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Characteristics and Treatments of Patients with Peripheral Arterial Disease Referred to UK Vascular Clinics: Results of a Prospective Registry

Open ArchivePublished:December 30, 2006DOI:https://doi.org/10.1016/j.ejvs.2006.11.010

      Background

      Peripheral arterial disease (PAD) is often associated with risk factors including cigarette smoking, hypertension and hypercholesterolaemia, and patients have a high risk of future vascular events. Good medical management results in improved outcomes and quality of life, but previous studies have documented sub-optimal treatment of risk factors. We assessed the management of cardiovascular risk factors in patients with PAD referred to specialist vascular clinics.

      Methods

      This was a prospective, protocol driven registry carried out in UK vascular clinics. Patients who were first-time referrals for evaluation of PAD were eligible if they had claudication plus ankle-brachial pressure index (ABPI) ≤0.9. Statistical associations between key demographic and treatment variables were explored using a chi-squared test.

      Results

      We enrolled 473 patients from 23 sites. Mean age was 68 years (SD 10) and 66% were male. Mean estimated claudication distance was 100 m, and ABPI was 0.74. Mean systolic blood pressure (SBP) was 155 mmHg, and 42% had a SBP >160 mmHg. Forty percent were current smokers and half had tried to give up in the prior 6 months, but there was no evidence of a systematic method of smoking cessation. Mean total cholesterol was 5.4 (SD1.2) mmol/l and 30% had levels >6 mmol/l. Antiplatelet therapy had been given to 70% and statins to 44%. Prior CHD was present in 29% and these patients had significantly higher use of antiplatelet therapy, statins and ACE-inhibitors.

      Conclusions

      In spite of attempts to raise awareness about PAD as an important marker of cardiovascular risk, patients are still poorly treated prior to referral to a vascular clinic. In particular, the use of evidence-based treatments is sub-optimal, while hypertension and cigarette smoking are poorly managed. More work needs to be done to educate health professionals about the detection and optimal medical management of PAD.

      Keywords

      Introduction

      Peripheral arterial disease (PAD) is a common and important manifestation of atherosclerosis. PAD affects about 5% of western populations aged between 55 and 74 years and usually presents with intermittent claudication (IC).
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      We undertook the Prospective Registry of Peripheral Arterial Risks, Events and Distribution (PREPARED-UK) of patients referred from primary care to specialist vascular clinics to understand how they had been treated prior to referral. Since all patients had IC as part of the entry criteria for the registry our assumption was that the treatments on referral provided information on the management of symptomatic PAD in primary care. We report on the baseline characteristics and treatments of these patients. This information may provide a benchmark by which future practice may be improved.

      Methods

      PREPARED-UK is a prospective cohort study designed to assess characteristics, treatments and outcomes of patients with IC presenting for the first time to Vascular Units in the UK. Follow-up of patients for 2 years is ongoing and will be reported separately, as will information on Quality of Life and health economics. The UK Multi-Centre Research Ethics committee approved the study protocol, patient information sheet and consent form, and these documents were then approved by Local Research Ethics Committees in the participating institutions. Patients were required to give written informed consent before their participation. Patients were also registered, with their consent, with the Office of National Statistics (ONS) for long-term follow-up.

      Study design

      A list of members of the Vascular Surgical Society of Great Britain and Ireland was obtained and names were sorted by NHS region. We wished to include 25 sites in the study each enrolling 20 consecutive patients. For each region we selected at random a name from the regional centre and 3 additional vascular units in that region. If centres or particular investigators were unable to take part we continued to invite other centres until we had enough centres to take part. Potentially eligible patients with IC were identified through vascular out-patient clinics of the participating hospitals. Participating centres were recognized to have vascular expertise and had access to treadmill testing, duplex scanning, diagnostic and interventional radiology, CT scans, and magnetic resonance imaging (MRI). Two of the centres were running nurse-led claudication clinics. One district hospital had no vascular laboratory while MRI was not available in another.

      Eligibility

      Patients were eligible if they had a good clinical history of IC occurring within a walking distance of about 400 metres or quarter of a mile, had an ankle/brachial blood pressure index ≤0.9, were presenting as a new referral to a vascular clinic of a participating hospital and were able to provide written informed consent. Patients were excluded if they presented with critical limb ischaemia including rest pain, necrosis or ulceration, spinal canal claudication or venous claudication, or if the claudication was incidental to presentation with another major medical condition. Claudication distance was based on patients estimates not on treadmill testing. A current smoker was defined as smoking within the previous 3 months, and an ex-smoker as a history of smoking but not within 3 months of enrolment. No assessments of cotinine levels or carbon monoxide were carried out as part of this study. Clinical assessments and blood test results for biochemistry, haematology and lipid profile were performed as part of routine procedures and not as a specific part of the registry protocol. They were performed in the local laboratories of the collaborating hospitals. Hence these results are not available for all patients.

