Cilostazol

Peripheral arterial disease (PAD) is a common manifestation of the atherosclerotic process and is defined as abnormal arterial flow to the lower extremities. It is essential that clinicians caring for patients with PAD not only accurately diagnose the disease, but realize that PAD is only one manifestation of the atherosclerotic process, which is a common link between PAD, cerebrovascular disease, cardiovascular disease, and death.

Epidemiology

Peripheral arterial disease is relatively common; the age-adjusted prevalence of PAD is 12% among adults; among those over age 75, as many as 20 to 30% may be affected, (1) while for those over age 85, 50 to 60% may be affected. (2) Both symptomatic and asymptomatic patients with PAD have an increased mortality when compared to those without PAD. (3) The excess mortality attributable to PAD appears to be related in large part to an increased risk of death from cardiovascular disease. For example, compared with patients without a history of PAD, the 10-year mortality rate for cardiovascular events is increased three- to six-fold in those patients with PAD. (4) Even in the absence of prior MI, the risk of cardiovascular death is similar in patients with PAD compared with patients with known coronary artery or cerebrovascular disease. (5) The rate of cardiovascular events increases with increasing PAD severity as measured by the ankle-brachial index (ABI), (6) even in septuagenarians and octogenarians. (7) Patients with critical leg ischemia, those with the lowest ABI values, have an annual mortality approaching 25%, a mortality rate that is higher than that for many malignancies. (8)

Clinical manifestations

Although up to three-quarters of patients with PAD are asymptomatic, (9) those with symptoms often complain of intermittent claudication, which is described as a cramping pain in the calf, thigh, or buttocks that occurs with walking or other forms of exercise and remits within 5 to 10 minutes with the cessation of activity and rest. Patients with lumbar spinal stenosis may present with lower extremity symptoms similar to PAD. However, the pain of neurogenic claudication from spinal stenosis is slower to remit after cessation of exercise and is often not present when the patient assumes the position of forward spinal tilt, such as when pushing a grocery cart.

Disease of the aorto-iliacs may manifest with Leriche's syndrome, which comprises claudication of the buttocks and thighs, along with impotence, due to diminished flow to the pudendal artery. Although the cardiovascular disease associated with PAD can progress rapidly, the arterial disease often progresses slowly in the extremities of patients with claudication.

Diagnosis

Although PAD is prevalent, physician awareness and detection of the disease is low, (10) perhaps due to the high rate of asymptomatic disease. (9) Additionally, busy clinicians often fail to examine the feet of their patients or may mistakenly associate an absent dorsalis pedis pulse with normal aging. This, in turn, leads to missed opportunities for the use of effective secondary preventive measures, such as aggressive treatment of dyslipidemia and hypertension, instituting an exercise regimen, discontinuing tobacco use, and the use of antiplatelet agents. (10) Clinicians, therefore, need to be familiar with the various modalities other than patient history used in the diagnosis of PAD (table 1).

Symptom questionnaires: The original 8-question Rose questionnaire, an instrument used to standardize diagnosis and categorize claudication, was subsequently modified by Leng and Fowkes to a 6-question survey, with a reported sensitivity of 91% and specificity of 99% in patients, average age 70. (11)

Physical examination: The diagnosis of PAD can be supported by the physical examination. In a review of published studies, absent pedal pulses, a unilaterally cool distal foot, prolonged venous filling time, and the presence of a femoral bruit were found to be useful in diagnosing PAD. Conversely, the capillary refill test, foot discoloration, atrophic skin, and hairless extremities were not found to be helpful. (12)

