Introduction
Occlusive disease of the lower extremities is present in 8-12 million persons in the United States and is an important cause of disability. It is also a predictor of all-cause mortality and an independent risk factor for cardiovascular morbidity and mortality; patients with intermittent claudication have a 2.5 times higher risk of cardiac events than that of an age-matched population. Severe triple-vessel coronary artery disease is found in almost 30% of patients undergoing routine coronary catheterization prior to peripheral bypass. Vascular endothelial dysfunction is a systemic phenomenon and a marker for atherosclerosis; impairment of flow-mediated dilation in the peripheral arteries has been shown to correlate with the presence of coronary artery disease. It is essential for the primary care clinician to emphasize prevention of disease, particularly in light of what is known about etiologic factors.

DeBakey first characterized the distribution of atherosclerotic disease in the lower extremity. Plaque formation predominates at the aortic bifurcation, at the tibial trifurcation, and in the superficial femoral artery at the adductor hiatus. Interestingly, occlusive disease often spares the internal iliac, profunda, and peroneal arteries.

Three distinct patterns of disease have since been described. Type 1 disease affects about 10-15% of patients and is limited to the aorta and common iliac arteries. It is most commonly found in younger men and women (ages 40-55) who are heavy smokers or who have hyperlipidemia. Type 2 disease (25% of patients) involves the aorta, the common iliac artery, and the external iliac artery. Type 3 disease is the most common (60-70% of patients) and is multilevel disease, affecting the aorta and the iliac, femoral, popliteal, and tibial arteries. Patients with type 2 and type 3 patterns of disease have typical risk factors for atherosclerosis: older age, male gender, diabetes, and hypertension. They also have a high incidence of coexisting cerebrovascular and coronary artery disease.

Clinical Findings

A. Symptoms and Signs
Lower extremity occlusive disease is manifested by several different clinical presentations: erectile dysfunction, claudication, rest pain, and gangrene. The symptoms and physical examination predict the location and severity of disease. Occlusive disease of the iliac arteries can produce male erectile dysfunction. The triad of bilateral hip and buttock claudication, erectile dysfunction, and absent femoral pulses is known as Leriche’s syndrome.

Claudication is characterized by fatigue, pain, or weakness in the calves, thighs, or buttocks brought on by walking and completely relieved after a few minutes of rest. The reproducibility of these symptoms helps to differentiate claudication from other causes of leg pain such as radiculopathy and musculoskeletal disorders. Ischemic rest pain, defined as pain in the absence of exertion, is usually described as a nocturnal pain located across the dorsum of the foot at the metatarsal heads. It can be reduced by placing the legs in the dependent position, usually by hanging them over the side of the bed. Rest pain, ischemic ulceration, or gangrene implies impending limb loss.

Examination of the pulses indicates the level of disease. Absent or weak femoral pulses or the presence of an iliac or femoral bruit suggests inflow disease. Similarly, normal femoral pulses but a diminished or absent popliteal pulse is indicative of superficial femoral artery stenosis and normal femoral and popliteal pulses and nonpalpable dorsalis pedis or posterior tibial pulse indicate tibial disease. An ankle-brachial index (ABI) is useful in gauging the degree of arterial insufficiency. A normal ratio of ankle to brachial systolic blood pressures is 1.0; less than 0.8 is consistent with claudication. Exercise, which lowers the ABI by exaggerating the difference in brachial and ankle blood pressures, can sometimes aid in detection of occlusive disease. Rest pain and nonhealing ulcers are common with an ABI less than 0.4. A toe-brachial index (TBI) can be used in diabetic or renal failure patients when an ABI cannot be obtained because the tibial arteries are calcified and noncompressible. A penile-brachial index (PBI) is obtained when vasogenic impotence is suspected. A PBI less than 0.6 suggests significant arterial disease. These measurements can also be used to monitor progression of disease and to assess the effect of therapeutic intervention.

Other findings on physical examination include atrophy of the skin, subcutaneous tissues, and muscles of the calf. Dependent rubor, hair loss, and coolness of the skin are signs of advanced ischemia. Ulcers from arterial occlusive disease are painful, well-circumscribed lesions generally located over pressure points, such as the first metatarsal head or heel. Ulcers that have failed to heal with 3 months of appropriate local wound care and ulcers associated with an ABI less than 0.3 are unlikely to heal without treatment to improve arterial blood flow and tissue perfusion.

