Introduction

Peripheral arterial disease (PAD) is usually defined as arterial disease which affects the arterial vasculature outside the heart. Aortic, renal and cerebral vascular diseases are addressed elsewhere in this text; therefore this chapter will focus on peripheral arterial disease of the lower extremities, distal to the aortic bifurcation.

The underlying pathologic abnormality of PAD of the lower extremities is obstruction of arterial flow, most commonly caused by atherosclerosis. However, other causes of arterial obstruction must also be entertained during diagnosis and include inflammatory diseases such as arteritis, entrapment syndromes, aneurysms and thrombosis in situ or thromboembolism. Atherosclerosis is a disease which primarily affects the intimal layer of elastic arteries, with the formation initially of a fatty streak, caused by adhesion moleculedependent infiltration of the intima of mononu-clear leukocytes, potentiated by chemoattractant chemokines. The leukocytes then become lipid laden, becoming macrophage foam cells, and the fatty streak is formed. Smooth muscle cells also infiltrate the plaque, with varying degrees of collagen formation. The resultant lipid-rich lesion, which is separated from the lumen of the artery only by a fibrous cap, can either rupture into the artery’ s lumen, triggering a thrombotic cascade and resulting in atherothrombosis and infarction, or become organized and ultimately even calcified, causing local obstruction to distal blood flow or stenosis.

PAD is an insidious condition, usually having a gradual onset and long latency before symptoms arise. It is associated with an increased risk of cardiovascular morbidity and mortality, and therefore evidence of PAD should direct health professionals to ensure that aggressive cardiovascular secondary prevention strategies are implemented.

Epidemiology and natural history

While the clinical interventions among patients with PAD traditionally focused on the impact of the arterial disease on the limbs, more recently the emphasis has shifted towards the risk of cardiovascular (CV) complications such as fatal and non-fatal myocardial infarction, and stroke faced by individuals with PAD. With respect to morbidity in the affected leg(s), only 1–3.3% of patients with intermittent claudication require amputation over a five-year period.⁵ However, some subgroups of PAD patients remain at higher risk of further limb pathology. Specifi-cally, 25% of patients with critical limb ischemia require amputation as the primary treatment⁵; patients who present with premature onset of PAD (i.e. at an age of ≤45 years) have an increased need for repeat limb intervention⁶ and those who continue to smoke after their PAD diagnosis have a worse prognosis for limb-related morbidity.⁷ A more ominous threat to patients with PAD is their poor CV prognosis, as approximately 40–60% of patients with PAD have concurrent coronary artery disease (CAD) and cere-brovascular disease. The annual major adverse cardiovascular event rate (myocardial infarction, ischemic stroke and vascular death) in PAD patients is 5–7%, with a five-year probability of a major non-fatal or fatal CV complication of 30–35%, and there is a 70% mortality rate after 15 years. A low ABI has also been shown to have a high specificity for future cardiovascular events, including stroke and myocardial infarction.⁸ Figure 65.1 shows the natural history of atherosclerotic lower limb PAD.

Figure 65.1 Natural history of atherosclerotic lower limb PAD over five years. PAD, peripheral arterial disease; CLI, critical limb ischemia; C V, cardiovascular; MI, myocardial infarction. (From Hirsch et al.¹⁸, with permission.)

Risk factors

Male sex is reported as a PAD risk factor, as there are more men than women with PAD in younger age groups, which is likely due to the greater prevalence of smoking among men than women. However, because of the increased life span of women compared with men, and the increased incidence of PAD with increasing age, the overall incidence of PAD is actually similar in both sexes (Fig. 65.2). Tobacco exposure is the major risk factor for PAD, with the risk in current smokers being 2.3 times that of non-smokers.⁹ In one population-based study, the prevalence of current or former smoking in persons with PAD with an ABI of less than 0.9 was 85% in men and 47% in women,¹⁰ which results in a population attributable risk of tobacco exposure for PAD of 50–76%.⁹ Furthermore, the degree of tobacco exposure has a dose–response relationship with PAD risk, increasing with increasing pack-years of smoking. Other risk factors for the development of PAD include increasing age (see Fig. 65.1), dyslipidemia, diabetes (increase in PAD risk of 2–4-fold³), hypertension (increase in PAD risk of 2–4-fold¹¹), impaired renal function (increase in PAD risk of threefold in women with a creatinine clearance of <30mL/min/1.73m²¹²), and prior history of coronary artery disease (increase in PAD risk of 1.5-fold¹¹). Dyslipidemia is a well-recognized risk factor, with an association between decreased ABI and increased total cholesterol and decreasing HDL cholesterol shown in the Cardiovascular Health Study.¹³ Similarly, a trend towards decreased ABI with higher triglyceride levels was noted, though this did not persist in multivariate analysis.¹³ Persons with diabetes mellitus are at particular risk of developing PAD, with a relative risk of 2–4 times that of non-diabetics.¹⁰ For every 1% increase in HbA1C in type 2 diabetes, the risk of PAD increases by 28%.¹⁴ Diabetics are also much more likely to develop further PAD complications, with a risk of major amputation 7–15 times greater than non-diabetics with PAD. This is likely due to the peripheral sensory neuropathy associated with diabetic foot conditions, meaning that diabetics often present later, as their disease has been asymptomatic. Diabetes also causes rheologic changes, with increased blood coagulability, and a greater predisposition to acute and subacute thrombotic episodes, and increased vascular inflammation with calcification of the intima and more widespread vascular disease.