Ankle-brachial index

A useful, simple test for diagnosing or assessing the impact of interventions is the ankle-brachial index (ABI), which has a sensitivity of 96% and sensitivity of 94 to 100% (13) and can be performed in any outpatient office or clinic. To perform an ABI, an appropriately sized blood pressure cuff is placed over the ankle of a supine patient, and with the use of a 5 to 10 mHz hand-held Doppler, systolic blood pressures are measured in the posterior tibial and dorsalis pedal arteries. The ABI for each extremity is determined by dividing the lower extremity pressure by the higher of the systolic brachial pressure. Whereas a normal value is greater than 1.0, values less than 0.9 are consistent with claudication in those with suggestive symptoms. ABI values of 0.81 to 0.9 are consistent with mild obstructive disease, 0.51 to 0.80 moderate disease, and values less than 0.50 are considered severe obstructive disease. (13) Patients in this latter category may not only experience rest pain, but may be unable to heal ischemic wounds without aggressive intervention. These patients also have a greatly increased mortality, even when compared to those with established, though less severe PAD. Those with an ABI of 0.3 or less have a risk of death that is nearly double of those with ABIs between 0.5 and 0.91 when followed for 52 months. (13)

The sensitivity of the ABI can be further increased in appropriate patients by the addition of exercise testing, which can be performed by having the patient walk on a treadmill at 1.5 to 2 miles per hour at a 10 to 15% incline for up to 5 minutes. (14) This should be considered when a patient has symptoms of claudication or risk factors for vascular disease and has normal ABI measurements at rest. Exercise testing is contraindicated in those with unstable coronary syndromes, critical ischemia, or in symptomatic patients with rest pain.

Older patients and those with diabetes may have stiff, calcified, non-compressible vessels and may have an ABI greater than 1.30, even in the presence of PAD. If PAD is suspected based on the presence of risk factors or symptoms in such patients, other diagnostic modalities should be considered. In patients with diabetes, the digital arteries of the toes are often spared from medial calcinosis, and therefore, the toe/brachial index may be useful. Other non-invasive tools include the use of segmental leg pressures, pulse volume recordings, Doppler waveform analysis, color duplex and color Doppler imaging, and magnetic resonance angiography.

Segmental leg pressure

Whereas an abnormally low ABI measurement provides information that arterial flow is compromised in the affected extremity, it provides no anatomic localization other than its occurrence somewhere in the affected leg. When multiple pressure measurements are obtained along the lower extremity, the site of the vascular obstruction can usually be identified. Appropriately sized pneumatic cuffs can be placed on (1) the proximal thigh just below the perineum, (2) the distal thigh, just above the patella, (3) the proximal calf, just below the knee, (4) the lower calf, just superior to the ankle, and (5) the first toe. (15) A decrease in pressure of 20 to 30 mm Hg from one segment to the adjacent more distal segment implies a significant arterial obstruction in the vessels between the pneumatic cuffs. (16)

Doppler waveform analysis and color duplex imaging

The finding of abnormal arterial waveforms as they are obtained sequentially down the lower extremity implies an arterial obstruction in the leg between where the normal and abnormal waveforms were obtained. The information obtained by Doppler waveform analysis can supplement that obtained with segmental leg pressures, identifying specific vessels responsible for symptoms.

Color duplex imaging combines real-time B-mode imaging with pulsed and color imaging. While B-mode imaging provides anatomic detail of the vessel, color Doppler provides information regarding the direction of flow and the presence of turbulence. Although this test can be useful in the evaluation, when compared with segmental leg pressures or waveform analysis, it requires a longer time for evaluation, a more skilled technologist, and more expensive equipment.

Magnetic resonance imaging

Refinements in magnetic resonance imaging have now improved its diagnostic capability for PAD, such that in some institutions, magnetic resonance angiography (MRA) has replaced conventional angiography prior to surgery, thereby eliminating the risks of angiography (eg, arterial puncture, plaque embolization, contrast-induced nephropathy). A meta-analysis of 34 studies including 1,090 subjects found MRA highly accurate for diagnosis of PAD in the entire lower extremity compared with conventional angiography or intra-arterial digital subtraction angiography, though three-dimensional gadolinium-enhanced MRA is superior to the two-dimensional MRA. (17)

Therapy

Because PAD is one manifestation of systemic atherosclerosis, therapy is not only directed at the affected extremity, but at the entire disease process to improve outcomes attributable to atherosclerosis in other vascular beds. Pharmacologic and non-pharmacologic interventions that target atherosclerotic risk factors should be used to improve quality of life, decrease the risk of amputation, MI, stroke and death (table 2).

