Lower extremity peripheral arterial disease (PAD) is a highly prevalent condition in the United States.
The risk factors for PAD are similar to those for arterial disease in the coronary and cerebrovascular territories.
There is growing evidence that several nontraditional risk factors, including inflammation, endothelial dysfunction, thrombotic and hemostatic markers, and platelet activity, may also be associated with increased PAD risk.
After a complete history and physical examination, the diagnosis of PAD should be confirmed with a vascular study.
The treatment of PAD includes a broad approach, focusing on reduction of the risk of the major factors associated with the development and progression of PAD.
The treatment of lower extremity, stable, claudication symptoms from PAD involves an initial approach of exercise and pharmacologic therapy and, if it is not successful, selective revascularization based on anatomy and lifestyle considerations.
Patients with critical limb ischemia should undergo immediate evaluation for possible revascularization.
The evaluation for an abdominal aortic aneurysm involves physical examination and abdominal ultrasonography.
Peripheral arterial disease (PAD) is a disease that obstructs blood supply to the extremities. The most common pathologic process is atherosclerotic disease, but it may also result from connective tissue diseases, vasculitis, hematologic disorders, thrombosis, embolism, fibromuscular dysplasia, mechanical obstruction, and occupation-related diseases. This serious and highly prevalent disorder is associated with significant morbidity and mortality, commonly with impaired function and quality of life.
Lower extremity PAD, a highly prevalent condition in the United States with an estimated general population prevalence of 12%, is estimated to affect approximately 8 to 12 million Americans. In primary care office practices, PAD is present in 29% of patients older than 70 years or older than 50 years with a history of smoking or diabetes. The prevalence of PAD and intermittent claudication increases progressively with age. Data from the 1999-2000 National Health and Nutrition Examination Survey (NHANES) demonstrated the prevalence of PAD (defined as an ankle-brachial index <0.90 in either leg) was 0.9% between the ages of 40 and 49 years, 2.5% between the ages of 50 and 59 years, 4.7% between the ages of 60 and 69 years, and 14.5% at the age of 70 years and older. NHANES data from 1999 to 2004 demonstrated a 44% increase in the odds of PAD for every 10-year increase in age. There are data to suggest that race or ethnicity plays a role in PAD. The prevalence among non-Hispanic blacks was 7.9%, the highest among other racial and ethnic groups (4.4% in non-Hispanic whites and 3% in Mexican Americans). Consistently, the Atherosclerosis Risk in Communities (ARIC) study demonstrated a significantly higher prevalence of PAD in African Americans than in whites. Collaborative data from seven community-based studies noted a higher rate of PAD in African Americans than in American Indians, Asian Americans, Hispanics, and non-Hispanic whites.
Despite the high prevalence of PAD, detection and awareness are lower than for arterial disease in other locations. A population-based telephone survey of a nationally representative sample of adults older than 50 years demonstrated that only 26% of respondents expressed familiarity with PAD.
Risk Factors for Peripheral Arterial Disease
The risk factors for PAD are similar to those for arterial disease in the coronary and cerebrovascular territories. Increasing age, hypertension, dyslipidemia, cigarette smoking, and diabetes mellitus are well-established risk factors for all arterial disease. Data derived from several observational studies demonstrate that cigarette smoking and diabetes are particularly strong risk factors for PAD. Data from the 1999-2000 NHANES survey found that in age- and sex-adjusted logistic regression analysis, current smoking had a greater than fourfold increased odds and diabetes almost a threefold increased odds of prevalent PAD. In a longitudinal cohort study, data from the Framingham Heart Study of 381 men and women who were observed for 38 years revealed that the odds ratio for development of intermittent claudication was 2.6 for the presence of diabetes mellitus and 1.4 for each 10 cigarettes smoked per day.
Dyslipidemia is also associated with an increased prevalence of PAD. In comparison of a panel of lipid risk factors for PAD, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, and apolipoprotein B were all significant predictors of increased risk of PAD, although the ratio of total cholesterol to HDL-C was the single strongest predictor (highest quartile versus lowest quartile relative risk, 3.9; 95% confidence interval, 1.7 to 8.6).
