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•	Highlights
•	Introduction
•	Symptoms
•	Risk Factors
•	Diagnosis
•	Complications
•	Lifestyle Changes
•	Medications
•	Reducing Heart Risks
•	Surgery
•	Resources
•	References

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Peripheral artery disease and intermittent claudication

Highlights

Peripheral Artery Disease (PAD) Risks

Smoking, unhealthy cholesterol levels, and diabetes are the main risk factors for PAD. According to a 2006 study in Circulation, they affect PAD in different ways:

• Smoking and high cholesterol are more likely to cause PAD progression in the large vessels of the legs. Painful cramps in the hips, thighs, and calves -- especially those that occur during exercise -- are the tell-tale symptoms.
• Diabetes is more likely to cause PAD progression in the small vessels of the feet. Symptoms include foot ulcers that are slow to heal.

According to the American Heart Association, quitting smoking is the best way to prevent PAD and slow its progression. Patients should also control cholesterol through exercise, diet, and medications.

PAD and Heart Disease

• Patients with PAD have a 1 in 5 chance of having a heart attack or stroke, or dying from a heart-related event, within the course of a year, indicates a 2007 study in the Journal of the American Medical Association (JAMA). Blood clots in other arteries (brain, heart) further double this risk.
• PAD also increases the risk of dying from heart surgery or other interventional heart procedures, suggests a 2006 Journal of the American College of Cardiology study. Surgeons should take extra care when treating patients with PAD.

Exercise is Essential

• Exercise is important for preventing PAD, and essential for those with the disease. According to a 2006 Circulation study, patients with PAD who are the most physically active have a third of the chance of dying than those who are inactive.
• For patients who have difficulty walking, arm aerobics may be a helpful alternative and can actually help improve walking ability, suggests research presented at the 2006 American Heart Association Scientific Sessions.

Introduction

Peripheral artery disease (PAD) occurs when the arteries in the extremities (feet, legs, hands, and arms) become clogged with a fatty substance called plaque. It most often occurs in the legs. The build up of plaque causes the arteries to become narrow and hard, which obstructs blood flow. This hardening of the arteries is called atherosclerosis. (Atherosclerosis that affects arteries to the heart and brain is the major process leading to heart disease and stroke.)

PAD is also called peripheral arterial disease and peripheral vascular disease.

Atherosclerosis of the extremities is a disease of the peripheral blood vessels. It is characterized by narrowing and hardening of the arteries that supply the legs and feet. The narrowing causes a decrease in blood flow. Symptoms include leg pain, numbness, cold legs or feet, and muscle pain in the thighs, calves or feet.

Symptoms

People with peripheral artery disease (PAD) may or may not have symptoms. Because of silent symptoms, many cases of PAD go undiagnosed.

Intermittent Claudication

Claudication comes from the Latin word "to limp." Claudication is crampy leg pain that occurs during exercise, especially walking. The pain is due to insufficient blood flow in the legs (caused by blocked arteries). Intermittent means the pain comes and goes. Intermittent claudication is the most prominent symptom of PAD. About a third to a half of patients with PAD have this symptom.

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. You should be sure to talk to your doctor about any leg or thigh pain you are experiencing.

PAD-related leg pain is relieved only by rest. Leg pain occurs in one leg in 40% of patients and in both legs in 60% of patients. Patients may also experience fatigue or pain in the thighs and buttocks.

There is also some evidence that people with PAD have blood cells that are prone to forming clots.

Advanced Peripheral Artery Disease (Ischemic Rest Pain)

In advanced cases, the arteries are so blocked that even rest does not help. Leg pain that continues when lying down is called ischemic rest pain. Ischemia is the medical term for insufficient blood flow to tissues.

People with ischemic rest pain are at risk for ulcers and gangrene. In severe cases, amputation may be required.

