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Cardiovascular Risk Factors and Peripheral Arterial Disease 135
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Table 14.2. Secondary causes of hypertriglyceridaemia/hypercholesterolaemia. Updated
Excessive alcohol intake
Diabetes mellitus
Hypothyroidism
Some types of liver disease
Some types of renal disease
Obesity/diet
Drugs: beta-blockers, thiazides, oestrogens, anabolic steroids, corticosteroids, tamoxifen, protease
inhibitors, retinoids, ciclosporin
• Triglyceride levels vary considerably within any one individual: this variability
includes the fact that fasting triglycerides may be considerably lower than nonfasting levels in some patients. There is evidence that postprandial triglyceride
levels also predict vascular risk, but this measurement is not easily standardised.
Therefore, assessment of triglyceride status is best represented by a fasting
sample (14-h overnight fast; water only allowed).
The current opinion is that fasting serum triglyceride levels are independent vascular risk factors [5]. Hypertriglyceridaemia is often associated with secondary
causes that aggravate the patient’s tendency to this type of dyslipidaemia (Table
14.2). These causes need to be addressed.
Fasting triglyceride levels are defined in the NCEP ATP III guidelines [1]:
• Borderline high: 150–199 mg/dl (1.7–2.2 mmol/l).
• Moderately elevated: 200–499 mg/dl (2.3–5.6 mmol/l).
• Severe hypertriglyceridaemia: =500 mg/dl (=5.6 mmol/l).
According to these guidelines [1], the treatment priority for cases with severe
hypertriglyceridaemia shifts from LDL-C to the triglyceride levels. This is because of
the increased risk of acute pancreatitis associated with severe hypertriglyceridaemia
[1]. For milder hypertriglyceridaemia, the priority for treatment remains the LDL-C
level [1].
D. The fasting HDL-C level in this patient was 46 mg/dl (1.2 mmol/l) – this is satisfactory.
Interpretation of fasting HDL-C values:
A raised HDL-C level is a protective factor, whatever the levels of other lipid variables [1, 6, 7]. The recent NCEP ATP III guidelines [1] recommend that HDL-C
levels should ideally be =40 mg/dl (=1.0 mmol/l) [1, 6, 7]. A low HDL-C level is also
predictive of the risk of stroke [8, 9]. The importance of HDL-C in reducing the risk
of vascular events is supported by the findings of a secondary prevention trial
(VA-HIT) [9].
E. The thyroid function tests were normal.
It is useful to routinely assess thyroid function in dyslipidaemic patients. This is
because hypothyroidism is not uncommon and it is associated with dyslipidaemia
(see Table 14.2). There is also some evidence showing that hypothyroid patients are
136 Vascular Surgery
Table 14.3. CHD equivalents according to the NCEP ATP III guidelines [1]. Updated
Peripheral arterial disease
Abdominal aortic aneurysm
Symptomatic carotid artery disease
Diabetes mellitus
Multiple risk factors conferring a calculated risk for a vascular event >20 per cent over the next 10 years
more likely to have “muscle-related” side effects if they are given a statin.
Hypothyroidism can also be difficult to spot unless the clinical features are obvious.
Replacement with thyroxine is usually associated with a beneficial change in the
lipid profile and body weight.
Question 2
What drug would you use to treat this patient’s dyslipidaemia? What are your target
levels?
The main target for lipid-lowering treatment is the LDL-C level. Since PAD is
considered a coronary heart disease (CHD) equivalent [1] (Table 14.3), the LDL-C
target is 100 mg/dl (2.6 mmol/l) in the USA [1] and 96 mg/dl (2.5 mmol/l) in Europe
[10]. The NCEP ATP III guidelines were revised in 2004 to include an optional LDLC target of 70 mg/dl (1.8 mmol/l) for very high-risk patients [11].
As explained above, the HDL-C and triglyceride levels are secondary targets.
A full fasting lipid profile should be obtained before making any decision regarding treatment. In the case presented above, the fasting values were: total cholesterol
= 228 mg/dl (5.9 mmol/l), HDL-C = 46 mg/dl (1.2 mmol/l), LDL-C = 155 mg/dl
(4.0 mmol/l) and triglycerides = 141 mg/dl (1.6 mmol/l).
The drug of choice is a statin to achieve the LDL-C target. Statins also improve
HDL-C and triglyceride levels, although these latter effects may be small.