Risk factor modification

It is imperative that primary care physicians identify and aggressively treat modifiable atherosclerotic risk factors such as smoking, dyslipidemia, diabetes, and hypertension. Smoking is an important risk factor for the development of PAD and primary care clinicians need to advise patients to stop smoking and assist them to reach this goal. Nicotine replacement (in the form of transdermal patches, spray, gum, or inhaler) or the antidepressant bupropion, combined with behavioral modification enhances the rate of smoking cessation18 and should be strongly recommended, even in older adults.

Dyslipidemia is a strong independent risk factor for atherosclerotic complications. Several large, well-done clinical trials have demonstrated the beneficial effects of lipid lowering in those with coronary heart disease. (19) In patients with claudication, lipid-lowering therapy reduces disease progression and claudication. (20) In the Heart Protection Study, over 20,000 high-risk subjects were randomized to the HMGcoA-reductase inhibitor simvastatin or placebo. High-risk subjects included not only those with known cardiovascular disease, but patients with diabetes and those with cerebrovascular or peripheral vascular disease. Those randomized to simvastatin had an approximately 25% reduction in cardiovascular events compared to those randomized to placebo; (21) similar results were found in the subset of patients enrolled with PAD (as defined by the presence of intermittent claudication or lower extremity vascular surgery or angioplasty) and no known cardiovascular disease. Interestingly, similar reductions were found in older adults and the subset of study patients who had LDL cholesterol levels below 100 mg/dL (the target currently recommended by the Adult Treatment Panel (ATPIII) of the US National Cholesterol Education Program for patients with cardiovascular, other vascular disease, or diabetes mellitus (22) before treatment, suggesting that there may not be a lower threshold for initiating therapy.

Diabetes mellitus is a common disorder associated with significant morbidity and mortality, and intensive control of blood glucose has been shown to reduce the risk of most complications. However, intensive control of blood glucose has not been shown to reduce the risk of PAD (23) or the risk of amputation related to PAD, (24) although it has been shown to reduce microvascular complications (ie, nephropathy, neuropathy, retinopathy). While these findings do not support intensive glycemic control for control of PAD, it should be strongly considered in order to reduce microvascular complications. Similarly, although hypertension is a known risk factor for cardiovascular disease, it is not presently known whether treatment of hypertension alters the progression of PAD. While diuretics and beta-blockers are recommended by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure as initial pharmacologic therapy unless indications for other agents exist,25 more recently the angiotensin-converting-enzyme inhibitor, ramipiril, has been shown to confer cardiovascular protection beyond what would be expected by its blood pressure lowering effects alone in a cohort of subjects with vascular disease or multiple risk factors for vascular disease. (26)

Exercise and specific medical therapy

Several small trials have evaluated the role and efficacy of exercise therapy for patients with PAD. A review of the literature found that exercise is associated with an increase in maximal walking distance of 150% (range 74% to 230%). (27) Additional studies are needed to demonstrate the cost-effectiveness and long-term benefits of exercise for PAD as well as to compare different aerobic exercise regimens.

The xanthine derivative pentoxifylline has been shown to increase walking distances in patients with claudication when used for up to 6 months, although its exact mechanism of action is not clearly understood, its long-term efficacy unproven, and its effects often are not dramatic. (28)

Cilostazol, a phosphodiesterase III inhibitor, has been shown to be superior to pentoxifylline in its ability to improve maximal walking distance and is generally well-tolerated; (29) it is more expensive than pentoxifylline, however. It is contraindicated for those with congestive heart failure, since a chemically-related agent has been shown to increase mortality in these patients.