Figure 65.2 The age-and sex-specific prevalence of PAD (and 95% CI) according to age for men (white bars) and women (shaded bars). (From Meijer et al¹⁰, with permission.)

The Framingham investigators have reported that age, sex, cholesterol, hypertension, cigarette smoking, diabetes and pre-existing CAD are associated with increased risk of intermittent claudication, and have developed and published an intermittent claudication risk score based on these risk factors.¹⁵ Bendermacher et al¹⁶ have also developed a prediction rule to guide general and family practitioners with regard to which patients to screen for PAD, based on age, smoking status and hypertension (Fig. 65.3).

Figure 65.3 The PREVALENT Risk Score. * Risk factors were examined using a stepwise multiple logistic regression model in 7454 subjects, which consistently removed gender, diabetes, hypercholesterolaemia, positive family history and body-mass index. (Adapted from Bendermacher et al.¹⁶, with permission.)

Diagnosis

Physical examination is an important part of the PAD evaluation, and a number of bedside tests can be performed. The most useful positively predictive clinical features for screening asymptomatic persons for PAD are a positive history of claudication (likelihood ratio (LR) for PAD 3.3, 95% confidence interval (CI) 2.3–4.8), listening for a femoral, iliac or popliteal bruit (LR 4.8, 95% CI 2.4–9.5, for the presence of one bruit at rest) and palpation for a pulse abnormality (femoral, popliteal, dorsalis pedis or posterior tibial; LR 3.1, 95% CI 1.4–6.6). For people with symptomatic PAD, clinical features such as cool skin (L 5.9, 95% CI 4.1–8.6), the presence of a bruit (LR 5.6, 95% CI 4.7–6.7, for the presence of one bruit at rest), and a pulse abnormality (LR 4.7, 95% CI 2.2–9.9) are positive predictors of PAD.¹⁹ However, reliance on a pulse abnormality alone can overestimate the incidence of PAD.¹ A scoring system for PAD risk using arterial Doppler signals has been published²⁰ and is useful for identifying those patients who require further testing with an ABI test. Commonly, patients with intermittent claudication are classified using either the Rutherford or the Fontaine staging approach. The Rutherford staging is currently recommended⁵ (Table 65.1).

Table 65.1 Classification of peripheral arterial disease: Rutherford categories

Reproduced with permission from Schmieder FA, Comerota AJ. Am J Cardiol 2001;87(12, suppl 1);3–13.

Ankle Brachial Index

The ABI is a simple bedside test which can be rapidly performed, and which is most often used in epidemiologic studies to assess the presence of PAD (Fig. 65.4). The ABI is useful for both diagnosis and assessment of the efficacy of therapeutic interventions, and has been shown to have a high sensitivity and specificity for PAD, with a sensitivity of +90% and specificity of 95% for detecting angiographically significant disease with an ABI of 0.9 or less.²¹ An ABI of < 0.9 has typically been used to diagnose PAD in large epidemiologic studies, and is recommended as the cut-off by both the American Heart Association¹⁸ and the Transatlantic Inter-Society (TASC) guidelines.⁵ Furthermore, the presence of a low ABI is highly specific for adverse CV prognosis, although its sensitivity is low. For example, a low ABI (< 0.8–0.9) has a sensitivity and specificity for the prediction of incident CAD of 16.5% and 92.7%, of incident stroke of 16.0% and 92.2%, and of CV mortality of 41.0% and 87.9% respectively.⁸ The ABI shows a U-shaped relationship with both all-cause and cardiovascular mortality (Fig. 65.5), with both ABIs of < 0.9 and > 1.4 associated with increased risk.²² Higher ABIs > 1.4 are associated with abnormal calcification of the arterial wall and resultant non-compressibility of the vessel, such as is common in diabetes.