Symptoms of advanced PAD can include:

• Calf muscles that shrink (wither)
• Hair loss over the toes and feet
• Thick toenails
• Shiny, tight skin
• Painful non-bleeding ulcers on the feet or toes (usually black) that are slow to heal

In some cases, blood clots form in the arteries in the legs, producing abrupt symptoms.

Risk Factors

About 10 million American adults have peripheral artery disease (PAD). Although it was once believed that PAD occurs more often in men than women, current research now indicates that both genders are equally susceptible. African Americans have twice the risk for PAD as Caucasians.

PAD Risk Factors

The most important risk factors for PAD and intermittent claudication are the same as the major risk factors for heart disease and stroke. People with a combination of these conditions (including PAD) are at increased risk of a more severe form of the heart or circulatory disease. Smoking and high cholesterol levels may increase the risk for PAD progression in large blood vessels (such as the legs), while diabetes increases the risk for PAD in small blood vessels (such as the feet). Quitting smoking and controlling cholesterol are the two best ways to slow PAD progression.

The most important risk factors for PAD include:

• Smoking. Experts believe that smoking is the number one risk factor for PAD and that smoking even a few cigarettes a day can interfere with PAD treatment. Smoking increases the risk for PAD by 2 - 25 times, with the danger being higher when other risk factors are present. One study reported that 90% of patients with PAD were current or former smokers. [For more information, see In-Depth Report #41: Smoking.]
• Diabetes. People with type 2 diabetes have 3 – 4 times the normal risk for PAD and intermittent claudication. In fact, their risk for PAD is higher than their risk for heart disease. People with type 2 diabetes also tend to develop PAD at an earlier age and have more severe cases. Patients with both diabetes and PAD are at high risk for complications in the feet and ankles. In one study, people with diabetes and intermittent claudication had a 30% chance of developing skin ulcers on their legs. [For more information, see In-Depth Report #60: Diabetes - type 2.]
• Unhealthy cholesterol and lipid levels. The risk for PAD increases by 10% with every 10 mg/dL increase in total cholesterol levels. Low levels of high-density lipoprotein (HDL, the so-called good cholesterol) and high triglyceride levels also increase the risk for PAD. [For more information, see In-Depth Report #23: Cholesterol.]
• Hypertension. High blood pressure doubles the chances for PAD. [For more information, see In-Depth Report #14: High blood pressure.]

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 heart and artery disease. Genetic factors that cause specific lipid and cholesterol abnormalities may increase the risk for PAD.
• Artery inflammation and damage. High levels of C-reactive protein can indicate persistent inflammation in the arteries. Such inflammation can cause significant damage in blood vessels, and is highly associated with PAD
• Age. PAD occurs more frequently in people over age 50 and affects 12 – 20% of Americans age 65 years and older.
• Ethnicity. African Americans are at highest risk for PAD. They are twice as likely to develop PAD as Caucasians.

Emerging or Possible Risk Factors

Homocysteine. Abnormally high blood levels of the amino acid homocysteine have been linked to an increased risk of heart disease, stroke, and PAD. Excessive levels occur with deficiencies of vitamins B6, B12, and folic acid. Scientists are continuing to research connections between homocysteine and heart and vascular disease. Some experts believe that high levels of homocysteine are only indicators, not causes, of heart disease.

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

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

Infectious Organisms. Some microorganisms and viruses may be able to trigger the inflammation and damage in the arteries that contribute 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. In one study, treatment with antibiotics in patients with evidence of a previous C. pneumoniae infection appeared to reduce PAD-related plaque build up. However, 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.

Diagnosis

PAD is greatly under diagnosed. Many patients do not report symptoms, or may not even have symptoms. People should be checked for peripheral artery disease if they have risk factors for heart disease, leg pain during walking, or ulcers on their legs.

Physical Examination

The doctor should perform a number of physical examinations to check for high blood pressure, heart abnormalities, blockage(s) in the artery in the neck, and abdominal aneurysms. The doctor should also examine the skin of the legs and feet for color changes, ulcers, infection, or injuries, and 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 method is also proving to be a helpful way to diagnose PAD in patients without symptoms of intermittent claudication.