B. Imaging
Catheter or magnetic resonance angiography demonstrates the extent of the disease and the condition of the distal target vessels for potential bypass operation. The standard study images the infrarenal aorta and iliacs (including oblique views of the pelvis and groin to visualize the origins of the hypogastric and profunda arteries), the runoff vessels, and the foot in a lateral position. Angiography is undertaken only for percutaneous treatment or in preparation for surgical intervention. Gadolinium-enhanced MRA is used in the evaluation of lower extremity occlusive disease, particularly in patients with renal insufficiency. Ultrasound is also used in routine follow-up of infrainguinal bypass grafts to screen for graft stenoses amenable to prophylactic angioplasty or segmental replacement. Radiographs of the lower leg and foot are often obtained to rule out osteomyelitis underlying an infected ulcer or to identify severe calcification of potential runoff vessels.

Treatment
A. Conservative Measures
Treatment of claudication begins with identification and control of risk factors and initiation of an exercise program. Tobacco cessation slows the rate of progression of arterial occlusive disease and reduces cardiovascular mortality. Lipid-lowering medications have been shown to produce a 40% risk reduction for new-onset claudication or worsening of claudication. A supervised, dedicated walking program sustained over 3-6 months has been shown to increase pain-free walking distance by as much as 150%. Exercise improves symptoms by increasing muscle anaerobic metabolism and shifting the energy of walking to muscles with higher O₂ delivery. A standard program is structured as four 30-minute sessions per week: walking along flat ground until discomfort occurs, resting until it subsides, and then resuming walking.

The main drug used in therapy is the phosphodiesterase inhibitor cilostazol (100 mg orally twice daily), which impairs platelet aggregation, increases calcium-mediated vasodilation, and has been shown to increase walking distance by 34% more than placebo. It is contraindicated in patients with heart failure and is not well tolerated in about 20% of patients due to side effects of headache, dizziness, and diarrhea. Propionyl-L-carnitine (1000 mg orally twice daily) has also been correlated with increased walking distance in patients with claudication. Its mechanism of action is unknown; it may improve skeletal muscle metabolism. Ginkgo biloba extract (120 mg/d) is a herbal medication with some reported benefit in claudication. It has been correlated with an increased risk of bleeding and so should be used with caution in patients on warfarin or clopidogrel. Aspirin (325 mg orally daily) is routinely prescribed for all patients who do not have drug allergy or intolerance. It is continued indefinitely after angioplasty or surgery to decrease thrombotic complications and impede progression of intimal hyperplasia. Clopidogrel (75 mg orally daily) or warfarin (dosed to maintain an INR of 2.0-3.0) may be selected for postoperative patients perceived to have a higher risk of graft thrombosis due to a hypercoagulable state, suboptimal conduit, or poor distal runoff.

Treatment of male erectile dysfunction requires evaluation of its possible causes (medications, diabetes mellitus, psychogenic factors, and arterial occlusive disease). Iliac or dorsal penile artery revascularization can be beneficial in some cases of vasculogenic impotence. Other patients may respond to sildenafil, 25-50 mg 30 minutes to 4 hours prior to sexual activity. It is contraindicated in patients taking nitroglycerin because of the risk of myocardial ischemia due to hypotension.

B. Surgery
Percutaneous or open operation is considered for good-risk patients with short-distance (less than two blocks) claudication that impairs their ability to work or perform activities of daily living. Development of rest pain or tissue loss indicates progression of disease and also warrants evaluation for limb revascularization.

Because many of these patients have coexisting ischemic heart disease, medical management should be optimized preoperatively. The roles of exercise testing and coronary angiography are discussed in Heart Diseases section. The carotid arteries should be imaged by ultrasound; endarterectomy may be indicated to minimize perioperative stroke risk.

1. Endovascular techniques
Common iliac artery stenoses are often amenable to percutaneous treatment. Stent angioplasty has been shown to decrease recurrence rates seen with angioplasty alone; most recent studies report a 70-80% 3-year patency rate with self-expanding (Wall) stents or balloon-expandable (Palmaz) stents. Stenting of distal lesions (external iliac or infrainguinal arteries) is not as successful, with reported 3-year primary patency rates of 55-60%. Stents do not appear to confer added benefits over angioplasty alone for femoral-popliteal lesions except in cases of postangioplasty arterial dissection or successfully recanalized short-segment arterial occlusion. Ideal lesions for angioplasty are discrete, short-segment (> 5 cm in length), concentric lesions in noncalcified large-diameter vessels. Often, endovascular techniques are used in conjunction with surgery for treatment of multifocal lower extremity occlusive disease such as an iliac stent being placed at the time of an ipsilateral femoral popliteal bypass. Some surgeons are evaluating long-segment closed superficial femoral artery endarterectomy combined with distal stenting as an alternative to femoral popliteal bypass in high-risk surgical patients with suboptimal vein available for bypass conduit. Few groups have achieved favorable results with percutaneous atherectomy devices or laser probes.

