Symptoms

Intermittent claudication is the most prominent symptom of peripheral artery disease (PAD). However, PAD is just as likely to be present without symptoms or to have problems in the legs that do not resemble intermittent claudication. Because of such silent symptoms, many cases of PAD go undiagnosed.

Intermittent Claudication

Intermittent claudication is an important symptom of peripheral artery disease (PAD) and occurs in between a third and half of these patients. Claudication is taken from the Latin word "to limp" and it is the pain that occurs in PAD patients when they exercise, particularly during walking.

In intermittent claudication, blood flow in the leg is insufficient to meet the needs of the person while exercising. The most frequently affected artery in intermittent claudication is the popliteal artery. This artery leads off from the femoral artery (the major artery in the thigh). It continues below the knee where it branches off and carries blood to the muscles in the calf and foot.

In general, the following occurs during physical activity:

In PAD, the artery becomes blocked and the free flow of blood is limited. During exercise, then, oxygen supply does not meet the muscles' demands.
In response to this higher demand, the body reduces chemicals that open blood vessels (e.g., nitric oxide) and increases chemicals that narrow blood vessels (thromboxane, serotonin, angiotensin II, endothelin, norepinephrine).
There is also some evidence that blood cells may become abnormal in PAD and prone to forming clots.

The result of these actions is leg pain during exercise, which is relieved only by rest. Leg pain occurs in one leg in 40% and in both legs in 60% of patients.

Symptoms of Advanced Peripheral Artery Disease (Ischemic Rest Pain)

In advanced cases, PAD obstructs the arteries in the leg to the degree that even rest offers no relief and pain can continue even when lying down, a condition called ischemic rest pain. (Ischemia is the medical term for insufficient blood flow to tissues.) In this severe situation, the arteries can become so obstructed that ulcers and gangrene can develop, leading in severe cases to amputation. Symptoms in such cases can include the following:

Withered calf muscles.
Hair loss over the toes and feet.
Thick toenails.
Shiny, tight skin.
Painful ulcers in the toe that typically are black and do not bleed.
In some cases, blood clots can form in the arteries in the legs, producing symptoms abruptly.

Risk Factors

Between eight and 10 million American adults have peripheral artery disease (PAD). The prevalence ranges from 3% in young adults to between 12% and 29% in people over 65. (These numbers are expected to rise as the population ages.) Intermittent claudication occurs in about one-third to one-half of PAD patients.

Although it is commonly believed that PAD occurs more often in men than women, current research now indicates that both genders are equally susceptible.

People in northern regions tend to have a higher risk than those in southern areas. In one study, Caucasians had a higher risk for PAD than people from India or the people of African descent from the Caribbean. Such findings are counter to studies suggesting higher risks for heart disease in African Americans and for diabetes in populations from India.

Heart Disease Risk Factors

The major risk factors for heart disease and stroke are also the most important risk factors for PAD and intermittent claudication. (The combination of such conditions with PAD also produces a more severe form of the heart or circulatory disease.)

They include the following:

Diabetes. People with type 2 diabetes have three to four times the normal risk for PAD and intermittent claudication. In fact, their risk for PAD is higher than their risk for coronary artery disease. They also tend to develop PAD at earlier ages and to have severe cases. Of note, patients with both diabetes and PAD are also at high risk for complications in the feet and ankles. For example, in one study, people with diabetes and intermittent claudication had a 30% chance of developing skin ulcers on their legs.
Unhealthy cholesterol and lipid levels. The risk for PAD is increased by 10% with every 10 mg/dL increase in total cholesterol levels. The risk is also associated with low high-density lipoprotein (HDL, the so-called good cholesterol) and high triglyceride levels.
Smoking. Smoking increases the risk for PAD by two to five times, with the danger being higher when other risk factors are present. And, in fact, one study reported that 90% of patients with PAD were current or former smokers and some experts believe it is a stronger risk factor for PAD than for heart disease.
Hypertension. High blood pressure doubles the chances for PAD.

Blood pressure is the force applied against the walls of the arteries as the heart pumps blood through the body. The pressure is determined by the force and amount of blood pumped and the size and flexibility of the arteries.

Family history of artery disease. Genetic factors are associated with specific lipid and cholesterol abnormalities, which in turn may increase the risk for PAD.
Evidence of inflammation and damage in the arteries. Tests that report elevated levels of C-reactive protein are indicators of persistent inflammation in the arteries, which is now known to cause significant damage in blood vessels. High levels strongly predict future heart attacks in patients with existing heart disease, particularly unstable angina. Inflammatory damage is also now highly associated with PAD. In fact, patients with both PAD and heart disease tend to have significantly greater indicators of inflammation than those with heart disease alone.

