Peripheral artery disease (PAD) is defined as a clinical disorder in which there is a stenosis or occlusion in the aorta or the arteries of the limbs. Atherosclerosis is the leading cause of PAD in patients >40 years old. Other causes include thrombosis, embolism, vasculitis, fibromuscular dysplasia, entrapment, cystic adventitial disease, and trauma. The highest prevalence of atherosclerotic PAD occurs in the sixth and seventh decades of life. As in patients with atherosclerosis of the coronary and cerebral vasculature, there is an increased risk of developing PAD in cigarette smokers and in persons with diabetes mellitus, hypercholesterolemia, hypertension, or renal insufficiency.
(See also Chap. 36) Segmental lesions that cause stenosis or occlusion are usually localized to large and medium-size vessels. The pathology of the lesions includes atherosclerotic plaques with calcium deposition, thinning of the media, patchy destruction of muscle and elastic fibers, fragmentation of the internal elastic lamina, and thrombi composed of platelets and fibrin. The primary sites of involvement are the abdominal aorta and iliac arteries (30% of symptomatic patients), the femoral and popliteal arteries (80–90% of patients), and the more distal vessels, including the tibial and peroneal arteries (40–50% of patients). Atherosclerotic lesions occur preferentially at arterial branch points, which are sites of increased turbulence, altered shear stress, and intimal injury. Involvement of the distal vasculature is most common in elderly individuals and patients with diabetes mellitus.
Fewer than 50% of patients with PAD are symptomatic, although many have a slow or impaired gait. The most common symptom is intermittent claudication, which is defined as a pain, ache, cramp, numbness, or a sense of fatigue in the muscles; it occurs during exercise and is relieved by rest. The site of claudication is distal to the location of the occlusive lesion. For example, buttock, hip, thigh, and calf discomfort occurs in patients with aortoiliac disease, whereas calf claudication develops in patients with femoral-popliteal disease. Symptoms are far more common in the lower than in the upper extremities because of the higher incidence of obstructive lesions in the former region. In patients with severe arterial occlusive disease in whom resting blood flow cannot accommodate basal nutritional needs of the tissues, critical limb ischemia may develop. Patients complain of rest pain or a feeling of cold or numbness in the foot and toes. Frequently, these symptoms occur at night when the legs are horizontal and improve when the legs are in a dependent position. With severe ischemia, rest pain may be persistent.
Important physical findings of PAD include decreased or absent pulses distal to the obstruction, the presence of bruits over the narrowed artery, and muscle atrophy. With more severe disease, hair loss, thickened nails, smooth and shiny skin, reduced skin temperature, and pallor or cyanosis are common physical signs. In patients with critical limb ischemia, ulcers or gangrene may occur. Elevation of the legs and repeated flexing of the calf muscles produce pallor of the soles of the feet, whereas rubor, secondary to reactive hyperemia, may develop when the legs are dependent. The time required for rubor to develop or for the veins in the foot to fill when the patient’s legs are transferred from an elevated to a dependent position is related to the severity of the ischemia and the presence of collateral vessels. Patients with severe ischemia may develop peripheral edema because they keep their legs in a dependent position much of the time. Ischemic neuropathy can result in numbness and hyporeflexia.
The history and physical examination are often sufficient to establish the diagnosis of PAD. An objective assessment of the presence and severity of disease is obtained by noninvasive techniques. Arterial pressure can be recorded noninvasively in the legs by placement of sphygmomanometric cuffs at the ankles and the use of a Doppler device to auscultate or record blood flow from the dorsalis pedis and posterior tibial arteries. Normally, systolic blood pressure in the legs and arms is similar. Indeed, ankle pressure may be slightly higher than arm pressure due to pulse-wave amplification. In the presence of hemodynamically significant stenoses, the systolic blood pressure in the leg is decreased. Thus, the ratio of the ankle and brachial artery pressures (termed the ankle:brachial index, or ABI) is 1.00–1.40 in normal individuals. ABI values of 0.91–0.99 are considered “borderline,” and those <0.90 are abnormal and diagnostic of PAD. ABIs >1.40 indicate noncompressible arteries secondary to vascular calcification.
Other noninvasive tests include segmental pressure measurements, segmental pulse volume recordings, duplex ultrasonography (which combines B-mode imaging and Doppler flow velocity waveform analysis examination), transcutaneous oximetry, and stress testing (usually using a treadmill). Placement of pneumatic cuffs enables assessment of systolic pressure along the legs. The presence of pressure gradients between sequential cuffs provides evidence of the presence and location of hemodynamically significant stenoses. In addition, the amplitude of the pulse volume contour becomes blunted in the presence of significant PAD. Duplex ultrasonography is used to image and detect stenotic lesions in native arteries and bypass grafts.