There is growing evidence that several nontraditional risk factors, including inflammation, endothelial dysfunction, thrombotic and hemostatic markers, and platelet activity, may also be associated with increased PAD risk. Multiple studies have shown elevated levels of inflammatory biomarkers in men and women with PAD. In a community-based sample from the Framingham Offspring Study, the group of inflammatory biomarkers was related to both ankle-brachial index and clinical PAD.
In the Edinburgh Artery Study, a population-based cohort study, several markers of endothelial function and inflammation were compared. C-reactive protein, interleukin-6, and intercellular adhesion molecule 1 were significant predictors of lower extremity atherosclerotic progression measured by ankle-brachial index during 12 years of follow-up independently of cardiovascular risk factors. Elevated levels of inflammatory biomarkers are also associated with greater functional impairment and faster functional decline in people with PAD. A study of proteomic profiling identified the protein β 2 -thromboglobulin as being elevated in subjects with PAD, and a significant correlation was observed between β 2 -microglobulin and the severity of disease. The association of β 2 -microglobulin with PAD may be related to vascular inflammation.
Abnormalities in hemostasis also associate with an increased prevalence of PAD. Data derived from the ARIC study found elevated levels of hemostatic markers in subjects with PAD. Specifically, higher levels of fibrinogen, von Willebrand factor, factor VIII, D-dimer, and thromboglobulin were associated with greater PAD prevalence. In a population of Scottish men and women aged 55 to 74 years, mean levels of fibrinogen, fibrin D-dimer, and plasma viscosity remained significantly higher among the diabetes/impaired glucose tolerant group with PAD compared with those with no PAD.
In contrast, fibrinogen and homocysteine were not associated with development of PAD in the Women’s Health Study. Considerable evidence links platelets, a major culprit in atherothrombosis, and the development of PAD. With use of data from NHANES, levels of mean platelet volume in peripheral blood independently associate with PAD (tertile 1, 4.4%; tertile 2, 6.1%; tertile 3, 7.0%; P for trend = 0.003), independent of traditional cardiovascular risk factors. Ongoing studies will determine the usefulness of markers of inflammation, endothelial function, hemostasis, and platelet activity in the risk prediction of PAD.
Although it is poorly understood, the pathophysiologic process leading to development of claudication and decline in functional status is thought to be progression of atherothrombosis, the combination of atherosclerosis and thrombosis. The proatherogenic state can be classified into increased vasoconstriction, inflammation, and platelet activation and endothelial dysfunction. The natural history of atherosclerosis in the extremities involves progressive occlusion of the vessel, typically in susceptible regions where turbulent blood flow occurs, such as the proximal superficial femoral artery and the popliteal artery at Hunter canal.
Vasodilator capability is severely decreased in subjects with PAD. Normal arteries dilate in response to several different stimuli, such as acetylcholine, serotonin, thrombin, and bradykinin, as well as shear stress induced by increases in blood flow that increase nitric oxide production. Endothelium from a subject with PAD is impaired; the production and bioavailability of nitric oxide in the artery wall are decreased. There is increasing evidence for the participation of inflammatory cells as mediators in atherogenesis and plaque rupture in arterial disease of all vascular beds. Inflammatory mediators play an essential role in the pathogenesis of cardiovascular disease, being involved at all stages of plaque development and eventual rupture.
Several studies have noted increased levels of inflammatory markers in subjects with PAD. Subjects with PAD have increased platelet activity, platelet hyperactivity (as assessed by platelet aggregation), mean platelet volume, platelet factor 4, β-thromboglobulin, and P-selectin expression receptors on platelets. Nevertheless, there is a lack of data comparing the association between platelet markers with different pathophysiologic mechanisms and PAD.
Other pathologic considerations for PAD include altered muscle structure and function. Repeated episodes of ischemia during exercise and reperfusion during recovery may promote oxidant injury to endothelial cells, muscle mitochondria, muscle fibers, and distal motor axons. Muscle denervation and alterations in muscle metabolism contribute to performance limitations.
PAD has two distinct manifestations, claudication and critical limb ischemia. Patients with claudication infrequently progress to chronic limb ischemia and have a combined annual amputation mortality rate of 2% to 4% per patient per year, whereas patients with chronic limb ischemia have a 6-month amputation risk of 25% to 40% and an annual mortality rate as high as 20% ( Fig. 31-1 ).