Emerging or Possible Risk Factors

Homocysteine. Abnormally high blood levels of the amino acid homocysteine are strongly linked to an increased risk of heart disease, stroke, and peripheral artery disease. (Not all studies support a strong association, however. Some research suggests that the harmful effects of homocysteine may be more pronounced in men than in women.) Homocysteine may harm the lining of the arteries and reduce blood flow. Excessive levels occur with deficiencies of vitamins B6, B12, and folic acid.

Click the icon to see an image of vitamin B12 sources.

Click the icon to see an image of sources of folate.

Some experts believe that high levels of homocysteine are only indicators, not causes, of heart disease. However, studies are noting a strong association between this compound and heart disease. For example, a 2000 study reported that lower homocysteine levels after taking folic acid and vitamin B12 were associated with more open blood vessels and improved blood flow

Infectious Agents. Some microorganisms and viruses have been under suspicion for triggering inflammation and damage in the arteries that contributes to heart disease and peripheral artery disease.

The primary suspect has been Chlamydia pneumoniae (a non-bacterial organism that causes mild pneumonia in young adults). This is based on the following:

High levels of antibodies against C. pneumoniae have been associated with a higher risk for heart events.
C. pneumoniae has been detected in plaques in the arteries of patients with heart disease.
In one study, treatment with antibiotics in patients with evidence of a previous C. pneumoniae infection appeared to reduce the plaques of peripheral artery disease. In any case, until better studies are conducted, experts do not recommend antibiotics to treat heart disease or PAD even in patients with evidence of C. pneumoniae.

It should be noted that many people have been infected with C. pneumoniae and some studies have found no evidence that it increases the risk for heart disease.

Other infectious organisms under investigation for triggering disease process in the blood vessels including the following:

Bacteria that cause periodontal disease. Many studies have reported an association between periodontal disease and a higher risk for heart disease. It has also been associated with PAD.
H. pylori (the bacteria responsible for peptic ulcers). This bacteria has been associated with both heart disease and PAD. However, because this bacteria occurs in the intestinal tract and has not been detected in arteries, it is not clear how this bacteria could affect blood vessels.

No clear association has been found with any of these, however.

Diagnosis

Evidence suggests that PAD is an important risk factor for heart disease and stroke but is greatly underdiagnosed. Many patients do not report symptoms or may not even have symptoms. People should be evaluated for peripheral artery disease if they have risk factors for heart disease, leg pain during walking, or ulcers on their legs.

Physical Examination

The physician should evaluate the patient with a number of physical examinations for high blood pressure, heart abnormalities, blockage in the artery in the neck, and abdominal aneurysms. The physician will also examine the skin of the legs and feet for color changes, ulcers, infection, or injuries. The physician will also check the pulse of the arteries in the leg.

Doppler Ultrasound and Ankle-Brachial Index

Intermittent claudication caused by peripheral artery disease is typically diagnosed using a procedure called Doppler ultrasound and a calculation called the ankle-brachial index. This procedure is also proving to be important for diagnosing PAD even in patients without symptoms of intermittent claudication.

The procedure involves the following:

The physician first takes a measurement of the systolic blood pressure of both arms while the patient is lying down. (The systolic pressure is the higher and first number in a blood pressure measurement. It is the force that blood exerts on the artery walls as the heart contracts to pump out the blood.)
The physician then applies cuffs to four different locations on each leg. An ultrasound probe is passed over arteries in the foot. The signal emitted from the strongest artery is recorded as the cuffs are inflated and deflated.

The physician divides the systolic pressure in the ankle by that in the arm. The result is called the ankle-brachial index (ABI), also called ankle-arm pressure index (API). The results suggest the following:

An ABI over .90. This result often rules out PAD, but if the patient has specific risk factors for artery disease, the physician may still suspect PAD. In such cases, the patient takes a treadmill test and another ABI measurement. If the API index drops, then the physicians makes a diagnosis of peripheral artery disease.
An ABI below .90. This is usually sufficient information to diagnose peripheral artery disease. The lower the index the greater the risk for heart attack, stroke, or other serious circulatory or heart events. (In patients with diabetes, the physician may perform additional tests, which may include ultrasound, pressure measurement in the first toe, or others that might confirm or refute a diagnosis of peripheral artery disease.)
Measurements of less than .50 are highly associated with impaired leg function.
Measurements of less than .40 indicate very severe blockage in the arteries in the leg and a risk for gangrene.

Computed Tomography Angiography

A new technology called computed tomography angiography (CTA) uses x-rays to visualize blood flow in arterial vessels throughout the body. This technique is highly effective in diagnosing PAD.

Treadmill Test

A patient is often given a treadmill test if the ankle-brachial index is questionable. Patients with claudication have a 50% to 60% reduction in peak performance, which is comparable to that in patients with congestive heart failure. The treadmill test is also useful for determining the severity of the pain while walking and for assessing the effectiveness of treatments.