      Study management

      A Steering Committee designed and agreed the protocol and the case record forms. The study was co-ordinated by the Clinical Trials and Evaluation Unit of the Royal Brompton Hospital, London, and the Northern Vascular Unit, Freeman Hospital and University of Newcastle, Newcastle. Centres were trained on study procedures by telephone call and were instructed to identify consecutive eligible patients presenting to the outpatient clinic. Case report forms were completed and any queries or missing data points were resolved by direct contact with the centre.

      Statistical methods

      This report is of baseline data of the study, and the main aim was to explore associations between demographics and treatments. The study planned to follow patients up for a minimum of two years. We estimated that the rate of death, stroke, myocardial and major limb amputation would be about 5% per annum or 10% over 2 years. A pragmatic sample size assumption would allow comparisons between major subgroups to (e.g. men and women, or prior CHD and no prior CHD). With a sample size of 500 we could detect absolute differences in clinical outcomes of 10% between major subgroups with an alpha error of 5% and beta error of 20% (80% power). We estimated that this sample size would also provide sufficient power to explore associations of age, gender and other important baseline demographic variables on the symptoms and signs of IC, and whether treatment was influenced by these variables. Variables were described as means and standard deviations, or proportions, as appropriate. The main pre-specified subgroup comparison was between patients with and without a history of coronary heart disease (CHD) defined as one or more of the following: prior myocardial infarction (MI), angina, coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). These groups were compared by the Student's t-test or the chi squared test as appropriate. Other baseline variables of interest were: age, gender, ankle-brachial pressure index (ABPI), systolic blood pressure (SBP), diabetes, hypertension, absolute claudication distance, smoking, antiplatelet and lipid lowering medication. Statistical associations were explored using a chi-squared test, splitting continuous variables into two or more categories as required.

      Results

      Participating centres

      Forty-two centres were invited to take part of which 23 agreed to participate. A total of 473 patients were enrolled between June 2002 September 2003. Nineteen centres enrolled 10 or more patients. The maximum number enrolled at a single centre was 51 and the average per centre was 21 patients. Since some centres enrolled fewer than the 20 patients requested, other centres were requested to enrol more patients in order to reach the pre-specified sample size of 500 patients. Although the intention was to enrol consecutive eligible patients, it seems that a number of centres were not able to achieve this.

      Patient demographics and risk factors

      The main demographic characteristics of enrolled subjects are given in Table 1. Mean age was 68 (SD 10) years and 66% were male. Mean systolic blood pressure was 155 (SD 24) mmHg, and 54% were being treated for hypertension. Systolic blood pressure >140 mmHg was recorded in 76%, and 42% had SBP >160 mmHg. Twenty percent had a history of prior diabetes (with 5% treated with insulin), 29% had a history of prior coronary artery disease and 20% were working at the time of enrolment.
      Table 1Baseline characteristics
      CharacteristicFemales, N=159Males, N=319p-valueN=478*
      Age at enrolment, mean (SD) (min – max)69.7 (9.6) (40, 87)66.7 (9.6) (34, 93)0.00168 (9.7) (34, 93)
      BMI, mean (SD) (min – max)26.2 (4.6) (17, 42)26.7 (4.3) (17, 40)0.2226.5 (4.4) (17, 42)
      Systolic blood pressure, mean (SD) (min – max)157.4 (25.2) (90, 220)153.3 (22.7) (75, 234)0.08154.7 (23.6) (75, 234)
       <100 mmHg [n(%)]1 (1)2 (1)0.713 (1)
       100–140 mmHg [n(%)]37 (23)75 (24)112 (23)
       140–160 mmHg [n(%)]47 (29)113 (35)160 (34)
       160–180 mmHg [n(%)]46 (29)80 (25)126 (26)
       >180 mmHg [n(%)]28 (18)48 (15)76 (16)
      Diastolic blood pressure, mean (SD) (min – max)80.8 (11.4) (90, 110)82.5 (12.4) (50, 130)0.1681.9 (12.1) (50,130)
      History of diabetes, n(%) Non insulin dependent16 (10)56 (18)0.03172 (15)
      Insulin dependent, n(%)9 (6)15 (5)0.6524 (5)
      History of Hypertension n(%)100 (63)165 (52)0.021265 (55)
      History of Hyperlipidaemia n(%)67 (42)139 (44)0.77206 (43)
      Angina n(%)28 (18)59 (19)0.8187 (18)
      Prior myocardial infarction (MI) n(%)18 (11)51 (16)0.1769 (14)
      Prior coronary artery bypass graft (CABG) n(%)10 (6)34 (11)0.1244 (9)
      Prior percutaneous coronary intervention (PCI) n(%)6 (4)11 (3)0.8617 (4)
      Any prior coronary heart disease (angina, MI, CABG or PCI)41 (26)100 (31)0.21141 (29)
      Prior cerebrovascular accident (CVA) n(%)10 (6)25 (8)0.5435 (7)
      In paid employment n(%)15 (9)79 (25)<0.00194 (20)
      *This is the total number of patients with baseline information. The denominator for each variable ranges from 460 to 473.
      Significant values are in bold.