The procedure is done as follows:

• The doctor measures the systolic blood pressure of both arms while the patient is lying down. (The systolic pressure is the "top" 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. For example, in a blood pressure reading of 120/80, 120 is the systolic number.)
• The doctor then puts blood pressure cuffs on 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. This is the ankle's systolic pressure.

The doctor divides the systolic pressure in the ankle by the systolic pressure in the arm. The result is called the ankle-brachial index (ABI), also called ankle-arm pressure index (API).

What the results mean:

• ABI over 0.90. This result often rules out PAD, but if the patient has specific risk factors for artery disease, the doctor may still suspect PAD. In such cases, the patient takes a treadmill test and another ABI measurement. If the API index drops, then the doctor makes a diagnosis of peripheral artery disease.
• ABI below 0.90. This is usually sufficient information to diagnose PAD. The lower the index the greater the risk for heart attack, stroke, or other serious circulatory or heart events. (In patients with diabetes, the doctor may perform additional tests, which may include ultrasound, pressure measurement in the first toe, or others that might confirm or dismiss a diagnosis of PAD.)
• ABI less than 0.50. These measurements are highly associated with impaired leg function.
• ABI less than 0.40. These measurements indicate very severe blockage in the leg arteries and a risk for gangrene.

Magnetic Resonance Angiography (MAR)

MRA is a type of magnetic resonance imaging (MRI). It provides a non-invasive alternative to a traditional angiogram. The MRA uses a magnetic field and radiofrequency waves to provide pictures of arteries and blood vessels. An angiogram uses dye, which is injected through a catheter that is inserted in the groin. MRA patients are given gadolinium (a contrast material) through an IV to improve the image quality.

Computed Tomography Angiography

A new technology called computed tomography angiography (CTA) uses x-rays to visualize blood flow in arteries 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 - 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 their back for at least 10 minutes in a warm room (so that the blood vessels will not narrow). The leg is turned outward, and the knee is slightly bent. The doctor passes a handheld scanner over the leg, which picks up sound waves coming from the arteries. These signals are recorded, and the wave forms are traced to detect abnormal blood flow.

Tests for Detecting Heart Disease

Patients with suspected PAD should have an electrocardiogram (ECG) and other tests that would detect heart problems. Evidence suggests that heart disease may be under diagnosed in patients with PAD. In one study, 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. There are several different types of electrocardiograms.

Ruling out Other Disorders with Similar Symptoms

A number of other tests may be ordered to rule out disorders with similar symptoms. Such disorders include:

• Arthritis
• Anemia
• Spinal stenosis -- narrowing of the spinal canal causing leg 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 that are not due to problems in blood vessels
• Muscle entrapment of the arteries or kinks in the arteries in the leg -- typically occur in young athletes
• Adventitial cystic disease -- a rare disorder that produces cysts that block the popliteal and other arteries and typically occurs in young people

Complications

Patients with peripheral artery disease (PAD) have the same risk of death from heart events or stroke as people with heart disease. The risk increases as PAD gets worse. The worse the leg condition, the poorer the overall health of the patient.

According to a 2007 Journal of the American Medical Association study, patients with PAD have a 21% chance of having a heart attack or stroke, or dying from a heart event, within 1 year. If patients have blood clots and blockages in other arteries (brain, heart) as well as the legs, this risk doubles. Another 2007 study indicated that patients with PAD also have an increased risk of dying shortly after heart surgery or other interventional procedures, such as heart catheterizations.

Although signs of heart disease are detected in only 20 - 40% of patients with PAD after an initial diagnosis, studies suggest that when intense heart-diagnostic tests are performed (such as angiography or thallium stress tests) co-existing heart disease is detected in up to 90% of all patients with PAD.