Waveform Analysis

A test called a wave form analysis may be used to confirm an abnormal API or pressure reading. The patient lies on his or her back for at least 10 minutes in a warm room (so that the blood vessels will not narrow). The leg is turned out and the knee is bent slightly. A probe is passed over the leg, which picks up sound waves coming from the arteries. These signals are recorded and the wave forms traced to detect abnormal blood flow.

Tests for Detecting Heart Disease

Patients with suspect PAD should have an electrocardiogram (ECG) and possibly other tests that would detect heart problems. Evidence suggests that heart disease may be underdiagnosed in these patients. In one study, for example, a third of patients had silent ischemia, which is heart disease without angina, the chest pain that indicates blockage of blood flow to the heart.

The electrocardiogram (ECG, EKG) is used extensively in the diagnosis of heart disease, from congenital heart disease in infants to myocardial infarction and myocarditis in adults. Several different types of electrocardiogram exist.

Ruling out Other Disorders with Similar Symptoms

A number of other tests can rule out disorders with similar symptoms, which include the following:

Arthritis.
Anemia.
Spinal stenosis (narrowing of the spinal canal causing leg and/or lower back pain).

Click the icon to see an image of spinal stenosis.

Thrombophlebitis (blood clots in the deep veins of the legs).

Click the icon to see an image of thrombophlebitis.

Peripheral neuropathy (nerve damage in the legs and feet, usually in people with diabetes).
Night cramps in older people not due to problems in blood vessels.
Muscle entrapment of the arteries or kinks in the arteries in the leg. These events typically occur in young athletes.
Adventitial cystic disease. This is a rare disorder that produces cysts that block the popliteal and other arteries and typically occurs in young people.

Lifestyle Changes

Given the aging population and the significant heart risks associated with peripheral artery disease (PAD), experts believe that aggressive therapies are important. There is substantial evidence, however, that peripheral artery disease (PAD) is underdiagnosed and undertreated.

The treatment goals for PAD and claudication are twofold.

To manage the pain of intermittent claudication, improve functioning, and prevent progression that might lead to gangrene and amputation.
To reduce the risk for cardiovascular disease (i.e., heart attack and stroke). There is substantial evidence to indicate that even when patients were treated for PAD, they are frequently not being given information or therapies to reduce the risk for cardiovascular disease.

Lifestyle changes are critical for every patient with PAD. Medication is often required to improve function and protect the heart. In very severe cases, surgery may be needed to improve blood flow.

Screening for and Managing Diabetes

People with type 2 diabetes have three to four times the usual risk for PAD and intermittent claudication. They also tend to develop PAD at earlier ages and to be at a significant risk for heart disease. Patients with both diabetes and PAD should be screened for heart disease. In a 2003 study, aggressive reduction of blood pressure in PAD patients who had diabetes significantly reduced their risk for heart attack and stroke. Aggressive reduction of cholesterol levels, usually with a statin drug, is equally important.

In addition, patients with both diabetes and PAD are at significant risk for heart disease and severe complications in the legs and feet. For example, in one study, people with diabetes and intermittent claudication had a 30% chance of developing skin ulcers on their legs.

Quitting Smoking

For smokers, quitting is essential. It is one of the primary risk factors for PAD and a major cause of complications. (Quitting smoking may not alleviate leg pain, at least not in the short term, but it certainly may slow the progress of the blockage and reduce risk to the heart.) Smokers in their thirties and forties have a heart-attack rate that is five times higher than their nonsmoking peers. Cigarette smoking may be directly responsible for at least 20% of all deaths from heart disease, or about 120,000 deaths annually.

Exercise

In addition to quitting smoking, exercise is the most important life-style measure for patients with PAD and intermittent claudication.

Exercise to Help the Heart. The benefits of regular moderate exercise for the heart are undisputed. People who maintain an active lifestyle have a 45% lower risk of developing heart disease than do sedentary people. Some studies suggest that for the greatest heart protection, it is not the duration of a single exercise session that counts but the total daily amount of energy expended. Therefore, the best way to exercise may be in multiple short bouts of intense exercise, which can be particularly helpful for older people.

Exercise Training to Improve Blood Flow in the Legs. Exercise training also changes blood flow in the leg and, in many cases, is proving to be as beneficial as medications and surgical procedures in increasing pain-free walking distance. The best results are seen in motivated patients who are given supervised training and who have a relatively short recovery time after exercise. Unfortunately, insurance does not usually cover these programs, and patients should understand that exercise must be regular and consistent, or benefits will be lost.

Eating Habits

The goals of a heart-healthy diet are to eat foods that help obtain or maintain healthy levels of cholesterol and lipids (fatty molecules) by achieving the following:

Reducing overall cholesterol levels and low-density lipoproteins (LDL), which are harmful to the heart.
Increasing high-density lipoproteins (HDL), which are beneficial for the heart.
Reducing other harmful lipids (fatty molecules), such as triglycerides and lipoprotein(a).

