Natural History and Nonoperative Treatment of Chronic Lower Extremity Ischemia

Asymptomatic Arterial Insufficiency

Asymptomatic PAD is defined as a decreased ankle-brachial index (ABI) without lower extremity symptoms. Most studies use an ABI below 0.9 as the reference standard for PAD. The presence of asymptomatic lower extremity occlusive disease varies, but available data indicate that for every patient with intermittent claudication, there are probably three others with similar disease who do not complain of symptoms or have atypical symptoms. Estimated ratios of symptomatic to asymptomatic patients range from 1 : 1.8 to 1 : 5.3.

The prevalence of asymptomatic PAD was 25.5% among 1537 participants in the Systolic Hypertension in the Elderly Program. Data from a nationwide cross-sectional study, based on more than 350 primary care practices, demonstrated that 13% of 6979 patients older than 50 years had abnormal ABIs, with or without symptoms of intermittent claudication. Only 24% of patients identified with chronic lower extremity ischemia had a previous diagnosis of PAD, and asymptomatic patients accounted for 48% of newly diagnosed PAD.

Incidence of Symptomatic Peripheral Arterial Disease

The majority of epidemiologic studies of PAD have focused on patients with intermittent claudication, defined as leg pain with walking (most often calf pain, but it can involve the thighs and buttocks well). Pain is induced by exercise and relieved by rest. Reported incidences of PAD depend on age and the definition of intermittent claudication and vary from 2.2% in a population aged 33 to 82 years to 17% in a population aged 55 to 70 years. In the Framingham Heart Study, the incidence of PAD was based on symptoms of intermittent claudication in subjects 29 to 62 years old. The annual incidence of intermittent claudication per 10,000 subjects at risk rose from 6 in men and 3 in women aged 30 to 44 years to 61 in men and 54 in women aged 65 to 74 years. The average rate of development of intermittent claudication over a 2-year period in subjects older than age 50 was 0.7% in men and 0.4% in women.

In the Edinburgh Artery Study of almost 1600 subjects older than 55 years, the 5-year cumulative incidence of PAD was 9%. In a study of 8400 Israeli men over a 21-year period, the cumulative incidence of PAD was 43.1 per 1000 population. In the Quebec Cardiovascular Study of 4570 men followed over 12 years, an incidence of 41 per 10,000 population per year was noted. In the Physicians' Health Study, 433 incident cases of PAD were reported among 22,071 relatively healthy men.

Prevalence of Symptomatic Peripheral Arterial Disease

Epidemiologic studies have used both questionnaires and noninvasive vascular laboratory screening to estimate the prevalence of PAD in the elderly adult population. Before the development of reliable noninvasive testing, the diagnosis of PAD was based on patient questionnaires. Among questionnaires, the World Health Organization/Rose Questionnaire and the Edinburgh Classification Questionnaire (ECQ) have been the most extensively utilized. The ECQ appears to be more robust, with a sensitivity of 91% and a specificity of 99% for the diagnosis of intermittent claudication. Using the ECQ, the prevalence of lower extremity arterial disease was estimated to be 4.6% in the Edinburgh Artery Study in men and women between the ages of 55 and 74 years. Other studies have found the prevalence of intermittent claudication in adults older than age 45 to be approximately 1% to 5% ( Table 34.1 ).

When the ABI is used as a reference standard, the detected prevalence of lower extremity arterial occlusive disease is greater, likely because of the inclusion of patients who are asymptomatic or have atypical symptoms. The overall age-adjusted prevalence of PAD diagnosed on the basis of the ABI is approximately 12%; for intermittent claudication, it is 1% to 2% up to age 50 and 5% to 7% above the seventh decade. In the Cardiovascular Health Study, the prevalence of a decreased ABI (<0.9) was 12.4% in adults aged 65 years or older in four US communities. Using the same criteria, investigators in the Rotterdam Study reported a PAD prevalence of 19% in subjects older than 55 years. In the Edinburgh Artery Study, the prevalence of lower extremity arterial occlusive disease diagnosed using the ABI was 17% in subjects between the ages of 55 and 74 years. In a Danish study, the prevalence of lower extremity arterial occlusive disease in 60-year-old subjects was 16% for men and 13% for women ( Table 34.2 ). Thus objective standards of measurement identify a greater number of patients with PAD than does reliance on patient description of symptoms.