Three statins have extensive trial-based evidence in terms of reduced mortality:
atorvastatin, pravastatin and simvastatin. There is also evidence that treatment with
statins decreases morbidity and mortality and improves symptoms in patients with
PAD [4, 12].
There is convincing evidence that statins reduce the risk of stroke [12–14].
Several studies have also shown that aggressive lipid lowering is associated with a
reduced progression of atherosclerotic carotid artery disease [13, 14]. Patients with
PAD are likely to have some degree of carotid artery disease. PAD is also a strong
predictor of the risk of stroke.
Question 3
What modifiable risk factors would you like to address in a high-risk patient, as in
this case?
Cardiovascular Risk Factors and Peripheral Arterial Disease 137
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Smoking
Smoking cessation is of paramount importance. The vast majority of PAD patients
are, or have been, smokers. Furthermore, smoking is associated with adverse effects
on several variables that predict vascular events. For example, smoking can lower
serum HDL-C levels, raise serum triglyceride levels, increase insulin resistance and
elevate plasma fibrinogen concentrations [15]. Plasma fibrinogen is an independent
predictor of the risk of MI and stroke. Smoking may even predict the progression of
PAD and graft occlusion after infrainguinal bypass surgery [16]. There is evidence
that the vascular risk is greater in smokers than in non-smokers, despite the use of
statins [17].
There is a need to establish smoking cessation clinics where specialist care can be
delivered. All clinicians should try to motivate patients to quit by spending a few
minutes explaining why smoking is harmful to them. In PAD, quitting may improve
claudication and reduce the risk of vascular events.
Antiplatelet Agents
This patient could not tolerate aspirin. It is estimated that this problem arises in
10–15 per cent of patients who are prescribed aspirin. There are several alternatives:
• “Cover” aspirin with a proton pump inhibitor (e.g. omeprazole).
• Eradicate Helicobacter pylori infection, if present.
• Use clopidogrel: the effectiveness of clopidogrel is based on the findings of
major trials (e.g. CAPRIE, CREDO and CURE), but there is no study specifically
designed to assess the effectiveness of this drug in PAD [18]. However, patients
with PAD had significantly fewer events on clopidogrel than on aspirin in the
CAPRIE trial. Unfortunately, this conclusion is limited by the fact that patient
subgroup analysis was not included in the original trial protocol [18].
Due to his intolerance of aspirin, this patient was prescribed clopidogrel
75 mg/day. He tolerated this antiplatelet agent without any problems.
Blood Pressure
Strict control of blood pressure in high risk patients is essential [19]. In order to
achieve this objective, there may be a need to use several antihypertensive drugs.
Some general recommendations are appropriate:
• Several experts suggest that angiotensin-converting enzyme (ACE) inhibitors
and angiotensin II receptor blockers should be avoided or used with caution in
PAD because these patients may have renal artery stenosis. If an ACE inhibitor
or angiotensin II receptor blocker is used, the plasma creatinine concentration
should be monitored soon after starting treatment.
• There is still some debate as to whether beta-blockers adversely affect the circu-
lation in the lower limbs of patients with PAD. It would appear reasonable,
however, to use a beta-blocker in post-MI patients with PAD.
138 Vascular Surgery
• Some blood pressure drugs exert beneficial or adverse effects on lipid levels,
haemostatic factors and perhaps more importantly, the long-term risk of developing diabetes.
Glucose Status
This topic was discussed above. It is also important to note that if the patient is diabetic, the blood pressure targets become stricter, especially if proteinuria is present.
Lipids
This topic has been discussed above.
Emerging Risk Factors
These factors [1, 4] include:
• Lipoprotein (a) (Lp(a)): there is evidence that Lp(a) is a marker of vascular risk,
especially in patients with a raised serum LDL-C. Raised Lp(a) levels may also
predict the risk of restenosis after surgery for PAD [16]. Serum Lp(a) levels are
difficult to lower, but the risk associated with this abnormality may decrease if
the LDL-C level is markedly reduced. Correcting hypothyroidism is associated
with a fall in serum Lp(a) levels. Similarly, postmenopausal hormone replacement therapy (HRT) may reduce serum Lp(a) concentrations. There are, as yet,
no intervention trials to show that lowering serum Lp(a) levels (e.g. by using
high doses of nicotinic acid) is associated with fewer vascular events.
• Homocysteine: raised plasma levels of homocysteine are thought to predict vas-
cular risk possibly by acting synergistically with established risk factors. The
link between homocysteine and PAD appears to be stronger than with CHD [4].