Any diet should also help keep blood pressure and weight under control.

General Recommendations. Although there are many major dietary approaches for protecting health, experts generally agree on the following recommendations for heart protection:

Choose fiber-rich food (whole grains, legumes, nuts) as the main source of carbohydrates, along with a high intake of fresh fruits and vegetables.

Dietary fiber is the part of food that is not affected by the digestive process in the body. Only a small amount of fiber is metabolized in the stomach and intestine, the rest is passed through the gastrointestinal tract and makes up a part of the stool. There are two types of dietary fiber, soluble and insoluble. Soluble fiber retains water and turns to gel during digestion. It also slows digestion and nutrient absorption from the stomach and intestine. Soluble fiber is found in foods such as oat bran, barley, nuts, seeds, beans, lentils, peas, and some fruits and vegetables. Insoluble fiber appears to speed the passage of foods through the stomach and intestines and adds bulk to the stool. It is found in foods such as wheat bran, vegetables and whole grains. Fiber is very important to a healthy diet and can be a helpful aid in weight management. One of the best sources of fiber comes from legumes, the group of food containing dried peas and beans.

Avoid saturated fats (found mostly in animal products) and transfatty acids (found in hydrogenated fats and many commercial products and fast-foods). Choose unsaturated fats (particularly omega-3 fatty acids found in vegetable and fish oils).

Click the icon to see an image of saturated fats.

Click the icon to see an image of trans-fatty acids.

In selecting proteins, choose soy protein, poultry, and fish over meat.
Weight control, quitting smoking, and exercise are essential companions of any diet program.

After embarking on any heart healthy diet, it generally takes an average of three to six months before any noticeable reduction in cholesterol occurs, although some people have reported better levels in as few as four weeks. An intensive program may be necessary to achieve significant improvements in cholesterol levels and to reduce other heart risk factors.

Vitamins

In general, no vitamins have been proven to reduce the risk for heart disease or PAD. Nevertheless, deficiencies in the B vitamins folate and B12 have been associated with a higher risk for heart disease in some (but not all) studies. Such deficiencies produce elevated blood levels of homocysteine, an amino acid that has been associated with a higher risk for heart disease and PAD. Folate improves blood flow through the arteries, which may be as important for the heart as its effect on homocysteine. It is unclear, however, whether folate and other vitamin B supplements can improve blood flow and reduce the risk for heart disease in PAD patients.

Alternative Agents

Glutathione. Glutathione is a natural compound produced in animal and plant cells, which is also a powerful antioxidant. In one small study, patients who took it experienced improved pain-free walking and there seemed to be improved blood flow. More research is warranted.

Gingko. One analysis of eight studies reported that the herbal remedy ginkgo biloba has some modest effect on pain-free walking. The drug has blood-thinning properties and is available over the counter. Although the risks for gingko appear to be low, there is an increased risk for bleeding at high doses and interaction with high doses of vitamin E and anti-clotting medications. This is particularly important since such medications are common in PAD patients.

Commercial gingko preparations have also been reported to contain colchicine, an agent that can be harmful in pregnant women and people with kidney or liver problems. It should be further noted that not all brands have any effect at all. In a 2002 study, one-third of 26 brands tested did not contain enough active ingredients to provide any benefits at all. It should be strongly noted that herbal remedies are not regulated and standards are not guaranteed.

Warnings on Alternative and So-Called Natural Remedies

Alternative or natural remedies are not regulated and their quality is not publicly controlled. In addition, any substance that can affect the body's chemistry can, like any drug, produce side effects that may be harmful. Even if studies report positive benefits from herbal remedies, the compounds used in such studies are, in most cases, not what are being marketed to the public.

There have been a number of reported cases of serious and even lethal side effects from herbal products. In addition, some so-called natural remedies were found to contain standard prescription medication. Of specific concern are studies suggesting that up to 30% of herbal patent remedies imported from China having been laced with potent pharmaceuticals such as phenacetin and steroids. Most reported problems occur in herbal remedies imported from Asia, with one study reporting a significant percentage of such remedies containing toxic metals.

The following website is building a database of natural remedy brands that it tests and rates. Not all are available yet (www.consumerlab.com).

The Food and Drug Administration has a program called MEDWATCH for people to report adverse reactions to untested substances, such as herbal remedies and vitamins (800-332-1088).

Medications

Managing Leg Pain and Improving Functioning. Agents used for improving leg pain and function are generally those that either prevent blood clots (typically anti-platelet agents) or open blood vessels. Such drugs also reduce the risk for heart disease and stroke. Aspirin is the least intensive anti-platelet agent that is used to reduce cardiovascular risk in patients with PAD. Clopidogrel (Plavix), a more potent platelet inhibitor, is sometimes recommended for patients with PAD and intermittent claudication. Cilostazol is a newer agent that improves blood flow and is proving to useful for disabling intermittent claudication. Other drugs may also be beneficial.

