Related articles on this website: In the Current Literature section: Ankle-Brachial Index as a Predictor of the Extent of Coronary Atherosclerosis and Cardiovascular Events in Patients with Coronary Artery Disease Papamichael CM, Lekakis JP, Stamatelopoulos KS, et al. Am J Cardiol. 2000;86:615-618. In the LipidManagement™ Newsletter section: Clinical Application of ATP III Guidelines Vol 6, No 3, Page 1 In the Slide Library section: ATP III: CHD Risk Equivalents

The prevalence of peripheral arterial disease (PAD), an atherosclerotic syndrome affecting any artery in the body besides the coronary and intracranial vessels, is a staggering 8 to 12 million adults in the United States.^1,2 Even more unsettling than the numbers alone is the fact that most individuals affected do not know they have it, because PAD is usually asymptomatic (see Table 1 - below). The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines include PAD among the forms of atherosclerotic disease that are considered coronary heart disease (CHD) risk equivalents (see ATP III sidebar - below). Based on this emphasis and a growing body of data, a more refined understanding of PAD that will affect diagnosis and treatment of PAD in the primary-care setting has emerged.

In most contexts, the term PAD refers to chronic arterial occlusive disease in the lower limbs.^2,3 The earliest and most common presenting symptom of PAD is intermittent claudication, or leg muscle pain during ambulation. As PAD progresses, many patients also experience pain at rest, usually in the foot. In later stages of the disease, the decreased blood flow in the lower limbs may result in ischemic ulceration and gangrene, necessitating major amputation in more than one-third of cases.²

Despite the high prevalence of PAD and the strong likelihood of significant morbidity and mortality, no national efforts have been directed toward encouraging the detection of this disease in the community-based office practice. The PARTNERS (PAD Awareness, Risk, and Treatment: New Resources for Survival) program evaluated the feasibility of detecting PAD in primary-care practice (see PARTNERS sidebar on page 2). The investigators also sought to raise physician awareness about this common disease, which is frequently overlooked and, consequently, undertreated. The Minnesota Regional Peripheral Arterial Disease Screening Program, which was conducted on a smaller scale, shared a similar goal and attained similar results—notably that PAD can be efficiently identified within the community, but that current standards of medical care are low.⁴

Risk Factors
PAD risk factors are virtually identical to those for cardiovascular disease (CVD).² The main risk factors are age and sex: PAD is more common in the elderly and in men than it is in the young and in women. (Less common, however, does not imply less cause for concern; PAD may be statistically more prevalent in the former populations, but it is still a serious problem in the latter populations.) Type 2 diabetes is also an important risk factor, particularly for large-vessel atherosclerotic occlusive disease. Smoking doubles or triples the risk for PAD, and hypertension may even quadruple it.²

Certain lipid and nonlipid biomarkers also serve as predictors for the development of symptomatic PAD. Among nearly 15,000 male middle-aged participants in the Physicians’ Health Study who were apparently healthy at baseline, 140 developed PAD (cases) over 9 years of follow-up.⁵ They were matched with 140 randomly selected men who had remained CVD-free (controls). Median baseline levels of TC, LDL-C, TG, apolipoprotein B-100, and the ratio of TC to HDL-C were significantly higher in the cases than in the controls, and HDL-C levels were significantly lower. Nonsignificant baseline elevations of lipoprotein(a) and homocysteine were also noted in the cases relative to the controls. Median levels of two inflammatory markers, C-reactive protein (CRP) and fibrinogen, were also significantly higher in the cases than in the controls. The TC:HDL-C ratio was the strongest PAD predictor among lipid parameters, whereas CRP was the strongest PAD predictor among nonlipid parameters. As with CVD, coexistence of multiple risk factors dramatically increases PAD risk.²

Diagnosis
The first step in diagnosing PAD is obtaining an accurate history.² Intermittent claudication can be differentiated from neuropathic pain on the basis that it begins with ambulation and remits within a few minutes after walking ceases. In contrast, neuropathic pain does not subside after cessation of ambulation and may, in fact, worsen as the patient continues to sit or stand. The second step is determining the ankle-brachial index (ABI), the ratio of the systolic blood pressure (SBP) at the ankle to the SBP at the brachial artery in the arm, as measured with a handheld Doppler ultrasound instrument³ (see Table 2 - below).

Contrast arteriography is considered the gold standard for PAD diagnosis. However, as a semi-invasive procedure, it is generally reserved for patients for whom a surgical or percutaneous intervention is planned.² Alternative diagnostic modalities for PAD include duplex ultrasonography and magnetic resonance angiography.

Treatment
The approach to PAD treatment is two-pronged: to address risk factors for atherosclerosis and to manage lower-extremity symptoms.²

 Risk-factor management.
The literature suggests that physicians first encourage patients who smoke to undergo formal smoking-cessation interventions; patients with PAD can be enrolled in a supervised walking exercise program. Finally, it is important to control patients’ blood pressure, blood sugar, and lipid levels, whether through lifestyle changes, pharmacotherapy, or both.

Controlling lipid levels may be particularly important; study findings have suggested that many lipid-lowering therapies may lessen or even prevent PAD.³ The results of two ongoing randomized, double-blind, placebo-controlled, multicenter trials, both of which are being conducted on patients with intermittent claudication, should help clarify this issue. In the first trial, 351 patients received the HMG-CoA reductase inhibitor (statin) atorvastatin (10 or 80 mg daily) or placebo. The 328 patients who completed the second trial received the acyl coA:cholesterol acyltransferase inhibitor avasimibe (50, 250, or 750 mg daily) or placebo.³



Symptom control. Patients with lower-limb symptoms should receive an antiplatelet agent such as aspirin, cilostazol, or clopidogrel.^2,3 Pentoxifylline appears to be only marginally effective in this regard. Other pharmacologic options to treat severe PAD include intravenous prostanoids, prostacyclin analogs, and thrombolytics. Patients with chronic limb ischemia that places them at risk for amputation may be candidates for surgical intervention (endarterectomy or bypass grafting) or an endovascular procedure.

Prognosis
The presence of PAD triples the risk for all-cause mortality and sextuples the risk for CVD and CHD mortality.³ In addition, the more severe the disease, the poorer the long-term prognosis. A study comparing outcomes in two groups of patients with PAD, one with critical leg ischemia (CLI; n=84) and one with intermittent claudication (n=213), showed that all-cause mortality and CVD mortality were significantly higher in the CLI group than in the intermittent claudication group.6 Of interest, CLI was an even stronger predictor of CVD mortality than was a history of CVD. Investigators concluded that patients with more advanced PAD are likely to have more widespread atherosclerotic disease. Consequently, they recommended an aggressive approach to secondary disease prevention in this high-risk group.

Clinical Implications
Two recent studies have shown that PAD can be detected with the ABI technique in the primary-care setting.^1,4 As research data continue to suggest that most patients diagnosed with PAD die of CVD-related events, physicians are encouraged to focus treatment strategies on reducing risk factors for atherosclerosis (ie, smoking, obesity, lack of exercise, hypertension, dyslipidemia, diabetes) in addition to providing relief for limb-specific symptoms. In the near future, results from two dditional trials and other studies will provide essential information regarding the benefits of lipid-lowering therapy in reducing symptomatic PAD.

References