      Features of claudication

      The mean estimated initial claudication distance (walking distance from start at which the symptoms appeared) was 100 m (interquartile range [IQR] 50–200 m) and mean estimated absolute claudication distance (point at which patient could walk no more and had to rest) was 150 m (IQR 75–250 m) (Table 2). Overall mean ABPI was 0.74, with slightly but non significantly lower values in the left leg compared to the right. Fifty three percent reported symptoms of claudication in both legs.
      Table 2Features of claudication
      CharacteristicFemalesMalesp-valueN=478
      Initial claudication distance (m) Median (IQR)*80 (40, 182)100 (50, 200)0.031100 (50, 200)
      Absolute claudication distance (m) Median (IQR)*110 (70, 210)80 (150, 300)0.013150 (75, 250)
      Ankle brachial pressure index: Left, mean (SD)0.72 (0.19)0.71 (0.22)0.930.72 (0.21)
      Ankle brachial pressure index: Right, mean (SD)0.74 (0.19)0.75 (0.22)0.480.75 (0.21)
      Bilateral claudication n(%)92 (58)165 (52)0.21257 (54)
      Previous vascular graft n(%)1 (1)8 (3)0.159 (2)
      Documented internal carotid stenosis (>50%), n(%)3 (2)11 (3)0.3414 (3)
      Known Aortic aneurysm n(%)4 (3)9 (3)0.8513 (3)
      *Distances estimated by patients and investigators, hence “rounding off” is likely.
      IQR=inter quartile range.

      Smoking status

      A history of smoking was present in 84% (39% current smokers and 45% ex-smokers), and in those that gave a history of smoking, estimated mean pack years smoked was 40 (Table 2). About 50% of smokers had attempted to stop smoking in the previous six months, and of the methods used, nicotine replacement therapy and “will power” (i.e. attempting to give up without external help or using nicotine replacement therapy) were the most common.

      Medications

      Seventy percent of patients were on antiplatelet therapy at enrolment and most were taking aspirin at a mean dose of 75 mg, which is the standard dosage used in the UK for cardiovascular risk reduction. Clopidogrel was used in 5% of patients (Table 4). The most common reason for not taking an antiplatelet agent was because it had never been prescribed. Forty four percent were taking a statin, 26% an ACE inhibitor, 18% a beta-blocker, and 29% were on a diuretic.

      Results of blood tests

      Cholesterol measurements were available for 73% of patients. Mean total cholesterol was 5.4 mmol/L (SD 1.2), and 31% had values ≥6 mmol/L. Other blood results including other lipid parameters, glucose levels and creatinine are given in Table 5.

      Comparison of patients with prior CHD versus no prior CHD

      Patients with a prior CHD history were significantly older, had a greater proportion of diabetes and hypertension, but fewer were current smokers, than those without a history of prior CHD (Table 6). Proportions of CHD patients taking antiplatelets, statins, ACE inhibitors and beta blockers were significantly higher. There was better control of blood pressure among CHD patients as measured by a significantly greater proportion with systolic blood pressure <140 mmHg.