Treadmill testing allows the physician to assess functional limitations objectively. Decline of the ABI immediately after exercise provides further support for the diagnosis of PAD in patients with equivocal symptoms and findings on examination.
Magnetic resonance angiography (MRA), computed tomographic angiography (CTA), and conventional catheter-based angiography should not be used for routine diagnostic testing but are performed before potential revascularization (Fig. 47-1). Each test is useful in defining the anatomy to assist planning for endovascular and surgical revascularization procedures.
The natural history of patients with PAD is influenced primarily by the extent of coexisting coronary artery and cerebrovascular disease. Approximately one-third to one-half of patients with symptomatic PAD have evidence of coronary artery disease (CAD) based on clinical presentation and electrocardiogram, and over one-half have significant CAD by coronary angiography. Patients with PAD have a 15–30% 5-year mortality rate and a two- to sixfold increased risk of death from coronary heart disease. Mortality rates are highest in those with the most severe PAD. Measurement of ABI is useful for detecting PAD and identifying persons at risk for future atherothrombotic events. The likelihood of symptomatic progression of PAD is lower than the chance of succumbing to CAD. Approximately 75–80% of nondiabetic patients who present with mild to moderate claudication remain symptomatically stable. Deterioration is likely to occur in the remainder, with approximately 1–2% of the group ultimately developing critical limb ischemia each year. Approximately 25–30% of patients with critical limb ischemia undergo amputation within 1 year. The prognosis is worse in patients who continue to smoke cigarettes or have diabetes mellitus.
TREATMENT Peripheral Artery Disease
Patients with PAD should receive therapies to reduce the risk of associated cardiovascular events, such as myocardial infarction and death, and to improve limb symptoms, prevent progression to critical limb ischemia, and preserve limb viability. Risk factor modification and antiplatelet therapy should be initiated to improve cardiovascular outcomes. The importance of discontinuing cigarette smoking cannot be overemphasized. The physician must assume a major role in this lifestyle modification. Counseling and adjunctive drug therapy with the nicotine patch, bupropion, or varenicline increase smoking cessation rates and reduce recidivism. It is important to control blood pressure in hypertensive patients. Angiotensin-converting enzyme inhibitors may reduce the risk of cardiovascular events in patients with symptomatic PAD. β-Adrenergic blockers do not worsen claudication and may be used to treat hypertension, especially in patients with coexistent CAD. Treatment of hypercholesterolemia with statins is advocated to reduce the risk of myocardial infarction, stroke, and death. The 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults recommends high intensity statin treatment in patients with atherosclerotic disorders, including peripheral artery disease. Platelet inhibitors, including aspirin and clopidogrel, reduce the risk of adverse cardiovascular events in patients with atherosclerosis and are recommended for patients with symptomatic PAD, including those with intermittent claudication or critical limb ischemia or prior lower extremity revascularization. Dual antiplatelet therapy with both aspirin and clopidogrel is not more effective than aspirin alone in reducing cardiovascular morbidity and mortality rates in patients with PAD. The anticoagulant warfarin is as effective as antiplatelet therapy in preventing adverse cardiovascular events but causes more major bleeding; therefore, it is not indicated to improve outcomes in patients with chronic PAD.
Therapies for intermittent claudication and critical limb ischemia include supportive measures, medications, nonoperative interventions, and surgery. Supportive measures include meticulous care of the feet, which should be kept clean and protected against excessive drying with moisturizing creams. Well-fitting and protective shoes are advised to reduce trauma. Elastic support hose should be avoided, as it reduces blood flow to the skin. In patients with critical limb ischemia, shock blocks under the head of the bed together with a canopy over the feet may improve perfusion pressure and ameliorate some of the rest pain.
Patients with claudication should be encouraged to exercise regularly and at progressively more strenuous levels. Supervised exercise training programs for 30- to 45-min sessions, three to five times per week for at least 12 weeks, prolong walking distance. Patients also should be advised to walk until nearly maximum claudication discomfort occurs and then rest until the symptoms resolve before resuming ambulation. The beneficial effect of supervised exercise training on walking performance in patients with claudication often is similar to or greater than that realized after a revascularization procedure. Pharmacologic treatment of PAD has not been as successful as the medical treatment of CAD (Chap. 39). In particular, vasodilators as a class have not proved to be beneficial. During exercise, peripheral vasodilation occurs distal to sites of significant arterial stenoses. As a result, perfusion pressure falls, often to levels lower than that generated in the interstitial tissue by the exercising muscle. Drugs such as α-adrenergic blocking agents, calcium channel antagonists, and other vasodilators have not been shown to be effective in patients with PAD.