Pain and Complications in the Legs from Oxygen Deprivation

The pain from intermittent claudication in the legs itself clears up in 40% of patients (although this does not eliminate any accompanying heart risks). Damage in the leg from oxygen loss progresses in about 35% of patients. Ischemic rest pain develops in about 10% of patients. This condition can lead to ulcers, gangrene, and, in extreme cases, amputation. People with diabetes are at highest risk for these complications.

Acute Occlusion

In rare cases, blood clots can develop suddenly in a major artery in the leg -- a condition called acute occlusion. Symptoms include numbness, pain, coolness, pale color, lack of pulse in the artery, and weakness. This is a very serious event, which can lead to amputation or even loss of life. Treatment options include clot-busting drugs delivered to the blockage or surgery to remove the clot.

Poor Physical and Mental Functioning

Peripheral artery disease can significantly impair daily physical functioning. Claudication pain severely limits physical activity. Even worse, intermittent claudication increases the risk for falling, usually because of unsteadiness, regardless of the severity of PAD. Intermittent claudication and PAD are also associated with mental decline.

Lifestyle Changes

There are two treatment goals for PAD and claudication:

• Manage the pain of intermittent claudication, improve functioning, and prevent PAD from getting worse, so that gangrene does not occur
• Reduce the risk for cardiovascular disease (heart attack and stroke)

Evidence indicates that even when patients are treated for PAD, they are frequently not given information or therapies to reduce the risk for heart 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 risk for PAD and intermittent claudication. They also tend to develop PAD at earlier ages and to have 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 patients with PAD 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.

Quitting Smoking

Patients who smoke should quit. Smoking is one of the primary risk factors for PAD and a major cause of complications. Quitting smoking may not make leg pain go away, at least not in the short term, but it certainly may keep blockages from getting worse. This reduces the risk to the heart.

Exercise

In addition to quitting smoking, exercise is the most important lifestyle change patients with PAD and intermittent claudication can make.

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. And, patients with PAD who are physically active have death rates that are a third of those who are less physically active, according to a 2007 American Heart Association report. Some studies suggest it is not the length of a single exercise session that counts, but the total daily amount of energy expended. Several, short sessions of intense exercise can be particularly helpful for older people.

Exercise Training to Improve Blood Flow in the Legs. Exercise training improves blood flow in the legs and, in some cases, can work as well as medications and surgical procedures in increasing pain-free walking distance. To maintain benefits, exercise must be regular and consistent. A 2006 study suggested that a regular walking program can significantly slow the rate of functional decline associated with PAD. Patients in the study walked three times a week.

Some patients with intermittent claudication find that their leg cramps make it difficult to walk or participate in lower-extremity exercise. A 2006 study suggested that upper-body aerobic exercise can still provide benefits. By increasing oxygen and blood flow through the body, arm aerobics may help reduce leg pain and improve a patient’s ability to walk. Patients in this study used an arm ergometer, a table-top device similar to bicycle pedals that is operated with the arms rather than the legs.

Eating Habits

The goals of a heart-healthy diet are to:

• Reduce overall cholesterol levels and low-density lipoproteins (LDL), which are harmful to the heart
• Increase high-density lipoproteins (HDL), which are beneficial for the heart
• Reduce 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 body's digestive process. 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 baked 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.

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

[For more information, see In-Depth Report #43: Heart-healthy diet.]

Vitamins

In general, no vitamins have been proven to reduce the risk for PAD or heart disease. Deficiencies in the B vitamins folate and B12 have been linked with elevated levels of homocysteine, an amino acid that has been associated with a higher risk for heart disease and PAD. This association led researchers to examine the effects of vitamin B supplements on heart and vascular diseases. Results from several recent studies, however, indicate that while vitamin supplementation lowers homocysteine levels, it has no effect on heart disease outcomes.

Alternative Medicine

Glutathione. Glutathione is a natural antioxidant produced in animal and plant cells. In one small study, patients who took it could walk with no pain, and there seemed to be an improvement in blood flow. More studies are needed.