2. Open surgery
Aortobifemoral bypass grafting using a synthetic prosthesis is the standard treatment for complex aortoiliac occlusive disease. In general, a bifurcated polytetrafluoroethylene or Dacron graft is anastomosed end to end with the infrarenal abdominal aorta and end to side to each common femoral artery. If both external iliac arteries are occluded, an end-to-side aortic anastomosis preserves inflow into the internal iliac arteries. For high-risk patients, an axillary-femoral or femoral-femoral bypass graft can be considered, though such extraanatomic grafts have lower long-term patency than bypass grafting (50% versus 80% at 10 years).

For infrainguinal occlusive disease, the bypass conduit of choice is the autogenous greater saphenous vein. Five-year patency rates of 75-80% can be achieved with vein bypasses to the dorsalis pedis artery or the posterior tibial artery at the ankle. By contrast, the 5-year patency of femoral-tibial bypasses performed with synthetic conduit is less than 40%. Some surgeons prefer prosthetic graft for femoral-to-above-knee-popliteal artery bypasses, as the reported long-term patency in this position is almost equivalent to that of vein graft. Others maintain an “all autogenous” policy for all infrainguinal bypass grafts. In as many as 30% of patients, the greater saphenous vein is inadequate because it is sclerotic, thrombosed, or less than 3 mm in diameter or because the patient has undergone varicose vein stripping or saphenous vein harvesting for coronary artery bypass or previous leg bypass. Alternative conduits in these patients include the lesser saphenous vein, arm vein, cryopreserved homologous vein, or prosthetic graft with a distal vein cuff.

Other determinants of long-term graft patency include quality of arterial inflow, patency of runoff arteries, and length of the bypass conduit. It is imperative to address any flow-limiting aortoiliac disease before performing any infrainguinal bypass.

Thomboendarterectomy involves resecting the thickened intima and media from the diseased artery and is an alternative to bypass for short-segment lesions in larger arteries. It can be used in type 1 disease to obviate the need for prosthetic graft. Common femoral or profunda femoral thromboendarterectomy is combined with distal bypass to improve inflow.

Operative mortality is 2-5% for open aortic surgery and 1-3% for infrainguinal bypass, largely attributable to cardiac complications. Risks specific to aortic surgery include renal insufficiency, bowel ischemia, impotence or retrograde ejaculation, and blue toe syndrome secondary to distal emboli. Late complications include graft thrombosis, graft infection, and aortoduodenal fistula. Complications of percutaneous techniques include problems at the puncture site (hematoma, pseudoaneurysm, arteriovenous fistula, retroperitoneal hemorrhage, occlusion), dissection or rupture of the artery during angioplasty, distal emboli from catheter manipulation, and contrast nephropathy. Patients with chronic renal insufficiency (serum creatinine < 1.5 mg/dL) undergoing angiography may be pretreated with intravenous hydration and acetylcysteine, 400 mg orally twice daily for 48 hours before and after contrast administration.

Prognosis
Twenty-five percent of patients with claudication will eventually develop ischemic rest pain or ulceration, though approximately 10% will require amputation. In part, the high rate of limb salvage reflects a high mortality rate from comorbid disease. Because of coronary artery disease, patients with claudication have a 5-year survival of 50%. For this reason, surgery is generally deferred until failure of drug therapy and exercise programs and impairment of activities of daily living.

The overall 5-year patency rate for infrainguinal saphenous vein grafts is 60-80%. Higher graft patency and limb salvage rates are achieved with suprageniculate bypasses and with patients presenting with claudication rather than rest pain or gangrene. Graft occlusion may convert a patient with claudication to one with limb-threatening ischemia because of loss of collateral flow. Conversely, a patient who undergoes bypass for distal gangrene may have a clinically silent graft occlusion after the ulcer heals. Surveillance duplex ultrasound is advised at 6-month intervals to detect stenotic, or “threatened,” grafts before they progress.

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