      Associations between baseline variables

      Apart from the pre-specified subgroup of patients with CHD, other exploratory analyses between baseline variables were undertaken. Differences between men and women are highlighted in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6. The main differences include (all p<0.01): women are older, have less paid employment, are more likely to be non smokers. Decreasing ABPI showed a significant association with older age (p=0.01), higher systolic blood pressure (p=0.03), and decreased absolute claudication distance (p=0.03). Antiplatelet and lipid lowering therapies were more frequently prescribed in older patients (p<0.01), those with higher systolic blood pressure (p=0.01), diabetes (p=0.01), hypertension (p<0.01) and smokers (p<0.01).
      Table 3Smoking status and methods used to give up
      DescriptionFemalesMalesp-valueN=478
      Smoking, n(%)
      Current62 (39)123 (38)<0.001185 (39)
      Ex-smoker
      Ex smoker=prior smoking who has given up >3 months prior to enrolment.
      56 (35)165 (52)221 (46)
      Non-smoker41 (26)16 (5)57 (12)
      Smoker other (e.g. pipe/cigars)0 (0)15 (5)15 (3)
      Pack years smoked, Median (IQR)
      Among those who are current or ex-smokers. 379 patients available for analysis.
      37 (21, 50)40 (30, 60)0.00340 (26, 55)
      Attempted to stop in last 6 months, n(%)
      Among those who are current or ex-smokers. 211 patients available for analysis.
      39/71 (55)71/145 (49)0.41110/216 (51)
      Method used by the 110 patients, n(%)
      Nicotine replacement therapy25 (64)22 (31)0.00347 (43)
      Bupropion3 (8)2 (3)0.235 (5)
      Counselling3 (8)7 (10)0.3910 (9)
      Other:13 (33)43 (61)0.00656 (51)
      Will power or no specific method10 (26)42 (59)0.00152 (47)
      Hypnosis3 (8)1 (1)0.134 (4)
      1 Ex smoker=prior smoking who has given up >3 months prior to enrolment.
      2 Among those who are current or ex-smokers. 379 patients available for analysis.
      3 Among those who are current or ex-smokers. 211 patients available for analysis.
      Table 4Medications
      DescriptionFemalesMalesp-valueN=478* (%)
      Antiplatelet therapy107 (67)228 (71)0.35335 (70)
      Types of antiplatelet (n=335)
       Aspirin101 (94)216 (95)0.64317 (95)
       Clopidogrel6 (6)12 (5)0.7218 (5)
       Dipyridamole4 (4)7 (3)0.6911 (3)
      Mean dose of Aspirin (mg)85900.3789
      Reason for not taking antiplatelet n=14352 (33)91 (29)
       History of peptic ulcer or gastritis6 (12)8 (9)0.2814 (10)
       Indigestion6 (12)3 (3)9 (6)
       Allergy0 (0)1 (1)1 (1)
       Never prescribed/recommended29 (56)65 (71)94 (66)
       Non-compliance2 (4)2 (2)4 (3)
       Taking Warfarin0 (0)0 (0)0 (0)
       Other9 (17)12 (13)21 (15)
      Statin69 (43)143 (45)0.77212 (44)
      Lipid lowering agent (other)2 (1)4 (1)0.996 (1)
      Warfarin7 (4)10 (3)0.4817 (4)
      Digoxin5 (3)10 (3)0.9915 (3)
      ACE Inhibitor41 (26)82 (26)0.98123 (26)
      Beta blocker36 (23)49 (15)0.0585 (18)
      Calcium antagonist42 (26)66 (21)0.16108 (23)
      Angiotensin II antagonist17 (11)15 (5)0.0132 (7)
      Nitrate21 (13)34 (11)0.4155 (12)
      Quinine13 (8)12 (4)0.0425 (5)
      Diuretic64 (40)74 (23)<0.001138 (29)
      Oral hypoglycaemic12 (8)46 (14)0.0358 (12)
      Insulin9 (6)17 (5)0.8826 (5)
      *The denominator varies from 469 to 473 due to some variables with missing values.