There are, as yet, no intervention trials to show that lowering plasma homocysteine levels (e.g. by folic acid, vitamin B12 or B6 supplements) is associated with
a reduced risk of vascular events.
• Haemostatic and fibrinolytic factors: there is strong evidence showing that the
plasma fibrinogen concentration is an independent predictor of vascular risk.
The levels of this coagulation factor also predict the progression of PAD and
possibly the risk of restenosis following bypass surgery [16]. Plasma fibrinogen
levels can be lowered by some fibrates used to treat dyslipidaemia. However, as
with other emerging risk factors, no trial-based evidence is available to show
that lowering fibrinogen levels is associated with a decreased risk of vascular
events. There is less evidence linking fibrinolytic factors with vascular risk.
• Markers of inflammation (e.g. C-reactive protein, CRP): serum CRP levels
predict the risk of a vascular event even when there is no vascular disease
present or when lipid levels are “normal”. We do not know whether CRP just
reflects the inflammatory component of atherosclerosis or whether it is actually
involved in its pathogenesis. Statins and fibrates lower serum levels of CRP [20].
Recent evidence suggests that we should also consider CRP levels (in the high
sensitivity range) as a target for treatment [21].
Cardiovascular Risk Factors and Peripheral Arterial Disease 139
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Question 4
Is it relevant to monitor renal function in this patient?
Yes, because about 33 per cent of PAD patients have atherosclerotic renal artery
stenosis [4]. It is therefore important to consider the presence of this condition,
especially if the renal function tests are abnormal. There is evidence that renal and
vascular disease progress in parallel [22]. Increased plasma creatinine levels are
associated with a higher risk of vascular events, even if these values are in the upper
end of the reference range. There is evidence that statins exert a renoprotective
action in patients with CHD or PAD [23, 24]. Impaired renal function may contribute to hyperuricaemia and hyperhomocysteinaemia [25]. These variables may
predict increased vascular risk.
References
1. Expert panel on detection evaluation, and treatment of high blood cholesterol in adults. Executive
summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on
detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III).
JAMA 2001;285:2486–97.
2. Haffner SM, Alexander CM, Cook TJ, et al. Reduced coronary events in simvastatin-treated patients
with coronary heart disease and diabetes or impaired fasting glucose levels. Subgroup analyses in the
Scandinavian Simvastatin Survival Study. Arch Intern Med 1999;159:2661–7.
3. Colhoun HM, Betteridge DJ, Durrington PN, et al. CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes
Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685–96.
4. Daskalopoulou SS, Daskalopoulos ME, Liapis CD, Mikhailidis DP. Peripheral arterial disease: a
missed opportunity to administer statins so as to reduce cardiac morbidity and mortality. Curr Med
Chem 2005;12:443–52.
5. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high density lipoprotein cholesterol level: a meta-analysis of the population-based
prospective studies. J Cardiovasc Risk 1996;3:213–9.
6. Wood D, Durrington P, Poulter N, McInnes G, Rees A, Wray R, on behalf of the Societies. Joint
British recommendations on prevention of coronary heart disease in clinical practice. Heart
1998;80(suppl 2):S1–29.
7. Sacks FM, for the Expert Group on HDL Cholesterol. The role of high-density lipoprotein (HDL)
cholesterol in the prevention and treatment of coronary heart disease: Expert Group
Recommendations. Am J Cardiol 2002;90:139–43.
8. Rizos E, Mikhailidis DP. Are high density lipoprotein (HDL) and triglyceride levels relevant in stroke
prevention? Cardiovasc Res 2001;52:199–207.
9. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart
disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410–7.
10. De Backer G, Ambrosioni E, Borch-Johnsen K, et al. Third Joint Task Force of European and Other
Societies on Cardiovascular Disease Prevention in Clinical Practice. European guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2003;24:1601–10.
11. Grundy SM, Cleeman JI, Merz CN, et al. National Heart, Lung, and Blood Institute; American College
of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the
National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation
2004;110:227–39.
12. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet
2002;360:7–22.
13. Cheng KS, Mikhailidis DP, Hamilton G, Seifalian AM. A review of the carotid and femoral intimamedia thickness as an indicator of the presence of peripheral vascular disease and cardiovascular
risk factors. Cardiovasc Res 2002;54:528–38.