Several factors might explain the lack of sensitivity of questionnaires and the increased prevalence of PAD with noninvasive testing. First, symptoms might not occur until the disease is advanced. This is particularly relevant in older patients, who may rarely walk more than one or two blocks at a time in the performance of their activities of daily living or who may assume that leg pain while walking is a natural part of the aging process. Second, patients with PAD may have other comorbidities, such as arthritis, cardiac disease, or pulmonary disease, affecting their walking ability to a greater degree than PAD.

Smoking

The specific mechanisms by which tobacco exerts its adverse effects on arteries remain poorly understood; however, a direct relationship between tobacco smoking and peripheral arterial disease is well established. All epidemiologic studies of lower extremity arterial disease have confirmed cigarette smoking as a strong risk factor for the development of such disease, with relative risk ratios ranging from 1.7 to 7.5. A case-control study revealed a sevenfold higher risk of developing PAD in ex-smokers compared with those who had never smoked, and the risk increased to 16-fold in current smokers compared with those who had never smoked. The diagnosis of lower extremity arterial disease is made up to a decade earlier in smokers compared with nonsmokers. More than 90% of all patients referred to vascular clinics for PAD have a history of smoking.

In addition to the chronic effects of smoking on the development of atherosclerosis, smoking has acute effects on lower extremity function. Smoking two cigarettes within a 10-minute period results in an acute lowering of the ABI in chronic smokers from 0.64 ± 0.14 to 0.55 ± 0.11 ( P = .008). In addition to having adverse influences on atherosclerosis, tobacco smoke may directly contribute to claudication. Smoking is associated with acute drops in treadmill walking distances, presumably related to the effects of carbon monoxide. An immediate and significant decrease in the time or distance patients can walk on the treadmill before they manifest claudication symptoms has been demonstrated when they breathe air containing carbon monoxide. Smokers have an increased risk of peripheral arterial disease progression, myocardial infarction, stroke, and death. Smokers also have an increased risk of major amputation.

Diabetes Mellitus

There is a strong association between diabetes mellitus and PAD. Two types of vascular disease are seen in patients with diabetes: microcirculatory dysfunction involving the capillaries and arterioles of the kidneys, retina, and peripheral nerves and a macroangiopathy involving the peripheral and coronary arterial circulations. The Framingham Study was one of the first major epidemiologic studies to demonstrate the association between diabetes and PAD. Diabetes increased the risk of claudication by a factor of 3.5 in men and 8.6 in women. Numerous subsequent studies have associated impaired glucose tolerance with a two- to fourfold increase in the risk of developing intermittent claudication. In an elderly white population, 20.9% of patients with diabetes mellitus and 15.1% of those with an abnormal glucose tolerance test had an ABI less than 0.9. In a Swedish study, 21% of patients with diabetes had signs of PAD. The duration and severity of diabetes mellitus correlate strongly with the incidence and severity of PAD.

Patients with diabetes mellitus more often develop symptomatic forms of PAD and have poorer lower extremity function than do those with PAD alone. The prevalence of diabetes in patients undergoing lower extremity revascularization ranges from 25% to 50% compared with a prevalence of 6% in the general population. The rate of lower extremity amputation is 7- to 10-fold higher in diabetic patients than in those without diabetes, with diabetes being the leading cause of nontraumatic lower extremity amputations. In addition to diabetes, insulin resistance and hyperinsulinemia are also risk factors for PAD. There is an increased mortality risk in PAD patients, but compared with PAD patients without diabetes, PAD patients with diabetes still have an almost threefold increased risk of death within 10 years.