      Table 5Blood Results
      DescriptionFemalesMalesp-valueN=478*
      Cholesterol result available n(%)122 (77)229 (72)0.25351 (73)
      Total cholesterol, mean (SD) mmol/L5.67 (0.11)5.28 (0.08)0.0045.4 (1.2)
       <4 mmol/L [n(%)]9 (7)29 (13)0.03638 (11)
       4–5 mmol/L [n(%)]23 (19)68 (30)91 (26)
       5–6 mmol/L [n(%)]46 (38)70 (30)116 (33)
       6–7 mmol/L [n(%)]26 (21)43 (19)69 (20)
       >7 mmol/L [n(%)]18 (15)19 (8)37 (10)
      HDL, median (IQR) n=1801.5 (1.3, 1.8)1.3 (1.1, 1.5)<0.0011.4 (0.6)
      LDL, median (IQR) n=1123.1 (2.5, 3.7)3.2 (2.3, 4)0.973.2 (1.0)
      Triglycerides, Median (IQR) n=2661.68 (1.27, 2.50)1.84 (1.25, 2.85)0.481.7 (1.3, 2.7)
      Glucose, Median (IQR) mmol/L n=2655.1 (4.8, 5.7)5.5 (4.9, 6.4)0.045.3 (4.8, 6.1)
       <5 mmol/L [n(%)]32 (38)52 (29)0.2884 (32)
       5–7 mmol/L [n(%)]41 (48)89 (50)130 (49)
       7–10 mmol/L [n(%)]7 (8)22 (12)29 (11)
       10–14 mmol/L [n(%)]2 (2)13 (7)15 (6)
       >14 mmol/L [n(%)]3 (4)4 (2)7 (2)
      Creatinine, mean (SD) μmol/L n=32390.4 (22.9)102.9 (28.5)<0.00198.9 (27.4)
       <60 μmol/L [n(%)]6 (6)3 (1)0.039 (3)
       60–100 μmol/L [n(%)]64 (61)121 (55)185 (57)
       100–120 μmol/L [n(%)]26 (25)60 (27)86 (26)
       120–150 μmol/L [n(%)]7 (7)21 (10)28 (9)
       >150 μmol/L [n(%)]1 (1)14 (7)15 (5)
      Haemoglobin, mean (SD) n=30413.5 (1.5)14.6 (1.4)<0.00114.2 (1.5)
      MCV, mean (SD) n=29191.2 (5.5)91.9 (6.6)0.3791.6 (6.3)
      Platelets, mean (SD) n=304283.2 (74.9)255 (85.8)0.005264.5 (83.3)
      White cell count, mean (SD) n=3028.3 (2.2)8.3 (1.9)0.968.3 (1.9)
      CRP, Median (IQR) n=685 (5, 7)5 (5, 6)0.425 (5, 6.5)
      *Blood tests were carried out according to local protocols, hence not all 473 patients had results available for analysis.
      Table 6Comparison of patients with prior CHD history (Prior MI, angina, CABG or PTCA) versus those with no prior CHD history
      Prior CHDNo Prior CHDp-value
      N=141N=337
      Age Mean (SD)69 (8.6)67 (10.1)0.012
      N (%) in subgroups by age
       <60 year20 (14)88 (26)0.011
       60–<7046 (33)108 (32)
       7075 (53)141 (42)
      Sex (% male)100 (71)219 (65)0.21
      APBI mean (SD)0.73 (0.17)0.73 (0.17)0.70
       <0.6337 (27)89 (27)0.60
       0.63–<0.7533 (24)61 (19)
       0.75–<0.8534 (25)93 (29)
       0.8534 (25)83 (25)
      Blood Pressure:
      Mean SBP (SD)151 (24.5)156 (23.1)0.044
      Mean DBP (SD)80.2 (12.1)82.7 (12.0)0.042
       SBP<14047 (34)68 (20)0.002
       SBP 14093 (66)269 (80)
      Diabetes (%)39 (38)57 (17)0.007
      Hypertension (%)107 (76)158 (47)<0.001
      Smoking
       Current35 (25)150 (45)<0.001
       Ex-smoker81 (57)140 (42)
       Non-smoker22 (16)35 (10)
       Other3 (2)12 (4)
      Mean (SD) total cholesterol level (mmol/l)5.1 (1.0)5.6 (1.3)0.001
      Antiplatelet (%)123 (87)212 (63)<0.001
      Lipid lowering (statin or other) (%)98 (70)117 (35)<0.001
      ACE inhibitor (%)54 (38)69 (20)<0.001
      Beta blocker (%)50 (35)35 (10)<0.001
      Angiotensin II antagonist (%)8 (6)24 (7)0.56
      1. Patients with one or more of the following features: prior myocardial infarction (MI), angina, coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI).
      2. P values for multiple subgroups (e.g. for age, ABPI, SBP and smoking) are for global comparisons.
      3. Calculated from the mean of ABPI from right and left leg.