140 Vascular Surgery
14. Rantanen K, Tatlisumak T. Secondary prevention of ischemic stroke. Curr Drug Targets
2004;5:457–72.
15. Tsiara S, Elisaf M, Mikhailidis DP. Influence of smoking on predictors of vascular disease. Angiology
2003;54:507–30.
16. Cheshire NJW, Wolfe JHN, Barradas MA, Chambler AW, Mikhailidis DP. Smoking and plasma
fibrinogen, lipoprotein (a) and serotonin are markers for postoperative infrainguinal graft stenosis.
Eur J Vasc Endovasc Surg 1996;11:479–86.
17. Milionis HJ, Rizos E, Mikhailidis DP. Smoking diminishes the beneficial effect of statins: observations from the landmark trials. Angiology 2001;52:575–87.
18. Robless P, Mikhailidis DP, Stansby G. Systematic review of antiplatelet therapy for the prevention of
myocardial infarction, stroke or vascular death in patients with peripheral vascular disease. Br J Surg
2001;88:787–800.
19. Chobanian AV, Bakris GL, Black HR, et al. National Heart, Lung, and Blood Institute Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National
High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint
National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure:
the JNC 7 report. JAMA 2003;289:2560–72.
20. Tsimihodimos V, Miltiadous G, Daskalopoulou SS, Mikhailidis DP, Elisaf MS. Fenofibrate: metabolic
and pleiotropic effects. Curr Vasc Pharmacol 2005;3:87–98.
21. Ridker PM, Cannon CP, Morrow D, et al. Pravastatin or Atorvastatin Evaluation and Infection
Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-reactive
protein levels and outcomes after statin therapy. N Engl J Med 2005;352:20–8.
22. Rahman M, Brown CD, Coresh J, et al. Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial Collaborative Research Group. The prevalence of reduced glomerular filtration
rate in older hypertensive patients and its association with cardiovascular disease: a report from the
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Arch Intern Med
2004;164:969–76.
23. Athyros VG, Mikhailidis DP, Papageorgiou AA, et al. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek
atorvastatin and coronary heart disease evaluation (GREACE) study. J Clin Pathol 2004;57:728–34.
24. Youssef F, Gupta P, Seifalian AM, Myint F, Mikhailidis DP, Hamilton G. The effect of short-term
treatment with simvastatin on renal function in patients with peripheral arterial disease. Angiology
2004;55:53–62.
25. Daskalopoulou SS, Athyros VG, Elisaf M, Mikhailidis DP. Uric acid levels and vascular disease. Curr
Med Res Opin 2004;20:951–4.
15. Angioplasty for Critical Arterial Stenosis
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Lars Norgren
A 62-year-old man, formerly a shopkeeper and a heavy smoker (26 cigarettes
daily until 5 years ago when he succeeded in giving up), presented with a history
of leg pain. Since retirement 2 years ago, he had started going for walks in the
nearby countryside. From the start, he could walk for 5 miles, but he felt some
pain in his left calf, which reduced after slowing down.
Question 1
Which of the following statements are correct?
A. This symptom is typical for both intermittent claudication and knee joint
arthrosis.
B. This man presents exceptional symptoms: in the vast majority of cases, both legs
are affected.
C. Intermittent claudication affects about 5 per cent of the male population over
the age of 55 years.
D. This man should be advised to stop walking to reduce the risk of pain.
E. The symptom is consistent with an occlusion or a critical stenosis of the
superficial femoral artery (SFA).
The man did not seek advice at that stage, but 2 years later, he suddenly experienced more severe pain in the left calf when he woke up in the morning. This happened 3 days before presentation. The pain disappeared slowly, but walking was
then restricted to about 20 m, at which point the pain started. He felt some numbness in the toes, and on awaking in the morning there was some pain in the foot,
which disappeared when he stood up.
141
142 Vascular Surgery
Question 2
What is the most likely reason for the new symptom?
A. Muscle rupture.
B. Deep vein thrombosis.
C. Thrombosis of an artery or collateral artery.
D. Minor stroke.
E. Aggravation of knee joint arthrosis.
At examination, femoral pulses were present but no popliteal or foot pulses could
be felt. Doppler flow was detected in the left posterior tibial artery, and in the right
posterior tibial artery and dorsalis pedis artery (DPA). Ankle brachial pressure
index (ABPI) of the affected leg was 0.4; that of the right leg was 0.8.