Gender

Early epidemiologic studies focused on PAD in men. The popular notion, based on the Framingham Study, was that symptomatic PAD in women lagged behind men by 10 years and that women were generally not affected by PAD until after menopause. Recent epidemiologic studies, however, indicate that the prevalence and incidence of PAD in men and women are similar, with the age-adjusted incidence of intermittent claudication equal in both genders. However, the frequency of PAD among diabetic women is markedly higher than that among diabetic men. In patients with a low ABI, coronary artery disease is less prevalent among women. Women also had a lower frequency of cerebrovascular disease. In another study, the prevalence of PAD was essentially identical in men and women, with other cardiovascular disease twice as prevalent in men. Progression of PAD, as measured by changes in ABI, appears to be the same in men and women.

Women with PAD may suffer a faster functional decline and have a somewhat varied distribution of atherosclerotic lesions. A prospective trial of 380 men and women showed that at 4-year follow-up, women were more likely than men to have a decline in walking distance and to develop mobility-related disability. Functional differences may be attributable to a smaller baseline calf muscle area in women, and women may be more susceptible than men to the development of aortoiliac arterial occlusive disease. Autopsy findings indicate, that women, compared with men, have more fatty streaks in the abdominal aorta but not in the coronary arteries.

It is likely that PAD is underdiagnosed in women to a greater degree than in men. Women are less likely than men to have diagnosed PAD on the basis of symptoms, even if clinically significant PAD is present on noninvasive examination. In addition, infrainguinal arterial reconstructions in women, compared with men, tend to be performed for more advanced disease, and such women tend to be older.

The reasons for the more advanced presentation of PAD in women are unclear. Some speculate that women more frequently assume a caretaker role and therefore are more likely to ignore their own medical care; or perhaps women are more likely to ignore mild to moderate pain, attributing it to a consequences of old age. It is clear that, as more data accumulate on PAD in women, the previous dictum of PAD being primarily a disease of men is proving to be incorrect.

Race

Few studies have assessed differences in PAD prevalence among different ethnic groups. One early study indicated that African American patients with PAD typically had a higher prevalence of infrapopliteal atherosclerosis, which was associated with a greater incidence of limb loss. PAD may be underreported in the African American population. In the Atherosclerosis Risk in Communities Study, more than 4000 African American men and women were screened for PAD. Despite a greater prevalence of hypertension and diabetes, the prevalence of PAD measured by questionnaire was lower among African American men than among white men. However, 3.3% of African Americans had an ABI below 0.9, compared with only 2.3% of whites. In the Cardiovascular Health Study, the nonwhite population had a 3.5-fold increased frequency of an ABI below 0.8.

Hyperlipidemia

Up to 50% of patients with lower extremity arterial disease have hyperlipidemia. In the Framingham Study, a fasting cholesterol level above 270 mg/dL was associated with a doubling of the incidence of intermittent claudication. Population studies have demonstrated that the relative risk of PAD is 2 times greater in patients with hypercholesterolemia, 1.7 times increased in patients with hypertriglyceridemia, and 2.0 times increased in patients with elevated levels of lipoprotein(a). On the other hand, triglyceride level is not an independent risk factor for PAD when corrected for other serum lipid variables. In an evaluation of multiple plasma lipid constituents on the risk of developing PAD, the ratio of total cholesterol to HDL cholesterol was the strongest predictor of PAD development, and the addition of screening for other lipid abnormalities did not improve predictive values. The addition of screening for two nonlipid variables—C-reactive protein and fibrinogen—did, however, improve the prediction of PAD risk.

Hyperhomocysteinemia

Prospective and retrospective studies have suggested an association between elevated levels of plasma homocysteine and premature vascular disease in the coronary, cerebrovascular, and peripheral circulation. Early studies suggesting this association, however, were based on small numbers of patients. Darius and colleagues evaluated plasma homocysteine level as an independent risk factor for PAD in 6880 primary care patients older than 65 years. Although PAD (defined as an ABI <0.9) was more frequently diagnosed in patients in the highest quintile of homocysteine levels (24.3%) than in those in the lowest quintile (13.0%; crude odds ratio 2.1), the association was less strong after adjusting for other atherosclerotic risk factors (odds ratio 1.4). Thus the association between hyperhomocysteinemia and atherosclerosis is mild.