      Discussion

      Our findings confirm that in spite of attempts to raise awareness about PAD as an important marker of cardiovascular risk, patients are still poorly managed prior to referral to a vascular clinic. About one third do not receive antiplatelet treatment, half do not receive lipid-lowering agents and three quarters do not receive ACE-inhibitors or angiotensin-II antagonists in spite of clear evidence supporting the routine use of these agents in patients with PAD.
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      There is concomitant poor management of blood pressure and cholesterol. About 40% of the cohort were current smokers and about half of these have tried to give up within the previous 6 months, but there did not appear to be any systematic approach to the provision of smoking cessation therapies. As expected there were high rates of conventional cardiovascular risk factors and about one third had a history of co-existing coronary heart disease. The latter group were much better treated with antiplatelet, cholesterol lowering and anti-hypertensive treatments. We also found significant associations between ABPI and age, systolic blood pressure and absolute claudication distance.
      The benefits of optimally managed hypertension are well established and a low ABPI appears to be an important predictor of morbidity and mortality in the elderly with systolic hypertension.
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      Morbidity and mortality in hypertensive adults with a low ankle/arm blood pressure index.
      In our study 76% of patients had a systolic BP>140 mmHg and 32% had systolic BP>160 mmHg. This finding is worrying since systolic hypertension has shown to be linked with the risk of both MI and stroke in the elderly and in patients with PAD, and this risk can be reduced by appropriate treatment.
      • Sutton K.C.
      • Wolfson Jr., S.K.
      • Kuller L.H.
      Carotid and lower extremity arterial disease in elderly adults with isolated systolic hypertension.
      Many hypertensive claudicants will require at least two blood-pressure-lowering drugs to achieve and maintain recommended blood pressure targets (≤140/85 mmHg), and compliance is a major problem.
      • Williams B.
      • Poulter N.
      • Brown M.J.
      • Davis M.
      • McInnes G.T.
      • Potter J.F.
      • et al.
      Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society.
      Treatment with an ACE inhibitor has been shown to reduce the risk of major cardiovascular events in patients with clinical as well as subclinical PAD.
      • Ostergren J.
      • Sleight P.
      • Dagenais G.
      • Danisa K.
      • Bosch J.
      • Qilong Y.
      • et al.
      Impact of ramipril in patients with evidence of clinical or subclinical peripheral arterial disease.
      Both the HOPE study and more recently the ASCOT trial have reported on subgroups of patients with PAD and shown that they obtain the same benefit as other groups of patients with cardiovascular disease without an increase in adverse event rates.
      • Yusuf S.
      • Sleight P.
      • Pogue J.
      • Bosch J.
      • Davies R.
      • DagenaisG
      Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.
      • Ostergren J.
      • Sleight P.
      • Dagenais G.
      • Danisa K.
      • Bosch J.
      • Qilong Y.
      • et al.
      Impact of ramipril in patients with evidence of clinical or subclinical peripheral arterial disease.
      • Dahlof B.
      • Sever P.S.
      • Poulter N.R.
      • Wedel H.
      • Beevers D.G.
      • Caulfield M.
      • et al.
      Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial.
      There is little evidence that Beta-blockers should be specifically avoided in PAD for reasons relating to worsening claudication or precipitating severe ischaemia.
      • Hankey G.J.
      • Norman P.E.
      • Eikelboom J.W.
      Medical treatment of peripheral arterial disease.
      • Radack K.
      • Deck C.
      Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease. A meta-analysis of randomized controlled trials.
      Smoking is one of the strongest risk factors for the development of PAD, for progression of disease and a poor outcome.
      • Hankey G.J.
      • Norman P.E.
      • Eikelboom J.W.
      Medical treatment of peripheral arterial disease.
      • Ingolfsson I.O.
      • Sigurdsson G.
      • Sigvaldason H.
      • Thorgeirsson G.
      • Sigfusson N.
      A marked decline in the prevalence and incidence of intermittent claudication in Icelandic men 1968–1986: a strong relationship to smoking and serum cholesterol–the Reykjavik Study.
      • Smith F.B.
      • Lowe G.D.
      • Lee A.J.
      • Rumley A.
      • Leng G.C.
      • Fowkes F.G.
      Smoking, hemorheologic factors, and progression of peripheral arterial disease in patients with claudication.
      • Cole C.W.
      • Hill G.B.
      • Farzad E.
      • Bouchard A.
      • Moher D.
      • Rody K.
      • et al.
      Cigarette smoking and peripheral arterial occlusive disease.
      • Lepantalo M.
      • Lassila R.
      Smoking and occlusive peripheral arterial disease. Clinical review.
      The 5-year mortality rate for patients with IC who continue to smoke is 40% to 50%.
      • Kannel W.B.
      • Skinner Jr., J.J.
      • Schwartz M.J.
      • Shurtleff D.
      Intermittent claudication. Incidence in the Framingham Study.
      Smoking cessation has been shown to not only reduce disease progression but also the mortality in PAD.
      • Hirsch A.T.
      • Treat-Jacobson D.
      • Lando H.A.
      • Hatsukami D.K.
      The role of tobacco cessation, antiplatelet and lipid-lowering therapies in the treatment of peripheral arterial disease.
      • Jonason T.
      • Bergstrom R.
      Cessation of smoking in patients with intermittent claudication. Effects on the risk of peripheral vascular complications, myocardial infarction and mortality.
      In our study about 40% were current smokers in contrast to the Euroheart survey of CHD patients <70 years in which 21% reported smoking.
      • Scholte op Reimer W.
      • de Swart E.
      • De Bacquer D.
      • Pyorala K.
      • Keil U.
      • Heidrich J.
      • et al.
      Smoking behaviour in European patients with established coronary heart disease.
      Half of the smokers in our study reported trying to give up within 6 months of entry, but a surprising finding was that only a half of those who reported trying to give up had been offered nicotine replacement therapy or smoking cessation counselling. Given that smoking is intrinsically linked to PAD in most patients, much of the risk reduction strategy should be directed to smoking cessation. Likewise the PARTNERS programme found only half of patients with PAD who smoked were prescribed interventions for smoking cessation, indicating a missed opportunity for prevention.
      • Hirsch A.T.
      • Treat-Jacobson D.
      • Lando H.A.
      • Hatsukami D.K.
      The role of tobacco cessation, antiplatelet and lipid-lowering therapies in the treatment of peripheral arterial disease.
      It has been shown that smokers are more likely to succeed with the help and support from healthcare professionals, and that combining nicotine replacement therapy and brief advice can improve long-term cessation rates.
      • Lancaster T.
      • Stead L.F.
      Individual behavioural counselling for smoking cessation.
      • Ludvig J.
      • Miner B.
      • Eisenberg M.J.
      Smoking cessation in patients with coronary artery disease.
      The UK National Institute of Clinical Excellence (NICE) has approved nicotine replacement therapy as cost-effective and recommended that it should be offered to all patients making a serious attempt to stop smoking.

      National Institute for Health and Clinical Excellence. Smoking cessation - bupropion and nicotine replacement therapy. Technology appraisal no.39.

