya S ,
        3. Khakharia A ,
        4. Binney ZO , et al
        . Association of statin dose with amputation and survival in patients with peripheral artery disease. Circulation 2018;137:1435–46.doi:10.1161/CIRCULATIONAHA.117.032361
        OpenUrlAbstract/FREE Full Text
      23. ↵
        1. Heart Protection Study Collaborative Group
        . Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial disease and other high-risk conditions. J Vasc Surg 2007;45:645–54.doi:10.1016/j.jvs.2006.12.054
        OpenUrlCrossRefPubMedWeb of Science
      24. ↵
        2. Joosten MM ,
        3. Pai JK ,
        4. Bertoia ML , et al
        . Associations between conventional cardiovascular risk factors and risk of peripheral artery disease in men. JAMA 2012;308:1660.doi:10.1001/jama.2012.13415
        OpenUrlCrossRefPubMedWeb of Science
      25. ↵
        2. Rapsomaniki E ,
        3. Timmis A ,
        4. George J , et al
        . Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people. Lancet 2014;383:1899–911.doi:10.1016/S0140-6736(14)60685-1
        OpenUrlCrossRefPubMedWeb of Science
      26. ↵
        2. Conen D ,
        3. Everett BM ,
        4. Kurth T , et al
        . Smoking, smoking cessation, [corrected] and risk for symptomatic peripheral artery disease in women: a cohort study. Ann Intern Med 2011;154:719–26.doi:10.7326/0003-4819-154-11-201106070-00003
        OpenUrlCrossRefPubMedWeb of Science
      27. ↵
        2. Lee Y-H ,
        3. Shin M-H ,
        4. Kweon S-S , et al
        . Cumulative smoking exposure, duration of smoking cessation, and peripheral arterial disease in middle-aged and older Korean men. BMC Public Health 2011;11:94. doi:10.1186/1471-2458-11-94
      28. ↵
        2. Dahabreh IJ ,
        3. Kent DM
        . Index event bias as an explanation for the paradoxes of recurrence risk research. JAMA 2011;305:822.doi:10.1001/jama.2011.163
        OpenUrlCrossRefPubMedWeb of Science

      Supplementary materials

      • Supplementary Data

        This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

      Footnotes

      • 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.