Peripheral arterial disease (PAD) is a common manifestation of systemic atherosclerosis.1 It's characterized by atherosclerotic occlusive disease primarily in the lower extremities, and is a powerful predictor for atherothrombotic disease in other vascular beds.2 PAD gradually restricts blood flow to the legs and feet, which can trigger muscle fatigue and pain when walking (claudication), leading to significant disability and diminished quality of life.2 Progression of PAD may cause critical limb ischemia, which raises the likelihood of amputation. Patients with PAD have advanced atherothrombosis and are at higher risk for stroke, myocardial infarction (MI) and cardiovascular (CV) death.

PAD is often a "silent" condition, producing no symptoms. As a result, it's underdiagnosed and undertreated, leaving thousands of Canadians at risk for CV events. The incidence of PAD rises with age -- about 4.3% of people over age 40 may have PAD, increasing to 14.5% in those older than 70.3 With our aging population, the prevalence of this condition and its associated morbidities is sure to grow. We need to do a better job of increasing awareness of PAD among the general public and healthcare professionals, and identifying patients at high risk.

What are the causes?
In PAD, the pathologic condition of atherosclerosis is identical to the forms that can occur in coronary, cerebral and renal vessels.4 Atherosclerosis begins with intimal injury, or damage to cells lining the blood vessels (endothelial cells), leading to the formation of fatty streaks, which progress to plaques. With a continuing build-up of fat, white blood cells and smooth muscle cells, plaques grow within the arterial wall.5 Inflammation is known to be a marker of atherothrombotic disease states, including PAD, and may also be a risk factor for their future development.6 In PAD, the aorta and arteries in the legs progressively narrow and become occluded by plaque. The condition can also occlude arteries in the arms, but this isn't nearly as common.

Who's at risk for PAD?
Basically, the risk factors for PAD are similar to those for coronary artery disease (CAD). The Framingham Heart Study reported higher incidence rates of PAD in men, who were nearly 2-fold more likely than women to develop the condition;1 this agrees with other findings in the literature.7,8 In addition, people who've had previous MI or stroke are more likely to develop PAD.2

Smoking and diabetes are the two most common traditional CAD risk factors associated with PAD. Others include increasing age, hypertension, hyperlipidemia, obesity and sedentary lifestyle.2 As with CAD, several markers are emerging as potential risk factors for PAD, such as elevated levels of C-reactive protein (CRP), homocysteine, plasma viscosity and fibrinogen.5 In contrast, alcohol use may be somewhat protective -- several epidemiologic studies suggest there's a linear, inverse relationship between PAD and alcohol intake in nonsmokers, i.e. the highest consumption (> 20 g/day) conferred the lowest risk.9

For smoking, PAD severity is closely linked to the amount smoked. Heavy smokers (> 25 cigarettes/day) face a 7-fold higher risk for PAD than nonsmokers, and even former smokers are twice as likely to develop the condition.10,11

In people with diabetes, the risk of PAD increases with age, duration of diabetes, and presence of peripheral neuropathy. Aboriginal and Hispanic patients with diabetes have a higher prevalence of PAD than whites, even after adjusting for other known risk factors. As well, amputation related to PAD is far more common in the diabetic population.

What are the classic symptoms?
The most frequent symptom of PAD is intermittent claudication. The term is derived from the Latin word claudicare, meaning "to limp."12 Intermittent claudication is usually described as cramps, tiredness or pain in the legs, thighs or buttocks that's brought on by exercise. This complex of symptoms occurs periodically, being consistently triggered by a specific intensity of activity and rapidly relieved by rest (within 3-5 minutes). Intermittent claudication occurs when muscles in the lower extremities aren't able to keep up with the higher metabolic demands of walking, due to poor oxygenation caused by an inadequate blood supply. This chronic ischemic state, in turn, results from occlusion and stenosis in the arteries feeding the legs. Other symptoms of PAD include cold legs or feet, foot or toe pain at rest that often disturbs sleep, and skin wounds or ulcers on feet or toes that heal slowly or simply don't heal.1,2 Rest pain and gangrene represent the most advanced form of PAD, demanding urgent vascular consultation. PAD patients may also present with acute limb-threatening ischemia if thrombosis occurs on top of pre-existing disease.

It's vital to remember that, in chronic PAD, a significant percentage of patients are asymptomatic, yet their risk of CV events is as high as in those with symptoms.8 In primary-care community cohort studies, patients with PAD have more commonly reported exertional leg pain atypical for claudication (46-48%) or no symptoms at all (20-48%) -- only 6-9% of participants had the classic symptoms of intermittent claudication.4 The bottom line is that we can't rely on intermittent claudication alone to make a diagnosis of PAD, or even as the screening criteria for further investigation.

How is PAD diagnosed?
The diagnosis is generally made using the history, physical exam and measuring the ankle-brachial index (ABI). Always consider PAD in the differential diagnosis when assessing patients who present with leg complaints (Table 1).