      In the current study we also found that there was a strong association between prior CHD history and an increased probability that patients were on antiplatelet therapy, lipid lowering agents, ACE inhibitors or β-blockers. About one third of patients with IC have evidence of coronary and/or cerebrovascular disease.
      • Gordon T.
      • Kannel W.B.
      Predisposition to atherosclerosis in the head, heart, and legs. The Framingham study.
      • Fowkes F.G.
      • Housley E.
      • Riemersma R.A.
      • Macintyre C.C.
      • Cawood E.H.
      • Prescott R.J.
      • et al.
      Smoking, lipids, glucose intolerance, and blood pressure as risk factors for peripheral atherosclerosis compared with ischemic heart disease in the Edinburgh Artery Study.
      It appears that patients with PAD and CHD patients are better treated than those with PAD alone suggesting that use of evidence based treatments in cardiology is better than for PAD. This may be due in part to CHD management being heavily influenced by specialist clinics, whereas PAD is largely managed in primary care.
      The most common reason for a patient not being on an antiplatelet agent was that it had never been prescribed or recommended. This is despite good evidence that the use of an antiplatelet agent reduces the risk of future cardiovascular events and death by about 25% in PAD.
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      • Robless P.
      • Mikhailidis D.P.
      • Stansby G.
      Systematic review of antiplatelet therapy for the prevention of myocardial infarction, stroke or vascular death in patients with peripheral vascular disease.
      There is evidence from the large CAPRIE study, that clopidogrel reduces the risk of death stroke and MI in patients with cardiovascular disease including PAD more effectively than aspirin.
      • CAPRIE steering committee
      A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).
      A Consensus Report, which reviewed all the available evidence for antiplatelet therapy in PAD, concluded that antiplatelet therapy should be used routinely in PAD with aspirin as first line treatment, and clopidogrel providing a useful alternative if aspirin was not tolerated.
      Antiplatelet therapy in peripheral arterial disease. Consensus statement.
      The CHARISMA trial of 15,000 patients with elevated vascular risk randomised to aspirin alone or aspirin plus clopidogrel, has not show any convincing evidence for dual antiplatelet therapy in patients with PAD.
      • Bhatt D.L.
      • Fox K.A.
      • Hacke W.
      • Berger P.B.
      • Black H.R.
      • Boden W.E.
      • et al.
      Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.
      Only about half the patients were taking a statin. Evidence for the benefit of statins in patients with CHD has been available for a number of years, but specific evidence for PAD patients has been largely lacking because they were not included in the large randomised trials. However, in the Scandinavian Simvastatin Survival Study, simvastatin significantly reduced the incidence of new claudication in patients with prior MI or angina.
      • Pedersen T.R.
      • Kjekshus J.
      • Pyorala K.
      • Olsson A.G.
      • Cook T.J.
      • Musliner T.A.
      • et al.
      Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin survival study (4S).
      In addition simvastatin and atorvastatin have been shown to improve pain free walking in claudicants.
      • Aronow W.S.
      • Nayak D.
      • Woodworth S.
      • Ahn C.
      Effect of simvastatin versus placebo on treadmill exercise time until the onset of intermittent claudication in older patients with peripheral arterial disease at six months and at one year after treatment.
      • Mohler 3rd, E.R.
      • Hiatt W.R.
      • Creager M.A.
      Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease.
      Clear evidence of the benefit of statins has now been confirmed in patients with PAD, as well as other groups at risk of cardiovascular events, in the large Heart Protection Study of 20,000 patients which was published during the course of enrolment for our study
      • Collins R.
      • Armitage J.
      • Parish S.
      • Sleigh P.
      • Peto R.
      MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.
      , and the meta-analysis of cholesterol lowering trials.
      • Baigent C K.A.
      • Kearney P.M.
      • Blackwell L.
      • Buck G.
      • Pollicino C.
      • Kirby A.
      • et al.
      Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
      The low use of statins is reflected by high cholesterol levels found, with over 50% having a cholesterol greater than 5 mmol/L.
      ABPI showed significant associations with older age, blood pressure and claudication distance. The usefulness of ABPI as a marker of generalised atherosclerosis is well documented and a number of cohort studies have reported a graded inverse relationship of decreasing ankle-brachial index to cardiovascular events.
      • Murabito J.M.
      • Evans J.C.
      • Larson M.G.
      • Nieto K.
      • Levy D.
      • Wilson P.W.
      The ankle-brachial index in the elderly and risk of stroke, coronary disease, and death: the Framingham Study.
      • Zheng Z.J.
      • Sharrett A.R.
      • Chambless L.E.
      • Rosamond W.D.
      • Nieto F.J.
      • Sheps D.S.
      • et al.
      Associations of ankle-brachial index with clinical coronary heart disease, stroke and preclinical carotid and popliteal atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Study.
      There are concerns that ABPI is not a routine measurement apart from in vascular clinics, even though the majority of detection and management of PAD is done in the primary care setting. Calls for wider screening to detect PAD in at risk populations (elderly, diabetics and those with other vascular risk factors) have been made and this may require more training and resources directed to health professionals in primary care.
      • Belch J.J.
      • Topol E.J.
      • Agnelli G.
      • Bertrand M.
      • Califf R.M.
      • Clement D.L.
      • et al.
      Critical issues in peripheral arterial disease detection and management: a call to action.
      As expected the mean age of women was higher than men, more men smoked and more men were in paid employment.
      Our study has a number of limitations. We used a pragmatic design in order to minimise extra work in busy vascular clinics. Patients enrolled were not selected at random from referring practices, and in some of the participating centres, they were not consecutive referrals. For these and other reasons generalising our results to wide populations of PAD patients in the UK and other countries may need to be done with caution. We used information from routine blood results and as a consequence there was missing information, and no central checking of laboratory values. Smoking history was obtained from patients without independent checks using cotinine levels, but previous studies have shown that information on smoking history provided by patients is generally reliable.
      Our study provides current evidence that the medical management of patients with PAD still needs improvement.
      • Khan S.
      • Cleanthis M.
      • Smout J.
      • Flather M.
      • Stansby G.
      Life-style modification in peripheral arterial disease.
      • Burns P.
      • Lima E.
      • Bradbury A.W.
      Second best medical therapy.
      Evidence in our study from those patients with co-existing CHD confirms that high rates of preventive treatment can be used in this population given the right motivation and knowledge. Improved blood pressure and cholesterol control, a systematic approach to smoking cessation and other lifestyle changes including exercise and appropriate diets, will help to improve the outlook of patients with PAD.
      • Khan S.
      • Cleanthis M.
      • Smout J.
      • Flather M.
      • Stansby G.
      Life-style modification in peripheral arterial disease.
      • Burns P.
      • Lima E.
      • Bradbury A.W.
      Second best medical therapy.
      In the UK it seems unlikely that vascular surgical clinics will have the resources to deliver this care in its entirety, although this might be possible in other European countries. It is recommended that patients with PAD should be followed up in units that specialize in vascular care and management of cardiovascular risk factors. These messages must be delivered as a matter of urgency to health professionals diagnosing and managing PAD in primary care, those responsible for health care planning policy, and society at large.