Others have noted differences between large-vessel PAD and small-vessel PAD. In a longitudinal study of 403 subjects with a mean follow-up of 4.6 years, current cigarette smoking, the ratio of total cholesterol to HDL-C, high-sensitivity C-reactive protein, and lipoprotein(a) were independent predictors of large-vessel PAD progression. This was in contrast to progression of small-vessel PAD, for which diabetes was the only significant predictor.
Diagnosis of Peripheral Arterial Disease
After a complete history and physical examination, the diagnosis of PAD should be confirmed with a vascular study. There are multiple modalities from which to choose for assessment of PAD. A simple, inexpensive, noninvasive tool that correlates well with angiographic disease severity and functional symptoms is the ankle-brachial index (ABI). In the supine position, the ankle and arm systolic pressures are approximately the same, and on standing, the ankle systolic pressure is somewhat higher than that of the arm. Thus, in the supine position, the measured ankle systolic blood pressure divided by the brachial systolic blood pressure is normally between 1.0 and 1.3. However, if a fixed obstruction of the arterial lumen is present, as is the case with atherosclerotic disease, a pressure gradient occurs, resulting in a reduced downstream pressure and concomitant reduction in the ABI.
An ABI < 0.9 is considered abnormal and diagnostic of PAD. ABI values between 0.90 and 0.99 are considered borderline and equivocal for PAD. Of note, recent data indicate that even borderline ABI values have significant increased risk for a cardiovascular event ( Fig. 31-2 ). An ABI ranging from 0.70 to less than 0.90 indicates mild disease; moderate disease correlates with an ABI ranging from 0.40 to less than 0.70; and severe disease is associated with an ABI of no more than 0.40. Studies evaluating the diagnostic accuracy of the ABI have demonstrated that it can differentiate between normal and angiographically diseased limbs with a sensitivity of 97% and a specificity of 100% and that the resting ABI is a significant predictive variable for the severity of angiographic disease.
Approximately one third of patients with PAD have typical claudication, defined as pain in one or both legs on walking, primarily affecting the calves, that does not go away with continued walking and is relieved by rest.
Ankle-Brachial Index Technique
The ABI can be measured in the office or hospital setting because the equipment required is inexpensive and portable ( Fig. 31-3 ). The study is done with the patient in the supine position after resting for at least 5 minutes. The “traditional” method for conduction of the ABI test is to use an ordinary blood pressure cuff and to measure the systolic blood pressure with a Doppler ultrasonic velocity signal probe. The blood pressure is measured in both arms, and if a discrepancy exists, the higher of the two systolic blood pressure values is used. The Doppler probe is then moved over the posterior tibial artery and then over the dorsalis pedis artery to measure the respective ankle pressures. The higher of the two ankle pressures is typically used to calculate the leg ABI. However, recent information indicates that use of the lower of the two may identify more individuals with PAD. The process should be repeated for the other leg. The lowest ABI between both legs is the ABI that stratifies the patient’s risk for functional impairment and adverse cardiovascular event.
Limitations of Ankle-Brachial Index
As with most tests, measurement of the ABI has some limitations. The pressures in the leg may be supranormal (ABI > 1.4) because of inability to compress the artery, especially in patients with diabetes. A supranormal pressure does not allow determination of whether an obstructive plaque is present, and thus the information is considered not diagnostic. If an incompressible artery is found, the patient should be referred to an accredited vascular laboratory for measurement of a toe-brachial index or other noninvasive testing.
Another problem that may preclude accurate analysis with the ABI is the presence of bilateral subclavian artery stenosis. The result of this hemodynamic occlusion is a false reduction in the “true” systemic circulation systolic pressure and inaccurate denominator in calculation of the ABI. Other limitations of the ABI that should be recognized in considering surgery include its inability to localize arterial lesions accurately and the lack of an association between ABI and the predicted potential for wound healing.
Ankle-Brachial Index in Asymptomatic Peripheral Arterial Disease
Up to two thirds of patients who have a reduced ABI do not have classic symptoms of intermittent claudication. Individuals with PAD who do not have classic intermittent claudication symptoms have significant functional impairment, functional decline, and cardiovascular events compared with those without PAD. The collaboration of 16 international cohorts including more than 48,000 individuals demonstrated that the ABI provided independent risk information over and above the Framingham risk score, and a low ABI significantly increased the risk of total and cardiovascular mortality and major coronary events across all Framingham risk categories. In fact, the ABI resulted in reclassification of the Framingham risk estimate in approximately 20% of men and one third of women. An analysis of 102 subjects with a recent stroke or transient ischemic attack found that 26% had asymptomatic PAD as detected by ABI measurement. Subjects with asymptomatic PAD had a fivefold greater adjusted increase in cardiovascular events than did subjects without PAD.
