Peripheral Arterial Disease

In patients with peripheral arterial disease, claudication is the most common complaint or presentation in greater than 75% of patients. Claudication is characterized by exertional tightness, cramping, fatigue, or aching pain and is reproducible from day to day, resolves within 2-3 minutes of rest, and tends to reoccur at the same distance with activity resumption. These symptoms tend to be progressive.

Claudication can be differentiated from the pseudoclaudication seen with spinal stenosis because spinal stenosis is usually associated with tingling, weakness, or clumsiness, often occurs with prolonged standing, and is relieved by changing body positions or sitting down.

The presence of peripheral vascular disease has been shown to be a significant risk factor, equivalent to the presence of diabetes and coronary artery disease, and requiring LDL reductions below 100 according to the new National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-3) guidelines (33). The diagnosis can sometimes be challenging because, in addition to lumbar canal stenosis and degenerative joint disease, arteritis, vasculitis, arterioembolism and atheromatous embolism, cystic adventitial disease, popliteal artery entrapment, and vasoconstrictor drugs can produce similar symptoms.

Of importance in diagnosing the condition, arterial dopplers of the lower extremities demonstrate arteriosclerotic deposition along with the ankle/brachial index (ABI). The ABI compares the pressure measured in the dorsalis pedis and posterior tibial arteries with the normal brachial pressure. An ABI of 0.9 or greater is considered normal, 0.890.75 is considered mild peripheral vascular disease, 0.75-0.5 is considered moderate disease, and less than 0.5 is considered severe disease.

It is important for the clinician to understand that 90% of patients with symptomatic peripheral vascular disease also have concomitant coronary disease with relative 5-year mortality rates with peripheral arterial disease being greater than Hodgkin's disease and breast cancer, according to data from the American Cancer Society.

Angiographic studies have shown that patients with peripheral arterial disease are 90% likely to also have coronary disease and 80% likely to have carotid disease. Aggressive risk-factor modification, including hypertension control, lipid regulation, tight gly-cemic control, judicious use of aspirin and clopidogrel, cessation of smoking, and use of other vasoconstrictors (including caffeine), is beneficial. An exercise walking program and use of medication, such as 400 mg of pentoxifylline (Trental) three times daily or cilostazol (Pletal), are also beneficial. In head-to-head comparisons, cilostazol showed significant improvement when compared with pentoxifylline and placebo in lean walking distance, according to Dawson's 2000 review (34).

Diabetes and smoking increase the absolute risk for arteriosclerotic vascular disease by 25-50% and frequently mask important presenting symptoms. Careful control of contributing risk factors are critical in managing peripheral vascular disease (4).

Over a 5-year period, 1-3% of patients with intermittent claudication may require amputation. The 5-year mortality rate for patients with intermittent claudication approaches 30%. A comprehensive approach to management of claudication is necessary and can improve symptoms. This comprehensive approach includes lipid profile, glycemic and hypertension control, and weight reduction and medication.

Peripheral arterial disease continues to be underdiagnosed. In one comprehensive review (19), 6979 patients either older than 70 years, or 50-69 years old with a history of cigarette smoking or diabetes, were evaluated. Only 49% of the patients with a prior diagnosis of peripheral arterial disease were identified by the physicians treating them and 45% of patients diagnosed with peripheral arterial disease in this study had gone previously undetected.

According to data released by Hiatt in 2001 (35), approximately half of patients with peripheral arterial disease will have symptoms of intermittent claudication. The percentage of patients that is symptomatic from the disease increases as patients get older, peaking in the patient population that is over the age of 70 years.

Intermittent claudication is associated with several abnormalities at the cellular level, including the following:

1. Hyperplastic mitochondria and demyelination of nerve fibers.

2. 50% reduction in muscle fibers compared with control.

3. Metabolic disturbances stemming from reduction in flow of oxygen delivery related to local tissue ischemia and injury with angiotensin II release.

4. Greater arterial ischemia with smaller type I and II muscle fibers.

Smoking is the most powerful modifiable risk factor for peripheral disease; intermittent claudication is three times more common in smokers than nonsmokers. The severity of the disease increases with the number of cigarettes smoked. Cessation of smoking has been reported to cause significant reductions in rest pain, MI, cardiac deaths, and overall 10-year survival (36).

The patient with type 2 diabetes is more prone to atherogenic dyslipidemia and the metabolic syndrome and has a fourfold increased risk of developing peripheral arterial disease, with the symptoms in patients with diabetes not directly correlating with gly-cemic control.

Peripheral arterial disease can be associated with various vascular complications including acute vascular compromise characterized by sudden severe ischemia with paresthesia, paralysis, poor temperature, pain, and pallor as a result of either embolism or arterial occlusion (37). Cholesterol emboli and/or fibrinoplatelet matter from the aorta or iliac vessels can cause "blue toe" syndrome. These conditions require immediate attention.