      Conflicts of Interest

      Shaukat Khan, Nicola Delahunty and Rebecca Mister have no conflicts of interest to declare. Gerard Stansby, Andrew Bradbury and Marcus Flather have received honoraria for speaking, travel expenses and hold research grants from sanofi-aventis and other pharmaceutical companies. Gerry Fowkes has received travel expenses, funds for research and fees for consulting form various pharmaceutical companies.

      Acknowledgements

      We are grateful to the patients who agreed to enter the study and all Investigators, Nurses and other staff who took part in the study at the participating hospitals. The study was carried out with support from an unrestricted educational grant from Sanofi-Aventis and we gratefully acknowledge the assistance of Caroline Horwood, Fiona Bride and Diane Reeves. The study was conducted, analysed and reported independently of the company. The manuscript was provided to Sanofi-Aventis prior to publication for comment. Modifications to the manuscript as a result of this review can be provided on request, but in our view did not materially alter the content. GS and MF have received research grants and honoraria for lectures from sanofi-aventis but hold no shares or other stock options in the company. We acknowledge the statistical support of Mona Abdullah and Duo Lau Wang of the London School of Hygiene and Tropical Medicine, and Michael Roughton from the Royal Brompton and Harefield NHS Trust.

      Principal Investigators

      Tabled 1
      Aberdeen Royal InfirmaryMs J Brittenden
      Addenbrookes HospitalMr K Varty
      Belfast City HospitalMr R J Hannon
      Birmingham Heartlands HospitalProfessor A W Bradbury
      Derriford HospitalMr S Ashley
      Ealing HospitalMr G Geroulakos
      Freeman HospitalProfessor G Stansby
      Frimley Park HospitalMr David Gerrard
      Gloucestershire Royal HospitalMr JJ Earnshaw
      Gwent Healthcare NHS TrustMr R L Blackett
      Hull Royal InfirmaryProfessor P McCollum
      Ipswich Hospital NHS TrustMr I S Osman
      Leicester Royal InfirmaryProfessor N J M London
      Morriston HospitalMr C P Gibbons
      Pinderfields HospitalMr P J Curley
      Queen Elizabeth HospitalMr Bhattacharya
      Royal Bournemouth HospitalMr S D Parvin
      Royal Free HospitalMr D M Baker
      Royal United HospitalProfessor Mike Horrocks
      Selly Oak HospitalMr R K Vohra
      Southampton General HospitalProfessor C P Shearman
      St Marys HospitalMr N J W Cheshire
      Walsgrave Hospitals NHS TrustMr D Higman

      Study Co-ordinators

      Tabled 1
      Aberdeen Royal InfirmaryKevin Cassar
      Addenbrookes HospitalCathy Fisher
      Belfast City HospitalKathy Mcguigan
      Birmingham Heartlands HospitalMs Emma Burke
      Derriford HospitalChryz Cosgrove
      Ealing HospitalStella Daskalopoulou
      Freeman HospitalShiela Dugdill
      Frimley Park HospitalClaire King
      Gloucestershire Royal HospitalMs Donna Parkin
      Gwent Healthcare NHS TrustJayne Warren
      Hull Royal InfirmaryMs Jennifer Bryce
      Ipswich Hospital NHS TrustDr Tony Jaipersad
      Leicester Royal InfirmaryMrs Sandra Smith
      Morriston HospitalVicky Boyce
      Pinderfields HospitalAmit Pannu
      Queen Elizabeth HospitalMr Marcus Cleanthis
      Royal Bournemouth HospitalSara Baker
      Royal Free HospitalPhyl Morris-vincent
      Royal United HospitalAbigal Parks
      Selly Oak HospitalMr Christopher Lee
      Southampton General HospitalJenny Williams
      St Marys HospitalLouise Allen
      Walsgrave Hospitals NHS TrustCarol Bick

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      Linked Article

      • Intermittent Claudication: A Plea for Guidelines for Medical Management
        European Journal of Vascular and Endovascular SurgeryVol. 33Issue 4
        • Preview
          The medical management of peripheral arterial disease, including intermittent claudication, has been a favourite topic for reviews in the last few years: a good recent synthesis of available evidence is by Hankey et al.1 PREPARED-UK has attempted to audit the medical treatment of patients newly referred with intermittent claudication in 2002–3. The audit cycle works by comparing current practice to recommended practice and identifying mechanisms to improve practice before a further audit, which hopefully will show improvement.
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