Cilostazol, a phosphodiesterase inhibitor with vasodilator and antiplatelet properties, increases claudication distance by 40–60% and improves measures of quality of life. The mechanism of action accounting for its beneficial effects is not known. Pentoxifylline, a substituted xanthine derivative, increases blood flow to the microcirculation and enhances tissue oxygenation. Although several placebo-controlled studies have found that pentoxifylline increases the duration of exercise in patients with claudication, its efficacy has not been confirmed in all clinical trials. Statins and angiotensin-converting enzyme inhibitors appear promising for treatment of intermittent claudication in initial clinical trials, but more studies are needed to confirm the efficacy of each class of drugs. There is no definitive medical therapy for critical limb ischemia, although several studies have suggested that long-term parenteral administration of vasodilator prostaglandins decreases pain and facilitates healing of ulcers. Enthusiasm for therapy with angiogenic growth factors abated when clinical trials of intramuscular gene transfer of DNA encoding vascular endothelial growth factor, fibroblast growth factor, hepatocyte growth factor, or hypoxia-inducible factor 1α failed to demonstrate improvement in symptoms or outcomes in patients with intermittent claudication or critical limb ischemia. Clinical trials assessing the ability of bone marrow–derived vascular progenitor cells to promote angiogenesis and preserve limb viability in patients with critical limb ischemia are ongoing. REVASCULARIZATION
Revascularization procedures, including catheter-based and surgical interventions, are usually indicated for patients with disabling, progressive, or severe symptoms of intermittent claudication despite medical therapy and for those with critical limb ischemia. MRA, CTA, or conventional angiography should be performed to assess vascular anatomy in patients who are being considered for revascularization. Nonoperative interventions include percutaneous transluminal angiography (PTA) and stent placement (Chap. 42). PTA and stenting of the iliac artery are associated with higher success rates than are PTA and stenting of the femoral and popliteal arteries. Approximately 90–95% of iliac PTAs are initially successful, and the 3-year patency rate is >75%. Patency rates may be higher if a stent is placed in the iliac artery. The initial success rates for femoral-popliteal PTA and stenting are approximately 80%, with 60% 3-year patency rates. Patency rates are influenced by the severity of pretreatment stenoses; the prognosis of occlusive lesions is worse than that of nonocclusive stenotic lesions. The role of drug-eluting stents and drug-coated balloons in PAD is under investigation.
Several operative procedures are available for treating patients with aortoiliac and femoral-popliteal artery disease. The preferred operative procedure depends on the location and extent of the obstruction(s) and the general medical condition of the patient. Operative procedures for aortoiliac disease include aortobifemoral bypass, axillofemoral bypass, femoro-femoral bypass, and aortoiliac endarterectomy. The most frequently used procedure is the aortobifemoral bypass using knitted Dacron grafts. Immediate graft patency approaches 99%, and 5- and 10-year graft patency rates in survivors are >90% and 80%, respectively. Operative complications include myocardial infarction and stroke, infection of the graft, peripheral embolization, and sexual dysfunction from interruption of autonomic nerves in the pelvis. The operative mortality rate ranges from 1–3%, mostly due to ischemic heart disease.
Operative therapy for femoral-popliteal artery disease includes in situ and reverse autogenous saphenous vein bypass grafts, placement of polytetrafluoroethylene (PTFE) or other synthetic grafts, and thromboendarterectomy. The operative mortality rate ranges from 1–3%. The long-term patency rate depends on the type of graft used, the location of the distal anastomosis, and the patency of runoff vessels beyond the anastomosis. Patency rates of femoral-popliteal saphenous vein bypass grafts approach 90% at 1 year and 70–80% at 5 years. Five-year patency rates of infrapopliteal saphenous vein bypass grafts are 60–70%. In contrast, 5-year patency rates of infrapopliteal PTFE grafts are <30%.
Preoperative cardiac risk assessment may identify individuals who are especially likely to experience an adverse cardiac event during the perioperative period. Patients with angina, prior myocardial infarction, ventricular ectopy, heart failure, or diabetes are among those at increased risk. Stress testing with treadmill exercise (if feasible), radionuclide myocardial perfusion imaging, or echocardiography permits further stratification of risk in these patients (Chap. 42). Patients with abnormal test results require close supervision and adjunctive management with anti-ischemic medications. β-Adrenergic blockers and statins reduce the risk of postoperative cardiovascular complications. Coronary angiography and coronary artery revascularization compared with optimal medical therapy do not improve outcomes in most patients undergoing peripheral vascular surgery, but cardiac catheterization should be considered in patients with unstable angina and angina refractory to medical therapy as well as those suspected of having left main or three-vessel CAD.