For the physical examination, have the patient lie supine after taking off shoes, socks and clothes covering the legs. Carefully compare and examine the lower extremities for bruits, abnormalities in skin colour (pale, red or purple), lack of hair and dry, brittle nails: are all possible signs of decreased arterial blood supply to the limbs.13 Palpable pulses may be diminished or absent in the femoral, popliteal, posterior tibial (PT) and dorsalis pedis (DP) arteries in patients with PAD. Capillary refill can be easily assessed by applying firm pressure to the plantar aspect of the great toe for 5 seconds. On releasing the toe, if it takes longer than 5 seconds for normal colour to return, that's considered abnormal and may indicate PAD.14

If the physical examination turns up any signs suggesting PAD, be sure to take a directed history for symptoms: find out whether the patient can perform normal activities of daily living (ADLs) and ask questions specific for intermittent claudication (Table 2).15

The main investigation used in diagnosing PAD is the ABI, a noninvasive, objective measurement of the ratio of ankle systolic pressure to brachial (arm) systolic pressure, which quantifies the degree of arterial insufficiency.16 It's widely used, inexpensive and can be done in an office setting using a handheld Doppler ultrasound device on both arms and legs. Testing requires a 5-10-MHz Doppler probe for arterial pulses and a blood pressure cuff. Normal ABI results are 0.90-1.30, while an ABI of 0.89 or less is diagnostic of PAD (Figure 1).16-18 Alternatively, the ABI can be measured by trained personnel in a vascular lab. The ABI is 95% sensitive and 99% specific for angiographically diagnosed PAD.17 Other techniques that provide more detailed anatomic information on PAD include duplex ultrasound scanning, treadmill testing, magnetic resonance angiography and computed tomography angiography, and conventional angiography.

Refer patients with PAD to a vascular specialist in any of the following situations: pain at rest, tissue loss, lifestyle-limiting claudication, high suspicion of PAD with normal ABI, and noncompressible/calcified vessels.

When should we screen?
Early detection of PAD allows for appropriate disease management that's designed to lower the chance of ischemic events and disease progression. If untreated, PAD can lead to serious health problems and may shorten one's life. The Canadian Cardiovascular Society (CCS) consensus conference on PAD issued guidelines on screening, diagnosis and treatment in 2005.19 It recommends routine screening for PAD with a directed physical exam and history in men over age 40, women over age 50, and younger people with one or more recognized CAD risk factors. Any patients with suspected PAD based on this screening should have an ABI. In addition, consider an ABI for asymptomatic men over 40 and women over 50 who are at high CV risk, especially if they smoke or have diabetes.19

What's the management approach?
Research shows that PAD is an important marker for life-threatening but treatable atherosclerosis in other organ systems -- it's linked to a 4-6-fold increase in CV death.20 Consequently, it's essential to aggressively manage all modifiable risk factors to cut morbidity and mortality in this high-risk population. The prognosis is generally favourable with treatment: the limb-loss rate is 1-2% per year for all PAD patients, but can be significantly higher in those with diabetes, while annual mortality is about 7% per year due to coexistent CAD and cerebrovascular disease.

The major goals in PAD therapy are:

• preventive measures to cut the risk of developing CV complications
• improvements in walking distance.

Specific interventions to manage risk factors include smoking cessation, hypertension and hyperlipidemia control, exercise programs, weight and diet management, and patient education. Since PAD is a chronic, lifelong condition, it's vital to empower patients to take better control of their lives. Key outcomes are to help them understand the disease, relieve pain and treat any other problems associated with the condition.17-19

Supervised exercise training is especially important, as it's been proven to extend walking distance.21 Encourage patients to get at least 30-45 minutes of exercise, 3-4 times weekly. 18,19 Studies show that pharmacologic intervention with cilostazol improves walking distance compared to placebo. Adding cilostazol to a supervised exercise program may be better than either therapy alone, according to a recent trial.22 Unfortunately, this drug isn't available yet in Canada. Pentoxifylline is not recommended, as there's no clear evidence that it helps patients walk further.19

All PAD patients require an antiplatelet agent to cut CV morbidity and mortality.18,19 Daily aspirin (75-325 mg) is recommended to lower the risk of MI, stroke and vascular death. Clopidogrel (75 mg daily) is considered an acceptable alternative antiplatelet therapy for patients who can't tolerate aspirin or are deemed "aspirin failures" (i.e. they continue to have CV events).18 The Clopidogrel vs Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial found that clopidogrel has significant benefits over aspirin in reducing MI, stroke and CV death in those with PAD.23

Antihypertensives are recommended to treat hypertension in patients with PAD. 18,19 The angiotensin-converting enzyme (ACE) inhibitors ramipril and perindopril have both demonstrated in randomized trials that they can prevent MI, stroke and CV death in people with pre-existing CVD, including those with PAD.24,25 In addition, there's strong evidence for the benefits of lowering cholesterol with statins in PAD patients.26

Angioplasty (with or without stenting) and surgery are also useful in managing PAD. Patients with focal plaques gain the most from angioplasty, which can produce rapid improvements in walking distance. How long the benefit lasts depends on the location and extent of the disease. Surgical management remains a cornerstone of therapy, but it's generally reserved for those with more extensive multifocal manifestation that hasn't responded to less-invasive measures. For patients with aorto-occlusive disease, the aorto-bifemoral bypass procedure has excellent long-term patency rates. Infra-inguinal bypass procedures are only used for those with limb-threatening ischemia. Femoral-popliteal and tibial bypass procedures with autogenous (patient's own) vein grafts are the gold standard for lower-limb revascularizations, which are important in limb salvage. These surgical procedures can be performed in conjunction with angioplasty, stenting or vessel recanalization to minimize the intervention required for limb salvage.