Recommendations for Screening for Ankle-Brachial Index
Given the wealth of information obtained from this simple hemodynamic test, current American College of Cardiology/American Heart Association (ACC/AHA) and Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) guidelines have provided Class IA recommendation for measurement of the ABI in “at-risk” populations. We recommend the following protocol for measurement of the ABI in at-risk populations ( Fig. 31-4 ).
Vascular Exercise Testing
The measurement of the ABI before and after exercise provides additional diagnostic information about the presence and severity of claudication. The normal response of the ankle systolic pressure is an increase with exercise. However, if significant lower extremity arterial obstruction is present, the ankle systolic pressure may decrease because of a pressure gradient across the blockage while the arm pressure may increase, resulting in reduced ABI.
The ABI typically will return to pre-exercise level within 5 minutes after cessation of exercise. Thus, if clinical suspicion is high that leg discomfort is due to claudication, an exercise test will provide confirmatory information in a patient with “normal” or borderline ABI. Alternatively, if the ABI does not change with exercise, leg discomfort with exercise may be due to another cause, such as spinal stenosis.
The clinical protocol for vascular stress testing may use a standard exercise treadmill or pedal plantar flexion (heel raises). One common regimen is for the patient to walk at a standard speed and grade for a predetermined period (i.e., 2 mph at 12% incline for 5 minutes) or until claudication develops. Immediately after cessation of exercise, the patient is asked to lie in a supine position, and the ankle systolic blood pressure is measured. The pedal plantar flexion exercise test involves the patient’s standing facing a wall while using light fingertip support for balance. The patient raises the heels as high as possible while keeping the knees straight and then immediately lowers them; the cycle is repeated 30 to 50 times or until claudication symptoms occur. As with treadmill testing, the ABI is calculated with the patient in a supine position immediately after completion of the exercise sequence. Postexercise measurement of the ABI may identify an additional 30% of patients with PAD.
Segmental Pressures and Pulse Volume Recordings
The ABI, although useful for diagnosis of the presence of PAD, does not provide for the level of disease, an important factor in determining how to treat claudication. A common procedure in many vascular laboratories is measurement of multiple or segmental pressures in the lower extremities along with pulse volume recordings that measure the magnitude and contour of the blood pulse volume. This combination of segmental pressures and pulse volume recordings has demonstrated 95% accuracy compared with angiography.
An alternative to pulse volume recording measurement is blood velocity waveform analysis, in which a continuous-wave Doppler probe is used over multiple arterial segments to detect the blood flow velocity and the velocity patterns. The normal blood flow pattern is triphasic (forward, reverse, and late forward flow), and a change in this pattern to biphasic or monophasic indicates a flow-reducing lesion. One major disadvantage of segmental pressure, pulse volume recording, and Doppler velocity waveform analysis is the inability to visualize the anatomy and to pinpoint the artery being studied. However, the pulse volume recording and Doppler velocity waveform analysis are particularly useful in assessing patients with supranormal pressures, such as may occur in diabetic patients, due to medial artery calcification.
Ultrasonic Duplex Scanning
Duplex ultrasound B-mode imaging combined with spectral Doppler analysis is used to localize occlusions more precisely than arterial segments or to more fully characterize the severity and morphology of occlusions. The artery characteristics provided from duplex ultrasound imaging include artery wall thickness, degree of flow turbulence, vessel morphology, and changes in blood flow velocity in areas of stenosis.
Compared with x-ray contrast angiography, the accuracy (specificity) of duplex ultrasound is very high (92% to 98%), although its sensitivity for assessment of stenosis is variable, depending on the size of the vessel.
Some data indicate that the sensitivity for stenosis measurement with duplex ultrasound is lower for smaller arteries than for larger arteries in the limb. The appropriate applications for duplex ultrasound include preparation for planned angioplasty or surgical procedure, detection of restenosis after an endovascular procedure, and surveillance of femoropopliteal or distal saphenous vein grafts for detection of myointimal lesions before graft failure.