Reducing the Risk for Heart Attack and Stroke. Experts now recommend that PAD patients be given the optimal treatments for managing any heart risk factors as well as treatments for intermittent claudication. All patients should take lifestyle measures to reduce the risk factors that place them in danger of heart attack and stroke. Patients with both diabetes and PAD should be screened for heart disease. Important heart protective drugs for PAD patients include the following:

The antiplatelet agents used to improve leg function also protect the heart.
The best protective anti-hypertensive agents for PAD patients may be angiotensin-converting�enzyme (ACE) inhibitors.
The cholesterol-lowering agents known as statins are proving to have specific benefits for PAD. Other agents may also be helpful.

Aspirin and Other Antiplatelet Agents

So-called antiplatelet drugs increase blood flow by reducing the risk for blood clots. They are used in mild PAD cases, for intermittent claudication, and to prevent blood clots after surgery. These agents are used to improve PAD itself and also to help prevent heart attack and stroke.

Aspirin. Aspirin is the mainstay antiplatelet agent for chronic intermittent claudication, particularly in patients who also are at risk for heart attack and stroke. The drug improves leg circulation and when used early in PAD may prevent clots from forming in the veins. It is taken daily by many PAD patients to reduce the risk for a heart attack or stroke, although it is uncertain if has any effect in delaying or preventing progression of atherosclerosis (hardening of the arteries) itself.

Clopidogrel. Clopidogrel (Plavix) is a powerful oral platelet inhibitor called a thienopyrindine and some experts recommend it for patients with both PAD and intermittent claudication. It may have greater heart and circulatory benefits for patients with PAD than aspirin does. It is showing significant benefits for patients with heart disease. A 2001 report on a major study of patients with acute coronary syndromes found a lower incidence of heart attacks, stroke, and death from heart disease in patients taking clopidogrel compared to those taking aspirin. Ticlopidine (Ticlid) is another effective thienopyrindine and has been used for PAD patients, but dangerous blood disorders, particularly thrombocytopenia, have been reported in patients who had taken it for heart disease.

Phosphodiesterase Inhibitors

Phosphodiesterase inhibitors are agents that help keep blood vessels open and blood flowing.

Cilostazol. Cilostazol (Pletal) has been approved for treating disabling intermittent claudication. A number of studies have now reported improved walking distance and quality of life with its use. It also has other heart-protective properties, including improvements in HDL and triglyceride levels. It is superior to pentoxifylline, the first agent approved for claudication. It is expensive, however, and is currently recommended for patients who do not respond to aspirin or less costly treatments. Common side effects include headache, swelling in the limbs, and gastrointestinal distress that includes diarrhea and flatulence. It does not appear to have adverse effects on the liver or kidney. Similar agents have had serious side effects in patients with heart failure, however, so such individuals should avoid cilostazol.

Dipyridamole. Dipyridamole, another phosphodiesterase inhibitor, may help prevent complications of peripheral artery disease when added to aspirin. Studies are mixed on the benefits of the combination. (The drug does not appear to have any advantages for PAD patients when used alone.)

Thrombolytics (Clot-Busters)

Alteplase (Activase), also called t-PA, and reteplase (Retavase) are thrombolytic agents (commonly known as a "clot-busters"). These agents break up existing clots, and may used in special circumstances. Thrombolytics may be employed in cases of acute vascular occlusion (the sudden development of a blood clot). They may be used as part of a surgical procedure if a clot is present. They are also being investigated as an alternative to surgery in severe cases of PAD. In such events, they can be administered directly into the artery using a specially catheter. They are being researched as the sole agent or with other anti-clotting drugs.

Other Agents Used to Improve Blood Flow in Intermittent Claudication

A number of unique agents are available or under investigation for intermittent claudication. Many are antiplatelet agents that contain other factors that provide additional benefits, including heart protection in some.

Pentoxifylline. Pentoxifylline (Trental) reduces the sticky properties of blood, improving its flow. It is approved in the US for managing claudication, although experts do not recommend its routine use. Unfortunately, major studies have reported only a small effect on walking ability. Some, in fact, reported no additional benefits compared to placebo (a "sugar" pill), although Italian studies published in 2002 found that pentoxifylline was associated with significantly improved walking distance compared to placebo. The most common side effects include headache, nausea (in nearly a third of those taking pentoxifylline), heartburn and gas, dizziness, blurred vision, and flushing.

Prostaglandins. Prostaglandins are vasodilators; they improve blood flow by relaxing smooth muscles and opening the blood vessels. Some may have anti-clotting activity.