Gingko. An analysis of eight studies reported that the herb ginkgo biloba has some modest effect on pain-free walking. The herbal remedy has blood-thinning properties. It is available over the counter.

Pine Bark Extract. Pine bark extract (Pycnogel) may help improve blood flow to muscles and reduce leg cramps, according to a small 2006 study of patients with intermittent claudication.

Medications

Treatments for PAD help manage leg pain and improve function, as well as reduce the risk for heart attack and stroke. Drugs used for improving leg pain and function are generally those that either prevent blood clots (typically anti-platelet drugs) or open blood vessels. Such drugs also help protect the heart.

Experts now recommend that patients with PAD be given treatments for managing both heart risk factors and intermittent claudication.

Aspirin and Other Antiplatelet Drugs

Antiplatelet drugs thin the blood and reduce the risk for clots. They are used in mild PAD cases, for intermittent claudication, and to prevent blood clots after surgery.

Aspirin. Aspirin is the main antiplatelet drug used to treat chronic intermittent claudication, particularly in patients who also are at risk for heart attack and stroke. The drug improves leg circulation and, when used in early PAD, may prevent clots from forming in the veins.

Clopidogrel. Clopidogrel (Plavix) is a powerful type of drug called a thienopyridine. Some experts recommend it for patients with both PAD and intermittent claudication. In patients with PAD, it may protect the heart and arteries better than aspirin. Ticlopidine (Ticlid) is another effective thienopyridine that has been used for patients with PAD, but dangerous blood disorders, (particularly thrombocytopenia), have been reported in patients who had taken it for heart disease.

Phosphodiesterase Inhibitors

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

Cilostazol. Cilostazol (Pletal) is used to treat disabling intermittent claudication. A number of studies have reported that the drug helps improve walking distance and quality of life. It also helps improve HDL and triglyceride levels. Cilostazol works better than pentoxifylline, the first drug approved for claudication. It is expensive, however, and currently only recommended for patients who do not respond to aspirin or less costly treatments. Common side effects include headache, swelling in the limbs, and stomach problems such as diarrhea and flatulence (gas). It does not appear to have bad effects on the liver or kidney. Similar drugs have had serious side effects in patients with heart failure, so such individuals should avoid cilostazol.

Pentoxifylline. Pentoxifylline (Trental) reduces the sticky properties of blood, improving its flow. It is approved in the U.S. for managing claudication, although experts do not recommend its routine use. Studies regarding the drug's effectiveness have been mixed. Some studies have reported a small effect on walking ability; another found the drug significantly improved walking distance. Other research has found that the drug does not work any better than a dummy pill (placebo). The most common side effects include headache, nausea, heartburn, flatulence (gas), dizziness, blurred vision, and flushing.

Dipyridamole. Dipyridamole may help prevent complications of PAD when taken along with aspirin. Studies are mixed on the benefits of the combination. Without aspirin, the drug does not appear to have any advantages for patients with PAD.

Thrombolytics (Clot-Busters)

Alteplase (Activase), also called t-PA, and reteplase (Retavase) are thrombolytic drugs. Such drugs are commonly called "clot-busters." They break up existing clots, and may be used in cases of acute vascular occlusion (the sudden development of a blood clot). They may also be used if a clot is present. Researchers are investigating whether thrombolytics are an effective alternative to surgery in severe cases of PAD. In severe cases, the drugs can be delivered directly into the artery.

Other Drugs Used to Treat Intermittent Claudication

Ramipril. The ACE inhibitor ramipril (Altace) improved blood flow to the legs, reduced leg pain, and helped maximize walking time in a small 2006 study of patients with intermittent claudication. Researchers still have to study whether this medication works best for specific patients (such as those with high blood pressure or diabetes).