Figure 65.4 Measurement of the Ankle Brachial Index. Systolic blood pressure is measured in both brachial arteries, and in the posterior tibial and dorsalis pedis arteries using a Doppler ultrasound device. The higher of the pedal systolic pressures is chosen on each side, and the higher of the two brachial pressures is chosen. The ABI for each side is calculated by dividing the ankle pressure by the arm pressure. (Reproduced with permission from Hiatt WR. N Engl J Med 2001; 344 (21):1608–21.)

Figure 65.5 All-cause and CVD mortality in a population-based cohort of American Indians, showing the “U” shaped relationship with ABI. (Reproduced from Resnick et al²², with permission.)

Performing an ABI

With the patient in a supine position, the brachial systolic pressure is taken in both arms and the highest pressure recorded. Some recommend that the pressure be recorded ideally with a handheld 5 or 10 mHz Doppler ultrasound¹⁷ though use of a stethoscope is acceptable, as long as the methods are consistent over time. Then the systolic pressure at the ankle, in both the anterior tibial and dorsalis pedis arteries, is determined using a 10–12cm sphygmo-manometer cuff around the ankle and the Doppler, and the highest pressure is recorded. The ABI is the ankle pressure divided by the brachial pressure. If the ankle arteries are non-compressible (such as in patients with diabetes mellitus or the very elderly) the ankle toe index can be a more informative test of distal disease, with an index of <0.70 indicating PAD. Some patients, in particular those with iliac disease, may not have a detectable abnormality on the ABI at rest, but complain of symptoms on exercise. The abnormality in these patients may only become apparent on exercise, as the inflow velocity increases, so a treadmill or plantarflexion test may be performed, with the ABI measurement repeated after exercise. Other useful non-invasive testing includes segmental Doppler pressure measurements, which uses a cuff method to identify pressure drops along the lower limbs, to try and isolate the lesion. However, weaknesses of this test are the possibility of missing iliac lesions, and the difficulty in interpreting results in the very old or diabetic subjects.

Treadmill testing

Treadmill testing is particularly useful for identifying PAD in patients in whom the disease is suspected but who have no reduction in ABI at rest. This is sometimes the case in patients with isolated iliac lesions. The procedure requires an initial measurement of either the ABI or full segmental Doppler leg pressures at rest. The patient is then asked to walk (typically on a motorized treadmill with a programmed schedule, such as at 3.2 km/h (2mph), 10–12% grade) for a maximum of five minutes or until maximal claudication pain occurs, unless another reason to stop such as coronary ischemia arises. Following this, the ankle pressure is again measured. A decrease in ABI of 15–20% is diagnostic of PAD. For patients who are uncomfortable using a treadmill, especially older patients, a six-minute walk test along a corridor can also be an effective exercise modality

Diagnostic imaging

This is usually reserved for patients in whom an intervention is being planned or to follow up graft patency. Historically, the gold standard for diagnosis of PAD has been conventional angiography, but because of its invasive and labor-intensive nature and the risks associated with it, non-invasive imaging tools are frequently used.

The primary use of angiography is detection of disease in the arterial tree in persons in whom an intervention is being planned, such as those with critical ischemia or severe intermittent claudication symptoms unresponsive to lifestyle or medical therapy. The advantages of angiography are that definition of the vascular tree is optimized, and hemodynamic parameters may be measured directly. However, as an invasive procedure, angiography carries risks of contrast nephropathy and/or anaphylaxis, access site bleeding or hematoma, atheroembolism, and rarely vascular disruption with dissection or rupture. It is therefore best reserved for carefully chosen patients.

Duplex ultrasound

is used to identify exact lesion sites in persons with symptoms or an abnormal ABI, and also has utility in venous graft surveillance post peripheral bypass procedures. The sensitivity and specificity for detecting lesions are high, reported as 94% by one meta-analysis.²³ Duplex ultrasound is especially powerful when using color-guided methods. However, it is labor intensive and requires a high level of technical expertise.