Prostaglandin E1. Early studies on prostaglandin E1 in intermittent claudication were promising. The drug must be injected, however, and more recent studies have not reported significant benefits.
Beraprost. Early studies using beraprost, a prostaglandin that can be taken orally, suggested that it might extend the limits of exercise in patients with intermittent claudication. Nevertheless, subsequent studies have not confirmed these positive results. The drug may have heart benefits but studies are mixed. Side effects include headache, stomach distress, and anemia, although they appear to be mild. More research is needed.

Naftidrofuryl. Naftidrofuryl (Nafronyl) is available in Europe for intermittent claudication. It is an anti-platelet agent that also blocks serotonin. Such actions enhance the ability for damaged muscle tissue to absorb oxygen from blood. It appears to improve quality of life and treadmill walking, although according to one study, not overall walking distance. It may have benefits for the heart.

FGF-2 and Growth Factors. Growth factors that promote angiogenesis (the production of new blood vessels) are also under investigation. Recombinant fibroblast growth factor-2 (FGF-2) is one such agent. Studies are reporting improved intermittent claudication, even in low doses. It may have severe adverse effects, however, and long-term safety is unknown. A genetically designed agent called vascular endothelial growth factor (VEGF) is also under investigation.

Mesoglycan. Mesoglycan has been studied for a few years. This drug breaks up blood clots and studies have suggested that oral mesoglycan may improve walking distance.

Reducing Heart Risk Factors

Many experts now recommend that PAD patients be given the optimal treatments for managing any heart risk factors as well as treatments for intermittent claudication. Some require medications if they cannot control these risk factors with lifestyle measures. Specific medications may be better than others for PAD patients.

Statins and Treatment for Unhealthy Cholesterol and Lipid Levels

Aggressively controlling cholesterol levels is known to reduce mortality rates in patients with peripheral artery disease. Unhealthy cholesterol levels are major contributors to atherosclerosis, the common factor in heart disease and peripheral artery disease. Many experts now recommend that patients with PAD receive lipid-lowering treatment, just as patients do who have atherosclerosis in the heart arteries.

A number of drugs are available for lowering cholesterol. Those discussed in this report may be particularly beneficial for PAD patients. Statins, for example, may have additional advantages for patients with PAD, regardless of cholesterol levels.

Other useful cholesterol-lowering agents are fibrates and nicotinic acid, which are important agents for people who need to lower triglycerides and increase HDL. In fact, some evidence suggests that this lipid imbalance may be a more important factor for PAD than high-LDL cholesterol. In fact, combinations of such drugs with statins may be particularly beneficial.

Statins. Statins are the most effective drugs for the treatment of high cholesterol, and may even become important agents for many people at risk for heart disease who have normal cholesterol levels or below. Statins inhibit the liver enzyme hMG-CoA reductase, which is used in the manufacturing of cholesterol. Statins are particularly effective for lowering LDL levels. They also reduce triglycerides, apparently in direct proportion to their LDL-lowering effects. Statins also raise HDL levels, but to a lesser extent than other anti-cholesterol drugs.

Statins include lovastatin (Mevacor), pravastatin (Pravachol), and simvastatin (Zocor). These are the most studied statins and have proven effectiveness and good safety record. Newer, synthetic statins include fluvastatin (Lescol) and atorvastatin (Lipitor).

Statins effectively reduce the risk of heart attack and stroke in both women and men and in adults at any age (including the elderly) with unhealthy cholesterol levels. They may have similar benefits even in statin users, including PAD patients, who are at high risk for heart disease, even if they had normal or low cholesterol levels.

Of note, evidence now strongly suggests that statins have specific benefits for patients with PAD, including improving symptoms of intermittent claudication. In a 2003 study, for example, statin use was associated with improved leg function, regardless of the patients' cholesterol levels.

Statins improve the function of the endothelium--the lining of blood vessels, thereby improving blood flow. (Oddly, this benefit apparently does not extend to people with diabetes.)
Statins appear to reduce inflammation in the arteries, which is now believed to be a major factor in blood vessel injury.
Some evidence suggests that statins may help curtail blood clotting, a major factor in heart attacks.
Some evidence suggests that they might promote growth of new blood vessels and might help prevent intermittent claudication.

Side effects include gastrointestinal discomfort, headaches, skin rashes, muscle aches, sexual dysfunction, drowsiness, dizziness, nausea, constipation, and peripheral neuropathy (numbness or tingling in the hands and feet).

The primary safety concern with statins has involved an uncommon condition called myopathy, which can cause muscle damage and in some cases, muscle and joint pain. The risk for myopathy is highest at higher doses and in older people, those who are small or frail, people who abuse alcohol, and those who are hypothyroid. There is also a higher risk if statins are used before surgery, and if people are taking multiple medications.

Statins also can effect the liver, particularly at higher doses, so periodic liver function tests should be administered. Statins should not be taken by anyone with liver problems or by women during pregnancy or breast-feeding. It should be noted that no studies have reported liver failure from statins, even in people with liver disease.