Naftidrofuryl. Naftidrofuryl (Nafronyl) is available in Europe for intermittent claudication. It is not approved in the United States. Nafronyl is an anti-platelet drug that also blocks serotonin. This action helps damaged muscle tissue absorb more oxygen from blood. Nafronyl appears to improve quality of life and treadmill walking. However, one study found it did not improve overall walking distance.

Investigational Drugs and Treatments

Growth Factors. Growth factors help new blood vessels grow, an action called angiogenesis. Studies show that recombinant fibroblast growth factor-2 (FGF-2) improves intermittent claudication, even in low doses. The drug may have severe side effects, and long-term safety is unknown. A drug 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.

Prostaglandins. Prostaglandins relax smooth muscles and open the blood vessels, which improves blood flow. These types of drugs are called vasodilators. Some may have anti-clotting activity.

• Prostaglandin E1. Early studies on prostaglandin E1 in intermittent claudication have been promising. However, more recent studies have not reported significant benefits. The drug is injected.
• Beraprost. Beraprost is a prostaglandin that can be taken by mouth. Early studies suggested that it might allow patients with intermittent claudication to exercise for longer periods of time. Subsequent studies have not confirmed these positive results. Side effects include headache, stomach distress, and anemia, although they appear to be mild.

Phlebotomy. Phlebotomy, the removal of blood from the body, is sometimes used to reduce the excess iron that accumulates in patients with PAD. However, a 2007 Journal of the American Medical Association study found that reducing iron stores did not significantly lower the risk of heart attack, stroke, or death in patients with PAD.

Reducing Heart Risks

If a patient cannot control heart risk factors with lifestyle measures, treatment may be needed.

Drug Treatment for Unhealthy Cholesterol and Lipid Levels

It is very important for people with PAD to keep their LDL ("bad cholesterol") levels to below 100 mg/dL. If patients have serious heart disease risk factors (high blood pressure, diabetes, other unhealthy lipids) in addition to PAD, they may need to aim for LDL levels below 70 mg/dL. Aggressive control of cholesterol levels is known to reduce death rates in patients with peripheral artery disease (PAD). Unhealthy cholesterol levels are major contributors to atherosclerosis, the common factor in PAD and heart disease. Many experts now recommend that patients with PAD receive drugs to lower cholesterol.

A number of medicines are available for lowering cholesterol. Those discussed in this report may have particular benefits for patients with PAD. [For more information on these cholesterol-lowering drugs, see In-Depth Report #23: Cholesterol.]

Statins. Statins are the most effective drugs for the treatment of high cholesterol. Statins block the liver enzyme hMG-CoA reductase, which the body uses to make cholesterol. Statins are particularly effective for lowering LDL levels and triglycerides. They also raise HDL levels, but not as much as other anti-cholesterol drugs.

Statins include:

• Lovastatin (Mevacor)
• Pravastatin (Pravachol)
• Simvastatin (Zocor)
• Fluvastatin (Lescol)
• Atorvastatin (Lipitor)
• Rosuvastatin (Crestor)

Statins reduce the risk of heart attack and stroke. Evidence strongly suggests that statins have specific benefits for patients with PAD. In a 2003 study, statin use was associated with improved leg function, regardless of the patients' cholesterol levels.

• Statins improve the function of the lining of blood vessels, which improves blood flow.
• 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 might promote growth of new blood vessels and help prevent intermittent claudication.

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

Statins can also cause an uncommon condition called myopathy. Myopathy can cause muscle damage and, in some cases, muscle and joint pain. The risk for myopathy increases with higher doses. The following increases one's risk of myopathy

• Older age
• Small size or frailty
• Alcohol abuse
• Hypothyroidism
• Use of multiple medications

There is also a higher risk of myopathy if statins are used before surgery.

Statins also can affect the liver, particularly at higher doses, so periodic liver function tests should be done. Statins should not be taken by anyone with liver problems or by women who are pregnant or breast-feeding.