If the specific anatomic location and further assessment of stenosis are warranted, then other noninvasive imaging techniques such as spiral computed tomography angiography and magnetic resonance angiography may be used in addition to or instead of duplex ultrasonography. Although noninvasive imaging studies are becoming more commonly used preoperatively, catheter-based angiography is still considered the “gold standard.”
Symptomatic and asymptomatic PAD is associated with an increased risk for morbidity and mortality. Pooled data from 11 studies in six countries found that PAD, defined by a low ABI (<0.9), was associated with an increased risk of subsequent all-cause mortality (RR, 1.60), cardiovascular mortality (RR, 1.96), coronary heart disease (RR, 1.45), and stroke (RR, 1.35) after adjustment for age, sex, conventional cardiovascular risk factors, and prevalent cardiovascular disease. An analysis from the Reduction of Atherothrombosis for Continued Health (REACH) registry spanning 44 countries demonstrated that patients with established atherosclerosis in more than one vascular bed had substantially higher event rates than did patients with atherosclerotic disease in only one vascular bed. In this cohort of approximately 68,000 patients, the annual rate of myocardial infarction, stroke, or death from cardiovascular causes for patients with PAD was 5%.
A recent prospective cohort demonstrated a similar high risk of mortality in symptomatic and asymptomatic patients with PAD, and it was significantly higher than in those without PAD. Data from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial showed an increased risk of all-cause death, cardiovascular death, myocardial infarction, and stroke in subjects with PAD versus no PAD and found no difference between symptomatic and asymptomatic PAD. In a longitudinal study of older men with diabetes without symptomatic PAD, 14-year mortality was significantly higher in subjects with asymptomatic PAD versus no PAD. In the multivariate analysis of the 14-year follow-up, PAD and diabetes were both associated with an increased risk of death, whereas PAD but not diabetes was associated with increased cardiac events and cardiovascular mortality. Data from the ARIC study between 1987 and 2001 found that for every 0.10 decrease in the ABI, the hazard for coronary heart disease increased by 25% in white men, by 20% in white women, by 34% in African American men, and by 32% in African American women.
In a recent collaboration of 16 international cohorts, the ABI provided independent risk information over and above the Framingham risk score. The hazard ratios for all-cause mortality at different levels of ABI compared with a reference ABI of 1.11 to 1.20 in all studies combined formed a reverse J-shaped curve for both men and women (see Fig. 31-2 ). For levels of ABI < 1.1, the hazard of death increased in a stepwise manner with decreasing ABI. An ABI > 1.40 was associated with an increased risk of death for men and women. Similar results were noted for cardiovascular mortality and major coronary events.
The treatment of PAD has evolved during the past decade to include a broad approach, focusing on reduction of the risk of the major factors associated with the development and progression of PAD. Furthermore, because PAD subjects are at high risk for coronary and cardiovascular events and mortality, much emphasis is placed on the reduction of cardiovascular risk. In fact, the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) considered PAD a coronary heart disease risk equivalent, thereby elevating it to the highest risk category. Nevertheless, patients with PAD are undertreated with regard to the use of lipid-lowering and antiplatelet drugs compared with patients with coronary artery disease.
A plethora of evidence exists that smoking is a very significant risk factor for the incidence of PAD and its consequences. Cessation of cigarette smoking is associated with a lower amputation rate, a lower incidence of rest ischemia, and an improvement in maximal treadmill walking distance. Among subjects with PAD who are not smokers, there is a lower rate of myocardial infarction and mortality than among PAD subjects who do smoke. Furthermore, PAD subjects who discontinue smoking have an improved 5-year survival versus that of those who continue to smoke. Physician advice must be the cornerstone of this strategy but should be in conjunction with other proven remedies, including group counseling sessions and pharmacologic interventions (nicotine replacement therapy, bupropion, and varenicline).
Although dietary modification is often the initial treatment for lowering of cholesterol concentration, the addition of pharmacotherapies may be necessary to achieve target total cholesterol, HDL-C, and LDL-C levels. All patients with PAD of any severity should achieve an LDL-C concentration of less than 100 mg/dL, whereas a target of less than 70 mg/dL is reasonable in subjects with PAD and atherosclerosis in other arterial beds.