The Fontaine classification of peripheral arterial occlusive disease divides it into the following four stages (38):

Stage I is asymptomatic, characterized by decreased pulses and ABI less than 0.9. Stage II is intermittent claudication. Stage III is characterized by rest pain. Stage IV is focal tissue necrosis and ulcer.

Common sites of claudication include obstruction in the aortoiliac artery, which produces ischemia in the hip, thigh, and buttock; obstruction in the femoral artery or its branches, which produce ischemia in the thigh and calf; and obstruction in the popliteal artery, which is manifested in the foot, ankle, and calf.

McDermott (37) describes a cascading sequence progressing from asymptomatic peripheral arterial disease to disability associated with reduced muscle strength, poor walking ability, and severe cellular dysfunction by the time intermittent claudication presents itself.

Claudication results in significant shifts in occupational, personal, and social activity, reduction in walking speed from 3 mph to 1-2 mph, and significant maximal walking distance limitations. Thirty percent of patients with claudication experience difficulty walking around the block and 65% have a great deal of difficulty walking a half of a block or 150 ft.

Patients can be stratified by risk according to their vascular history, physical examination and pulse palpation, ABI measurements, and noninvasive laboratory tests. Clinical diagnosis of claudication depends on measurements of the ABI and arterial dopplers.

The ABI is 95% sensitive and 99% specific for peripheral arterial disease, according to the Trial of Angioplasty and Stents in Canada (TASC) working group (39). The treatment goals in all patients with peripheral arterial disease are as follows (35):

1. Improve functional status by improving symptoms.

2. Preserve the limb by decreasing the need for revascularization.

3. Prevent progression of arteriosclerotic vascular disease by using glycemic and lipid controls.

4. Reduce cardiovascular and cerebral vascular mortality by using antiplatelet agents, vasodilators, and statin therapy.

Patients with proximal or unilateral disease, stenosis or short occlusions, no improvement after exercise, or severe symptoms are candidates for aggressive intervention. Patients who continue to smoke, have severe concomitant angina or chronic obstructive pulmonary disease, or have extensive multiple occlusions with distal involvement are less likely to be amenable to surgical intervention. Strategical placement of stents has provided a less invasive way of improving symptoms in some patients (39).

Peripheral vascular disease has been associated with six modifiable risk factors including the following:

1. Dyslipidemia.

2. Diabetes.

3. Hypertension.

4. Obesity.

5. Smoking.

6. Elevated homocysteine levels.

Claudication exercise programs have been effective in patients who are well-motivated in improving walking distance, exercise performance, and physical functioning. They do not work well in noncompliant patients or in patients who have limited availability of supervised programs. Supervised programs usually involve five sessions per week, most of which are supervised.

Presently, cilostazol (Pletal) seems to be the most effective medication, with pentoxifylline (Trental) improving symptoms in some patients. Other medications, such as propionyl-L-carnitine, prostaglandins, angiogenic factors, and L-arginine, remain to be studied. Antiplatelet therapy can provide additional adjuvant benefit in these patients, decreasing the likelihood of embolization (18).

Cilostazol and several of its metabolites are inhibitors of phosphodiesterase-3, therefore cilostazol is contraindicated in individuals who can have congestive heart failure or have any known or suspected hypersensitivity to any of its compounds. Although there is no direct evidence that cilostazol causes or exacerbates congestive heart failure, other phosphodiesterase-3 inhibitors have increased mortality in patients with class III or class IV congestive heart failure. Thus, cilostazol should not be taken by these patients.

Patients who are good candidates for angioplasty and stenting are those with the following:

1. Noncalcified lesions.

2. Concentric stenoses.

3. Larger vessel involvement.

4. Short segment disease.

5. Nonconcomitant coronary comorbidity.

6. Treated coronary disease with normal renal function.

7. Patent vessels distal to the treated lesion and no evidence of diabetes.

Revascularization is usually indicated for life-limiting complaints; acute severe symptoms associated with pain, immobility, and loss of sensation; nonhealing ulcers; gangrene; and continued disability despite appropriate nonsurgical intervention. Aggressive early diagnosis and management can prevent many of the major complications associated with claudication (37).

The availability of stenting has provided an added option to identify patients earlier. Additionally, in some patients, magnetic resonance angiography has been an important noninvasive tool to further evaluate the use of dye in the peripheral vascular system.

Table 2

Strategies to Reduce Risk of Macrovascular Disease in Diabetics

Reduce blood pressure to <130/80 mmHg

• Reduce LDL to <100 mg/dL with statin therapy

• Raise HDL to >55 mg/dL in women or >45 mg/dL in men

Reduce triglycerides to <150 mg/dL

Lose weight with diet and exercise

• Add ramipril (Altace) for overall risk reduction

HDL, high-density lipoprotein; LDL, low-density lipoprotein.

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