Nicotinic Acid (Niacin). Nicotinic acid is the active compound found in niacin (vitamin B3). It raises HDL levels more than any other anti-cholesterol drug, and is the first choice for patients with low HDL levels. Nicotinic acid is also extremely effective in reducing triglyceride levels. It may be beneficial for some patients with PAD.

Brands of nicotinic acid include Niacor, Nicolar, and Slo-Niacin. An extended-release form (Niaspan), taken at bedtime, may have fewer side effects than other types of niacin. 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 doctor's direction in order to ensure its safety and effectiveness. Combinations with other drugs, particularly statins, may add significant benefits.

Many patients can not tolerate the side effects of niacin. 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 can occur between 5 minutes to hours after taking the drug and can last for varying lengths of time. The body does get used to these effects eventually, so they generally go away. Gastrointestinal problems are common. Other side effects include dry skin and mucous membranes and darkening of the skin.

About 3 - 5% of people taking nicotinic acid develop liver abnormalities, which go away after the medication is stopped. The extended form of 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 have a jump in blood glucose levels. But some studies have reported that diabetics who use niacin had little trouble with glucose control. Niacin's effects on HDL and triglycerides are especially suited for the lipid imbalances that are common in diabetes.

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 lowering cholesterol than gemfibrozil. Most fibrates have been shown to lower the risk of heart attack. A study on fenofibrate suggested that it reduced certain clotting factors (another risk factor for heart disease).

Fibrates may be good choices for many patients who need to lower triglyceride levels and increase HDL, but who cannot take nicotinic acid.

In one study, patients with PAD who took bezafibrate experienced fewer non-fatal heart attacks and the severity of intermittent claudication was reduced.

Side effects of fibrates 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 including warfarin, some oral drugs used for diabetes, and certain antibiotics. Fibrates also interact with grapefruit juice.

Managing High Blood Pressure

Evidence suggests that best drugs for patients with high blood pressure and PAD may be angiotensin-converting-enzyme (ACE) inhibitors. These drugs 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)
• Lisinopril (Prinivil, Zestril)

They are important drugs for patients with PAD and diabetes who also have high blood pressure.

Side effects include an irritating cough, excessive drop in blood pressure, and allergic reactions. In some people, the cough is intolerable. Iron supplements or the drug picotamide may help reduce the frequency of coughs.

One rare, but severe, side effect is granulocytopenia, which is an extreme reduction in white blood cells.

In rare cases (0.3%), patients who take ACE inhibitors suffer a sudden and severe allergic reaction called angioedema, which 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, ACE inhibitors are generally not given with potassium-sparing diuretics or potassium supplements.

ACE inhibitors can harm a developing fetus and should not be used during pregnancy.

[For more information on blood pressure drugs, see In-Depth Report #14: High blood pressure.]

Surgery

In severe cases, surgery may be needed to open blocked blood vessels. Many surgical procedures can be accomplished with minimally invasive endovascular techniques, such as angioplasty and stenting, which can help open small blocked arteries below the knee and prevent amputation. If there is extreme blockage in the leg artery, bypass surgery and vein grafting may be required.

Leg Bypass Surgery

For many years, leg bypass surgery was the main type of surgery used for extensive PAD. This procedure involves the creation of a tube (graft) that acts as a new blood vessel. Grafts can be made from synthetic material (artificial vein) or from a vein taken from a different location in the patient's leg (natural vein). The graft reroutes blood flow in the leg, around the blocked artery. In one study, the natural vein remained open after 4 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 higher risk for blood clots, and the consequences of re-blockage are must more severe than when the natural vein recloses. To keep the artificial vein open, oral anti-clotting drugs such as aspirin or warfarin, may be used. (Such drugs do not work at all with natural vein bypass.)

In general, less invasive surgical procedures such as balloon angioplasty and stenting are now more frequently performed.

Percutaneous Transluminal Angioplasty

Percutaneous transluminal angioplasty (PTA) is an approach that has several variations. The object of the procedure is to open the blocked 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 less expensive and more effective than leg bypass surgery.