In the Scandinavian Simvastatin Survival Study (4S), simvastatin (20 to 40 mg/day) significantly reduced the incidence of intermittent claudication from 3.6% to 2.3% during a median period of 5.4 years in 4444 patients with prior myocardial infarction or angina and a baseline plasma total cholesterol concentration between 212 and 309 mg/dL (relative risk reduction, 0.62%; 95% CI, 0.44%-0.88%). In subjects with established PAD, statin therapy may reduce the incidence of cardiovascular events. In a subgroup analysis of 6748 subjects with PAD from the Heart Protection Study, simvastatin 40 mg daily was associated with a reduction in cardiovascular events, regardless of the presenting cholesterol levels. Statin therapy also improves pain-free walking time. Although statin drugs have the strongest data supporting use, cholesterol lowering by other means is effective in decreasing cardiovascular events as well.
Blood Pressure Control
Antihypertensive therapy is effective at reducing cardiovascular events in subjects with PAD. Concern has been raised about the use of beta blockers in the treatment of hypertension among patients with intermittent claudication, but data do not elicit such fears. In fact, a meta-analysis of 11 studies of beta blocker therapy in patients with intermittent claudication found no significant impairment on walking capacity. As a result, these drugs are not contraindicated in patients with PAD. There is some evidence that angiotensin-converting enzyme inhibitor therapy may improve cardiovascular events and increase walking distance in selected patients with PAD. In the Heart Outcomes Prevention Evaluation (HOPE) trial, ramipril (5 to 10 mg/day) decreased cardiovascular events in subjects with PAD.
Regarding drug choice, all drugs that lower blood pressure are effective at reducing the risk of cardiovascular events. According to the TASC II guidelines, thiazide diuretics and angiotensin-converting enzyme inhibitors should be considered as initial blood pressure–lowering drugs in PAD to reduce the risk of cardiovascular events.
The Antithrombotic Trialists’ Collaboration, a systematic overview of 135,000 high-risk patients from 287 trials, demonstrated a reduction in myocardial infarction, stroke, and death with antiplatelet therapy in patients at risk for cardiovascular events. Among 42 PAD trials that included 9214 patients and used a variety of antiplatelet agents, compared with placebo, antiplatelet therapy (combining all agents) demonstrated a significant 23% reduction in the odds of cardiovascular events. However, nearly two thirds evaluated nonaspirin antiplatelet agents, questioning whether the overall benefit of antiplatelet therapy in PAD may have been driven by therapeutic regimens other than aspirin.
Subsequently, the prevention of progression of arterial disease and diabetes (POPADAD) trial found no benefit of aspirin 100 mg/day in diabetic subjects with asymptomatic PAD (ABI < 1.0). However, a subgroup analysis from the POPADAD trial demonstrated a borderline interaction, suggesting a greater benefit in those with an ABI ≤ 0.9 ( Fig. 31-5 ). A recent meta-analysis of randomized trials of aspirin versus placebo in participants with PAD did not show a significant reduction in cardiovascular events with aspirin. However, aspirin was associated with a 35% reduction in the incidence of nonfatal stroke.
Several hypotheses have emerged as to why aspirin was not found to significantly decrease cardiovascular events in subjects with PAD, including insufficient power, wrong dose, the variation in patient phenotype studied, and perhaps that PAD represents a diffuse form of atherosclerosis with a high inflammatory burden and platelet activity, which may be less responsive to aspirin. The overall benefit of antiplatelet therapies in the Antithrombotic Trialists’ Collaboration was driven by data from trials using picotamide, dipyridamole, and ticlopidine. Importantly, aspirin has been shown to have other benefits, including delay in the rate of progression, reduction of the need for intervention, and reduction of graft failure in patients who have undergone revascularization procedures.
The Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial demonstrated that clopidogrel (75 mg/day) had a modest although significant advantage over aspirin (325 mg/day) for the prevention of cardiovascular events in 19,185 patients with a recent stroke, myocardial infarction, or PAD. Overall, there was a 9% relative risk reduction for cardiovascular events, yet among the subset of patients with PAD, clopidogrel resulted in 23% fewer cardiovascular events compared with aspirin. However, the CHARISMA trial found no significant benefit of dual antiplatelet therapy with aspirin plus clopidogrel versus aspirin alone in patients with established coronary artery disease, cerebrovascular disease, or PAD as well as in patients with multiple atherosclerotic risk factors.