An angiography was performed, depicting lesions as shown in Fig. 15.1, as less
than 50 per cent stenosis of the left external iliac artery (EIA), two short stenoses of
more than 70 per cent of the left SFA, and an occlusion of a deep femoral artery
branch. On the right side, there was one stenosis of the SFA of about 70 per cent.
There were also short occlusions of the anterior tibial artery bilaterally.
Immediately following the diagnostic angiography, it was decided to perform a
balloon percutaneous transluminal angioplasty (PTA) of the stenoses of the left
SFA. The right leg was left untreated.
Question 3
Which of the following statements are correct?
A. There is normally no indication to treat an asymptomatic limb.
B. It is never possible to reopen occlusions of the deep femoral artery branches.
C. A stenosis of less than 50 per cent is not critical and does not normally need to
be treated.
D. The critical stenosis of the SFA in our case is probably the primary reason for
this patient’s initial symptoms.
E. The deep femoral artery occlusion could well be the reason for the aggravation
of the patient’s symptoms.
At follow-up after 30 days, the patient had improved and could walk his daily
5 miles, albeit with some tolerable claudication.
Question 4
Which investigations are relevant for the follow-up of this case?
A. Digital subtraction angiography.
Angioplasty for Critical Arterial Stenosis 143
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Fig. 15.1. Lesions found on angiography. 1, <50 per cent stenosis of left external iliac artery; 2, two short
stenoses (<70 per cent) of left superficial femoral artery; 3, occlusion of a left deep femoral artery branch; 4,
short stenosis (70 per cent) of the right superficial femoral artery; 5, short occlusions of anterior tibial artery
bilaterally.
B. ABPI measurement.
C. Spiral CT angiography.
D. Duplex investigation.
E. Laser Doppler flux measurement.
144 Vascular Surgery
Question 5
What advice and adjunctive treatment should be given to this patient?
A. Continuing exercise, but stopping if pain appears.
B. Antiplatelet drug treatment.
C. Antiplatelet drug + warfarin treatment.
D. Avoid cycling. Hip flexion increases the risk of new femoral stenotic or occlusive
lesions.
E. Continuing exercise.
Commentary
Intermittent claudication affects about 5 per cent of the male population over
55 years and about 2.5 per cent of the female population [1]. Calf pain during
walking, caused by occlusion or stenosis of the SFA, is the most common symptom;
in the majority of cases, only one leg is symptomatic to start with. [Q1: C, E] Only
about 25 per cent of patients suffering intermittent claudication deteriorate to critical limb ischaemia (CLI) [2, 3]; the majority remain stable or even improve. The
major risk is cardiovascular complications.
When a sudden deterioration appears, as in our case, a thrombotic event is most
likely. [Q2: C]
An ABPI of 0.8 indicates the presence of asymptomatic peripheral arterial occlusive disease (PAOD). Symptoms are hidden due to the walking restriction from the
more severely diseased contralateral leg. An ABPI of 0.4 can be consistent with CLI,
but symptoms are not convincing. Usually, the definition of chronic CLI requires
stable symptoms for at least 2 weeks [4]. The symptoms fit more appropriately into
the definition of acute ischaemia, with a viable, unthreatened leg [5].
Critical stenosis produces a measurable pressure gradient and/or reduced blood
flow. Usually, more than a 75 per cent reduction of the cross-sectional area is
required, which means more than a 50 per cent reduction of the luminal diameter.
[Q3: A, C, D, E] Also, a less pronounced grade of stenosis may produce haemodynamic
disturbances and symptoms, especially during exercise. Two or more stenoses after
each other may also become significant at a lesser grade of stenosis.
In principle, non-disabling claudication symptoms do not justify interventional
treatment. Had this patient sought advice before the acute symptoms appeared, he
would have been told to continue exercising and to try to continue walking when
pain appeared. The acute symptoms changed the scene, although the leg was not in
danger. In this situation, an angiography should be performed soon to enable treatment. A duplex examination could be carried out first as a screening procedure.
PTA was performed on the two subsequent and critical SFA stenoses, while the
uncritical CIA stenosis was left. If in doubt about whether to treat a stenosis, than a
measurement of the pressure gradient over such a stenosis is valuable. If this gradient is less than 10 mm Hg (mean pressure), then there is no indication to dilate.
The occluded profunda branch is a delicate problem. It might be a thrombotic
occlusion, preventing collateral blood flow to the distal SFA. One could consider
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