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

Anticoagulants such as warfarin or heparin and antiplatelets such as aspirin may used to prevent blood clots occurring during surgery. All of these drugs increase the risk for bleeding. Thrombolytic drugs may be used 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. Repeat surgery may be needed. Major complications following surgery include pneumonia, stroke, kidney failure and heart attack.

Balloon Angioplasty. 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 blockage. When inflated, it opens the artery.

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

Stenting. More recent angioplasty techniques use an expandable metal mesh tube (stent). A self-expanding stent called the SMART stent was approved in late 2003. The SMART stent is used specifically for patients whose PAD is caused by a blockage in the iliac artery, which runs through the pelvic area. Stents can be effective in opening arteries, but 20 - 30% of patients have new blockages within a year of surgery. In 2005, researchers began testing a drug-eluting stent coated with paclitaxel. They hope that the drug may prevent blockages from recurring in the leg arteries. A paclitaxel-eluting stent is already approved in the U.S. for treating coronary artery disease.

Drug-eluting stents may not be recommended for patients who had recent heart surgery, or women who are nursing or pregnant. Patients who receive a drug-eluting stent may need blood thinning drugs for at least several months.

Drug-Coated Balloon. A new technique uses a drug-coated balloon instead of a stent. The balloon is sprayed with paclitaxel. When the balloon is inflated inside the leg artery, the drug is transferred to the plaque that is causing the blockage. Doctors think that this type of minimally invasive angioplasty surgery might provide an important alternative to stents. Although stents have been very useful in heart surgery, they can sometimes cause later complications in PAD.

Brachytherapy. 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.

Laser Treatment. Laser light pulses are being investigated as a way to vaporize 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.

PolarCath. 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.

Intermittent Pneumatic Compression

Intermittent pneumatic compression (Arterial Flow, VenaFlow) is a mechanical technique normally used to treat leg ulcers or swelling from fluid build-up. The device is an inflatable fabric device that goes around the lower leg. The inflated device puts pressure on the limb. Some devices 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 patients with PAD who cannot undergo surgery. It may even prove to be a viable alternative to medical treatments in some cases.

Resources

• www.padcoalition.org -- Peripheral Arterial Disease Coalition
• www.nhlbi.nih.gov -- National Heart, Lung, and Blood Institute
• www.americanheart.org -- American Heart Association
• www.acc.org -- American College of Cardiology
• www.diabetes.org -- American Diabetes Association
• www.vdf.org -- Vascular Disease Foundation
• www.sirweb.org -- Society of Interventional Radiology

References

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Ahimastos AA, Lawler A, Reid CM, Blombery PA, Kingwell BA. Brief communication: ramipril markedly improves walking ability in patients with peripheral arterial disease: a randomized trial. Ann Intern Med. 2006 May 2;144(9):660-4.

Garg PK, Tian L, Criqui MH, Liu K, Ferrucci L, Guralnik JM, et al. Physical activity during daily life and mortality in patients with peripheral arterial disease. Circulation. 2006 Jul 18;114(3):242-8.

Saw J, Bhatt DL, Moliterno DJ, Brener SJ, Steinhubl SR, Lincoff AM, et al. The influence of peripheral arterial disease on outcomes: a pooled analysis of mortality in eight large randomized percutaneous coronary intervention trials. J Am Coll Cardiol. 2006 Oct 17;48(8):1567-72.

Steg PG, Bhatt DL, Wilson PWF, D’Agostino R, Ohman EM, Rother, J. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA. Mar 21 2007;29(11)7:1197-1206.

Zacharski LR, Chow BK, Howes PS, Shamayeva G, Baron JA, Dalman RL, et al. Reduction of iron stores and cardiovascular outcomes in patients with peripheral arterial disease: a randomized controlled trial. JAMA. 2007 Feb 14;297(6):603-10.

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