Serum Markers

Fibrinogen and C-reactive protein have been implicated in the pathogenesis of PAD. Their role in the pathogenesis of atherosclerosis is unclear; however, they are thought to be potential markers of endothelial dysfunction, and elevated fibrinogen levels have been found to be an independent risk factor for PAD. C-reactive protein is an acute-phase reactant that is elevated in acute inflammatory conditions. Persistent elevations are observed in chronic inflammatory disorders, consistent with the modern concept of atherosclerosis as an inflammatory disorder. Other atherogenic risk factors such as age, smoking, diabetes, and hyperlipidemia are associated with elevated levels of C-reactive protein in the absence of PAD. Elevated C-reactive protein may be an epiphenomenon associated with, but not causative of, an atherogenic state.

Elevated C-reactive protein and D-dimer, a marker of ongoing fibrin formation and degradation, are associated with poorer physical functioning in PAD patients. Measurements of walking distance, walking speed, and balance are significantly worse in patients with elevated C-reactive protein and D-dimer. Other inflammatory biomarkers, such as soluble adhesion molecules and tumor necrosis factor-α (TNF-α), have also been studied with monocyte expression of TNF-α and found to be associated with a decrease in maximal treadmill walking time.

Infection

Although controversial, there is evidence that atherosclerosis may be associated with an inflammatory process caused by chronic infection with Chlamydia pneumoniae or other infectious agents. A meta-analysis of pooled data from 38 studies calculated an overall odds ratio of 1.6, suggesting only a mild causative role at best. C. pneumoniae may therefore be primarily an innocent bystander in the atherosclerotic process rather than a cause. In support of this argument, the association between atherosclerosis and C. pneumoniae infection appears to be higher in retrospective cross-sectional and case-control studies than in prospective case-control studies, and the association is inversely proportional to length of follow-up.

Alcohol Consumption

Mild to moderate alcohol consumption is associated with a reduced risk of cardiovascular disease and reduced cardiac mortality, with an inverse relationship between alcohol consumption and PAD. The beneficial effects of alcohol are thought to be due to its influence on hemostasis, lipid profiles, and the decreased generation of oxygen free radicals.

Cardiovascular Overlap

Because atherosclerosis is a systemic process, significant overlap exists between PAD and other forms of cardiovascular disease—primarily coronary artery and cerebrovascular disease. Hertzer and colleagues clearly demonstrated a high incidence of coronary artery disease in vascular surgery patients. Their conclusions were based on a series of 1000 patients undergoing major vascular surgery in whom they performed preoperative coronary angiography, regardless of a history of coronary artery disease or cardiac symptoms. More than 90% of patients had significant coronary artery disease, much of which was asymptomatic. The authors also found an increased frequency of severe coronary artery disease with age, from 22% among patients younger than 50 years to 41% among patients 70 years of age or older ( Table 34.3 ).

The well-recognized overlap between PAD and other types of cardiovascular disease has been confirmed in numerous large epidemiologic studies and clinical trials ( Table 34.4 ). In the Cardiovascular Health Study, 60% of patients with PAD had a history of other symptomatic cardiovascular disease, such as myocardial infarction, angina, or stroke. Forty percent of patients with coronary artery or significant cerebrovascular disease also had PAD. Similar findings were reported in a large epidemiologic study in which 1886 patients aged 62 years or more were screened for cardiovascular disease. Seventy percent of patients with PAD had associated coronary artery or cerebrovascular disease (34% cerebrovascular, 58% coronary artery).

Progression of Symptoms

Knowledge of the natural history of PAD is essential when planning therapeutic strategies. When patients with intermittent claudication are followed for 5 years, approximately 50% to 75% have either no change in symptoms or experience improvement. Approximately 25% experience symptom progression, with 5% to 25% requiring therapeutic intervention and only 2% to 4% needing major amputation. Both continued tobacco use and diabetes mellitus are correlated with deterioration in the most consistent predictor of an adverse outcome—that is, the severity of objectively determined arterial occlusive disease at the first patient encounter.