Although a benefit of dual antiplatelet therapy versus aspirin alone was noted in subjects with prior myocardial infarction, ischemic stroke, or symptomatic PAD, no reduction in cardiovascular events was noted in the subgroup of subjects with PAD. In a prospective randomized trial, picotamide significantly reduced mortality in diabetic patients with PAD compared with aspirin. This may reflect its greater potency, given a dual mechanism of action through inhibition of platelet thromboxane A 2 synthase and antagonism of thromboxane A 2 receptors. Future studies of this compound are warranted.
Current guidelines recommend an antiplatelet agent in subjects with PAD, such as aspirin or clopidogrel. On the basis of the limitations of data available, recommendations for aspirin as an important therapeutic tool for secondary prevention in patients with PAD should not be modified. To best inform evidence-based clinical practice guidelines, more high-quality clinical trials are needed.
Oral anticoagulation with warfarin has not been established to reduce cardiovascular events in patients with PAD because it is no more effective than antiplatelet therapy and confers a higher risk of bleeding. The Department of Veterans Affairs Cooperative Study tested combined oral anticoagulation and antiplatelet therapy in patients with PAD. No significant difference was found between groups, and there were 133 deaths in the combined treatment group and 95 deaths in the group receiving aspirin alone.
More recently, the Warfarin and Antiplatelet Vascular Evaluation (WAVE) trial randomized PAD patients to combination therapy with an antiplatelet agent and an oral anticoagulant agent (target international normalized ratio, 2.0 to 3.0) or to antiplatelet therapy alone. In this trial, the combination treatment arm was not more effective than antiplatelet therapy alone in preventing major cardiovascular complications and was associated with a more than threefold increase in life-threatening bleeding.
In addition to treatment of cardiovascular risk factors and coexisting diseases to prevent cardiovascular events (myocardial infarction, stroke, and death) associated with atherosclerosis, therapies exist to provide a significant reduction or elimination of PAD symptoms. Claudication drug therapy for relief of symptoms may involve drugs different from those that would be used for risk reduction (an exception may be lipid-lowering therapy).
Cilostazol is a phosphodiesterase type 3 inhibitor with properties that inhibit platelet aggregation and vascular smooth muscle proliferation and improve the lipid profile and vasodilation. A meta-analysis of six randomized trials demonstrated that cilostazol improved maximum walking distance and pain-free walking distance. An advisory from the U.S. Food and Drug Administration stated that cilostazol should not be used in patients with congestive heart failure because other phosphodiesterase type 3 inhibitors have been demonstrated to worsen survival in this cohort. The effect of cilostazol on cardiovascular morbidity and mortality remains unknown.
Pentoxifylline is a xanthine derivative used to treat patients with intermittent claudication. Its mechanism of action is thought to be a rheologic modifier—increase in red blood cell deformity and decreases in fibrinogen concentration, platelet adhesiveness, and whole-blood viscosity. A meta-analysis demonstrated a modestly improved walking distance, substantially less effective than either cilostazol or a supervised exercise program.
For patients with symptomatic PAD, exercise therapy is a key component of reducing symptoms. A supervised program of treadmill-based walking exercise can induce a training response characterized by large improvements in treadmill exercise performance, peak oxygen consumption, endothelial function, and quality of life. Exercise is more effective than angioplasty for improvement of walking time and is also more effective than antiplatelet therapy, but it does not differ significantly from surgical treatment. Possible mechanisms underlying the exercise response in PAD include improvements in endothelial function, skeletal muscle metabolism, and blood viscosity and a reduction in systemic inflammation. Although it is less well studied, exercise may also improve survival. In a prospective observational study of 225 men and women with PAD in whom physical activity was measured with a vertical accelerometer, individuals in the highest quartile of measured activity had a significantly lower mortality than those in the lowest quartile (hazard ratio, 0.29; 95% CI, 0.10-0.83).
The dietary approach for treatment of PAD is the same as for patients with coronary artery and carotid artery atherosclerotic disease. Patients are advised to balance calorie intake and physical activity to achieve and to maintain a healthy body weight; to consume a diet rich in vegetables and fruits; to choose whole-grain, high-fiber foods; to consume fish, especially oily fish, at least twice a week; and to limit intake of saturated fat to <7% of energy, trans -fat to <1% of energy, and cholesterol to <300 mg/day.