Aspirin, at doses of 81 to 325 mg daily, have been recommended for those with PAD. (30) Other anti-platelet agents, such as ticlopidine and clopidogrel, have also proven effective for those with PAD. Ticlopidine, which inhibits adenosine 5'-diphosphate-stimulated fibrinogen binding to its platelet receptor, is superior to placebo in its ability to increase walking distance. (31) However, due to the risk of drug-induced neutropenia and thrombotic thrombocytopenic purpura (TTP), it has been supplanted by a newer, chemically-related drug, clopidogrel, which has a lower incidence of side effects. This latter agent reduces cardiovascular risk when compared with aspirin in patients with atherosclerosis, although the absolute reduction in risk was small. (32) In this study, 115 patients needed to be treated with clopidogrel rather than aspirin for 2 years to prevent one vascular event.

Other agents currently available with potential use for those with PAD include levocarnitine, and prostaglandins. (33) Additional evidence to support their use is warranted before they can be recommended for routine clinical practice.

Conclusions

Peripheral arterial disease is a common manifestation of the atherosclerotic process and is associated with significant morbidity and mortality. Clinicians should be aware of its risk and consider screening for PAD, just as they screen for malignancy, diabetes mellitus, dyslipidemia, and hypertension. For those found to have PAD, risk factor reduction, such as smoking cessation, initiation or augmentation of an exercise regimen, treatment of hypertension and diabetes mellitus, as well as aspirin and/or clopidogrel, and statin therapy should be employed whenever possible. Patients with non-healing ulcers or tissue loss accompanied by a low ABI, rest pain, or severe, debilitating claudication should be referred to vascular surgeons or interventional radiologists for consideration of more aggressive interventions.

Free vascular screenings: May 14, 2004

Primary care physicians are encouraged to refer patients for free vascular screenings at one of more than 100 locations around the country as part of the American Vascular Association's (AVA) National Screening Day.

The 20-minute AVA Screening program includes the following:

* A "quick" carotid duplex scan for the detection of carotid stenosis combined with a cardiac rhythm strip and blood pressure measurement to address stroke risk reduction.

* An aortic ultrasound scan for the detection of abdominal aortic aneurysm.

* An ankle brachial index for the detection of peripheral arterial disease.

All participating centers will receive a comprehensive array of public education materials to distribute and resources to assist them in the performance of the program.

To qualify as one of the locations, centers must have have accredited noninvasive vascular testing resources.

The American Vascular Association is a public health advocacy organization whose mission is to reduce deaths and disabilities due to vascular disease. The AVA is a public education initiative of the Society for Vascular Surgery.

For more information, call 1-800-282-2010, or visit the website at http://www.vascularweb.org.

Log on to www.geri.com

* Heart disease in older women

Gender differences affect diagnosis and treatment Deadline: June 1, 2004

* Sleep disorders in older adults

A primary care guide to assessing 4 common sleep problems in geriatric patients Deadline: July 1, 2004

* Insomnia, depression, and aging

Assessing sleep and mood interactions in older adults Deadline: August 1, 2004

* A sleep review of systems

Evaluating effects of medical disorders on sleep in older patients Deadline: September 1, 2004

Accredited through Mount Sinai School of Medicine's Brookdale Department of Geriatrics and Adult Development, the first and foremost department of geriatrics in the United States.

Log on to www.geri.com

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(20.) Leng GC, Price JF, Jepson RG. Lipid-lowering for lower limb atherosclerosis. The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd. Last accessed 3.18/04 at http://212.49.218.202/abstracts/ab000123.htm.

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Dr. Federman is Firm Chief, Primary Care, VA Connecticut Health Care System; West Haven; and associate professor of medicine, department of internal medicine, Yale University School of Medicine, New Haven, CT.

Dr. Bravata is with the Clinical Epidemiology Research Center (CERC), VA Connecticut Health Care System, West Haven; and assistant professor of medicine, department of internal medicine, Yale University School of Medicine, New Haven, CT.

Dr. Kirsner is Chief of Dermatology, Miami VA Medical Center; and associate professor of medicine, department of dermatology, University of Miami School of Medicine, Miami, FL.

Disclosure: None of the authors have any potential conflict of interest with any product mentioned in the manuscript. Dr. Bravata is supported by a Career Development Award from the Department of Veteran Affairs Health Services Research & Development.

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