Contrast computed tomographic (CT) angiography

is a further option for imaging the peripheral arterial system. Previously hampered by poorer image quality and slow scanning times, the new generation of multidetector array CT scanners offer high-quality images at high imaging speeds, although image reconstruction can be time consuming. Multidetector row spiral CT angiography (CTA) has been shown to provide sufficient clinical information, although at lower therapeutic confidence, when compared with digital subtraction angiography (DSA). It has excellent sensitivity and specificity for depicting arterial occlusions (sensitivity and specificity of 88.6% and 97.7%) and stenoses of at least 75% (92.2% and 96.8% respectively).²⁴ A meta-analysis of CTA compared with DSA showed sensitivity and specificity of detecting a stenosis >50% for CTA of 92% and 93%, respectively.²⁵ Another study randomized patients to either contrast MR angiography or multi-detector row CTA and found similar clinical utilities, but decreased costs in the CTA group.²⁶ However, the limitations of CTA include difficulty in interpretation of images in which there is a high degree of scatter caused by highly calcified vascular segments, the potential for renal impairment due to contrast injections, and the exposure to ionizing radiation.

Contrast-enhanced magnetic resonance (MR) angiography

is an alternative to CTA and has the clear advantage of providing a “road map” of the arterial system of the lower limbs. Again, it is operator dependent, of limited use in patients with a contrast allergy, pacemaker or cardiac stent, and is expensive. Nevertheless, it has been shown to have better diagnostic accuracy than duplex US and to have similar accuracy to DSA, with sensitivity and specificity of greater than 90% quoted for stenoses of > 50% in studies using three-dimensional gadolinium-enhanced methods.²⁷

Therapeutics

Smoking cessation aids have been shown to be cost effective, with cost per life-year saved less for smoking cessation aids than for other secondary prevention steps commonly used post myocardial infarction (Fig. 65.6).

Figure 65.6 Cost effectiveness of smoking cessation strategies post MI when compared with other routine secondary prevention methods. (Reproduced with permission from Parrott S, Godfrey C. BMJ 2004; 328:947–9.)

Exercise

Patients with PAD benefit from a regular exercise program to optimize walking ability and maximal walking time.³⁹ A meta-analysis of 21 trials of walking therapy found that walking to near maximal pain, for 30 minutes and as partf a program lasting more than six months, increased the distance to onset of claudication pain by 179% (225.3 m) and the distance to maximal claudication pain by 122% (397.5m).⁴⁰ Resistance training is not as beneficial as regular walking to near maximal pain threshold for 30 minutes at least four times a week, and supervised programs have been shown to be more beneficial than non-supervised, although there are nevertheless benefits to be gained from the home-based programs. There is also preliminary evidence from two small RCTs (n = 35⁴¹ and n = 67⁴²) which suggests that arm ergonometry may be as successful as treadmill training in increasing initial claudication distance and maximal walking distance. This may offer an exercise alternative to those with severely reduced mobility.

Although one theory is that walking induces angiogenesis and collateral growth around the occluded or stenosed area, it is actually more likely that the benefits are due to improvements in muscle tone with muscle hypertrophy, improved endothelial function and altered gait.¹⁸ It was also shown in one trial that exercise therapy was more beneficial for walking times than percutaneous revascularization therapies⁴³ although this has not been replicated elsewhere. Exercise training for patients with PAD is optimally supervised by an exercise physiologist, physical therapist or nurse, in the setting of a cardiac rehabilitation program or similar,¹⁸ with the option of further non-invasive monitoring, since these patients may have concomitant cardiac disease. Supervised exercise sessions are typically scheduled three times a week, for a period of three months, with 30–60-minute sessions each time.⁵ Exercise also has further benefits in that it can improve dyslip-idemia, hypertension and risk of type 2 diabetes mellitus, as well as reducing overall adiposity and Body Mass Index.

Therapies for secondary event prevention

As discussed, patients with PAD are at very high risk of adverse vascular events elsewhere in the arterial tree, such as MI and stroke. Diabetes, hypertension and elevated cholesterol are not only etiologic factors in the pathogenesis of PAD, they also contribute to high rates of CV events among patients with established PAD. Therefore, it is generally accepted that control of etiologic risk factors will result in improved cardiovascular prognosis. Below we present evidence to support this practice.

Glycemic control in patients with diabetes

Control of blood glucose is advisable in patients with diabetes, to reduce the risk of adverse CVD events. The Steno-2 trial⁴⁴ randomized 160 type 2 diabetes patients to conventional or intensive control with a target HBA1C of < 6.5%, in conjunction with tight blood pressure and lipid control with a mean follow-up of 13.3 years. It reported reduced risks of cardiovascular mortality (hazard ratio (HR) 0.43, 95% CI 0.19–0.94, P = 0.04) and of cardiovascular events (HR 0.41, 95% CI 0.25–0.67, P < 0.001) with intensive glycemic control. However, a conflicting message has been given by the ACCORD study, in which an increase in total mortality was noted in the intensive control intervention arm, which aimed to reduce HBA1C in type 2 diabetes patients to <6.4%.⁴⁵

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