There have also been a few reports of peripheral neuropathy in patients taking statins. This condition causes sensation changes in the limbs, fingers and toes, including numbness, tingling, or pain.

Fibrates. Fibrates (sometimes called fibric acid derivatives) break down the particles that make triglycerides. Gemfibrozil (Lopid) is the standard fibrate. Newer fibrates, including fenofibrate (Tricor) and bezafibrate (Bezalip), may be more effective in lower cholesterol than the Lopid. Most fibrates have been shown to lower the risk of heart attack. They may have the following benefits for PAD patients:

They are good choices for many patients who need to lower triglyceride levels and increase HDL but who cannot take nicotinic acid
A study on fenofibrate further suggested that it reduced certain clotting factors (another risk factor for heart disease) and also uric acid (a risk factor for gout).

In one 2002 study, PAD patients who took bezafibrate experienced fewer non-fatal heart attacks and the severity of intermittent claudication was reduced. However, the drug had no effect on stroke.

Side effects may include gastrointestinal discomfort, aching muscles, sensitivity to sunlight, and skin rashes. Impotence has been associated with fibrates in less than 1% of patients. Fibrates have been known to cause gallstones, so people with gallbladder problems should not use these drugs. The drugs may cause abnormal heart rhythms and can affect the liver and kidney. They interact with a number of drugs and substances including warfarin, some oral drugs used for diabetes, certain antibiotics, and grapefruit juice.

Nicotinic Acid (Niacin). Nicotinic acid is the active compound found in niacin, or vitamin B3. It raises HDL levels higher than any other anti-cholesterol drug and is the first choice for patients with low HDL levels. It is also extremely effective in reducing triglyceride levels. This agent then may have role for some patients with peripheral artery disease.

Brands include Niacor, Nicolar, and Slo-Niacin. An extended-release form (Niaspan), administered at bedtime, may have fewer side effects, including headaches and flushing, than rapidly-acting niacin agents. Although niacin is available over the counter, the active form used for cholesterol is given in much higher doses and is available only by prescription. It is important to take this medication under a physician's direction in order to ensure its safety and effectiveness. Combinations with other agents, particularly statins, may add significant benefits.

Many patients find its side effects intolerable, however. About a quarter of patients taking rapid-acting forms of nicotinic acid stop taking them. The most common side effects are flushing of the face and neck, itching, headache, blurred vision, and dizziness. They usually occur between five minutes to hours after taking the drug and can last for minutes to, uncommonly, hours. The body does become tolerant to these effects eventually, and they generally subside. Gastrointestinal problems are common. Other side effects include dry skin and mucous membranes and darkening of the skin.

About 3% to 5% of people taking nicotinic acid develop liver abnormalities, which disappear after the medication is discontinued. The extended form (Niaspan) appears to be safe for the liver, but people with chronic liver disease should not use any form of nicotinic acid. People with gout should avoid nicotinic acid, since it elevates uric acid.

The role of nicotinic acid in people with diabetes is less clear. About 30% of patients who take niacin experience elevated levels in blood glucose, which could be a problem for people with diabetes. Niacin's effects on HDL and triglycerides, however, are especially suited for the lipid imbalances that are common in diabetes. And, some studies have reported that diabetics who use niacin had little trouble with glucose control.

ACE Inhibitors and Managing High Blood Pressure

People should aggressively control hypertension. Evidence suggests that the most protective agents for patients with high blood pressure and PAD may be angiotensin-converting�enzyme (ACE) inhibitors, which are described below.

Other important blood-pressure lowering agents are beta blockers and diuretics, calcium-channel blockers, and newer agents called angiotensin-receptor blockers (ARBs). Diuretics are low cost agents that have a proven track record for reducing mortality rates in most patient groups. Beta blockers potentially narrow blood vessels and are not ordinarily prescribed for patients with severe PAD.

Angiotensin Converting Enzyme Inhibitors. Angiotensin converting enzyme (ACE) inhibitors block the effects of the angiotensin-renin-aldosterone system, which is thought to have many harmful effects on the heart and blood vessels. ACE inhibitors include captopril (Capoten), enalapril (Vasotec), quinapril (Accupril), benazepril (Lotensin), ramipril (Altace), perindopril (Aceon), and lisinopril (Prinivil, Zestril). ACE inhibitors are expensive, however, and the role for most people with high blood pressure may be limited. Nevertheless, they appear to be important agents for patients with peripheral artery disease and those with diabetes.

Side effects include an irritating cough, excessive drops in blood pressure, and allergic reactions. (In some people, the cough is intolerable. Iron supplements or the drug picotamide may prove to help reduce the frequency of coughs.) One rare but severe side effect, granulocytopenia, which is an extreme reduction in white blood cells, has been observed. In rare cases (0.3%), patients suffer a sudden and severe allergic reaction called angioedema that causes swelling in the eyes and mouth and may close off the throat.

Although ACE inhibitors can protect against kidney disease, they also increase potassium retention in the kidneys. This increases the risk for cardiac arrest if levels become too high. Because of this action, they are not generally given with potassium-sparing diuretics or potassium supplements.

They can harm a developing fetus and should not be used during pregnancy, particularly in the second and third trimester.

Surgery

In severe cases, procedures to open obstructed blood vessels using angioplasty or with the use of grafts that bypass the obstructed blood vessels are effective. Some evidence suggests that surgical procedures are advantageous in patients with obstruction above the knee and that more conservative measures might be just as effective for obstructions below the knee.

Surgical Bypass

Surgical bypass has, until recently, been the gold standard for extensive PAD. It involves using a graft that acts as a new blood vessel that allows the blood to flow around the obstructed artery. The new graft may be a natural vein taken from a different location in the leg or it may be made from a synthetic material. In one study, the natural vein remained open after four years in nearly half of the patients, while the synthetic vein (made from polytetrafluoroethylene [PTFE]) had closed in all but 12% of patients.

Artificial veins tend to pose a much a higher risk for blood clots and the consequences of re-obstruction are must more severe than when the natural vein recloses. To keep the artificial vein open certain oral anti-clotting agents, such as aspirin or warfarin, may be used. (Such agents are not effective at all with the natural vein.)

Percutaneous Transluminal Angioplasty

Percutaneous transluminal angioplasty (PTA) is an approach that has several variations. The object of the procedure is to open the obstructed blood vessels that are causing intermittent claudication. Angioplasty is being increasingly used, especially in patients who have other medical conditions. Some experts believe that it is not only much less expensive, but it is also more effective than surgical bypass.

The procedure requires only a local anesthetic and patients can return to normal activity in 24 to 48 hours. Complication rates are low. The effects are not permanent, but it the procedure can be repeated without any greater risk than with the original one.

Procedures. The standard procedure is balloon angioplasty. A thin tube is inserted through an artery in the groin and passed through the blocked artery. A wire is threaded through the tube. A deflated balloon is passed over the wire to the obstruction. There, it is inflated and opens the artery.

Because of the risk for reclosure from blood clots after the operation, various other procedures are used or are being investigated.

More recent techniques employ a stent, an expandable metal mesh tube that is implanted during angioplasty at the site of the blockage. A new type of self-expanding stent called the SMART stent system was approved in late 2003. The SMART stent is used specifically for the treatment of PAD caused by a blockage in the iliac artery, which runs through the pelvic area.
Another approach uses radioactive implants (brachytherapy) in combination with PTA, which help prevent the arteries from closing after angioplasty. In a major 2002 analysis, this approach produced greater benefits compared to PTA alone, at least in the short term.
Lasers are also being investigated that uses light pulses to remove cholesterol plaque and blood clots from the blood vessels. A 2004 report suggested that laser therapy may be particularly useful in patients with PAD who are not good candidates for bypass surgery.
A new type of angioplasty treatment called PolarCath opens blocked arteries by cooling and dilating them with a nitrous oxide-filled balloon. A 2004 study showed that this procedure, also called cryoplasty therapy, has a 9-month failure rate of less than 20%, which is significantly lower the 40%-50% failure rate reported after angioplasty or stenting procedures.

Preventing Blood Clots and Reclosure of the Artery. Anticoagulants, such as aspirin, warfarin, or heparin, may used to prevent blood clots occurring during surgery. All of these agents increase the risk for bleeding.

Alteplase (Activase), also called t-PA, and reteplase (Retavase) are thrombolytic agents (commonly known as a "clot-busters"). These agents break up existing clots. They may be used either before, during, or after angioplasty if a blood clot is present.

Reclosure of the blood vessels from blood clotting, even long after surgery, is an important complication and is still a risk even with stenting and brachytherapy. Repeat surgery may be needed.

Other Complications. An English study reported major complications following surgery in 2.4% of cases. They included pneumonia, stroke, kidney failure and heart attack. Emergency follow-up surgery for bleeding or sudden blockage from a blood clot was required in 2.3% of cases.

Intermittent Pneumatic Compression

Intermittent pneumatic compression (e.g., Arterial Flow, VenaFlow) is a mechanical technique normally used to treat leg ulcers or swelling from fluid build-up. The device involves enclosing the lower leg in an inflatable fabric appliance, such as a cuff-like legging or boot. A pump is used to inflate the appliance, which then exerts pressure on the limb. Typically, a controlling unit applies different frequencies and pressures. Some devices, for instance, apply pressure in a wave-like motion that simulates the natural increase in blood flow during walking. A 2002 analysis of 26 studies suggested that this treatment may be beneficial for PAD patients who cannot undergo invasive surgeries. It may even prove to be a viable alternative to medical treatments in some cases.

Peripheral Artery Disease and Intermittent Claudication

Description

Alternative Names

Introduction