Peripheral artery disease and intermittent claudication
Highlights
Peripheral Artery Disease
Peripheral artery disease (PAD) is a type of atherosclerosis. It occurs when arteries in the extremities (most often the legs) become narrowed by cholesterol-rich material called plaque. Because PAD interferes with circulation, advanced cases increase the risk for gangrene and amputation. Patients with PAD are at increased risk for heart attacks and strokes.
Risk Factors of PAD
The main risk factors of PAD include:
- Smoking
- Diabetes
- Unhealthy cholesterol and lipid levels
- High blood pressure
Symptoms
Many people with PAD do not have symptoms. When symptoms do occur, crampy leg pain (intermittent claudication) is the main symptom. This symptom occurs off and on, usually with exercise, and disappears when at rest. When PAD becomes more severe, symptoms can include:
- Pain or tingling in the feet or toes
- Weakened calf muscles
- Painful non-bleeding ulcers on the feet or toes that do not heal
Treatment
Treatment for PAD includes both lifestyle measures and medications that help reduce symptoms and prevent disease progression. These include:
- Regular exercise, which is essential for patients with PAD
- Heart-healthy diet, low in saturated fat, to reduce unhealthy cholesterol levels
- Smoking cessation
- Medications to help control high blood pressure and cholesterol. Other drugs include antiplatelet medications to prevent blood clots and phosphodiesterase inhibitors to help improve walking distance.
- In severe cases, surgery may be needed to open blocked blood vessels.
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, obstructing 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 a type of peripheral vascular disease, which also includes carotid artery disease, renal artery disease, aortic disease, venous problems, and some other conditions, such as vasculitis.
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.
Symptoms may be felt as pain, achiness, a sense of fatigue, or nonspecific discomfort that occurs with exercise. Symptoms should go away only with rest, within several minutes. Symptoms may only initially be present when walking uphill, walking faster, or walking for longer distances.
Because the most frequently affected artery in intermittent claudication is the popliteal artery, symptoms are most common in the calf muscles. 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. Talk to your doctor about any leg or thigh pain you have.
Leg pain occurs in one leg in 40% of patients and in both legs in 60% of patients. Patients may also have 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.
Typical symptoms may include:
- Pain or tingling in the foot or toes, which may be so severe that even the weight of clothes or bed sheets cause or worsen the discomfort
- Pain is worse when leg is elevated and improves by dangling legs over the side of the bed
People with ischemic rest pain are at risk for ulcers and gangrene. In severe cases, amputation may be required.
Other findings 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
Sometimes, 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. Between 15 - 20% of people over age 65 suffer from the condition.
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. Between 80 - 90% of patients with PAD are current or former smokers. Progression to a more critical state of illness is likely for patients who continue to smoke. [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 5 - 10% with every 10 mg/dL increase in total cholesterol levels. Levels of HDL ("good cholesterol") below 40 mg/dL and high triglyceride levels also increase the risk for PAD. LDL ("bad cholesterol") levels should be kept below 100 mg/dL in all patients with PAD, and probably as low as 70 mg/dL when other risk factors are present (such as diabetes, coronary artery disease, smoking, and HDL below 40 mg/dL). [For more information, see In-Depth Report #23: Cholesterol.]
- Hypertension. High blood pressure, especially when combined with other cardiovascular risk factors, increases 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.
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.
Ankle-Brachial Index
Intermittent claudication caused by peripheral artery disease is typically diagnosed using a calculation called the ankle-brachial index. This method also helps 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. A doppler 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, 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.
Doppler Ultrasound Imaging
Doppler ultrasound imaging is commonly the first imaging test of the arteries performed and also may be used to follow patients. It is able to provide an anatomic view of the arteries and report on velocity and flow characteristics. It is non-invasive and is performed usually in an outpatient setting.
Invasive Angiography, Magnetic Resonance Angiography (MRA), and Computed Tomography Angiography (CTA)
Before considering invasive procedures to treat peripheral artery disease, the surgeon needs a better understanding of which arteries are involved, how severe the blockage is, and the state of the blood vessels surrounding the blockage. In the past, invasive or conventional angiography was typically performed. This type of angiogram uses dye, which is injected through a catheter that is inserted in the groin.
Magnetic resonance angiography (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. Patients are given gadolinium (a contrast material) through an IV to improve the image quality. In many medical centers, MRA is considered almost or as accurate as invasive angiography and will frequently be the only test required.
A new technology called computed tomography angiography (CTA) uses x-rays to visualize blood flow in arteries throughout the body. This technique is also highly effective in diagnosing PAD. While it involves more radiation exposure than an MRA, it can be used in patients who have contraindications to magnetic resonance imaging.
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 heart failure. The treadmill test is also useful for determining the severity of the pain while walking and 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
Complications
Coronary Artery Disease and Stroke
Patients with peripheral artery disease (PAD) have the same risk of death from heart events or stroke as people already diagnosed with heart disease. The risk increases as PAD gets worse. The worse the leg condition, the poorer the overall health of the patient.
If patients have blood clots and blockages in other arteries (brain, heart) as well as the legs, the risk for any vascular complication involving the heart, the brain, or the leg arteries increases much more.
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.
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.
Managing Diabetes, Cholesterol, and High Blood Pressure
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. Aggressive reduction of blood pressure in patients with PAD who have diabetes can significantly reduce the risk for heart attack and stroke. Aggressive reduction of cholesterol levels, usually with a statin drug, is equally important. However, while management of these factors can help reduce cardiovascular death rates, it is unclear whether it affects the progression of PAD.
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. Continued smoking is associated with the majority of patients who progress from milder forms of PAD to critical limb ischemia involving severe pain, skin ulcers, and possible amputation. Smoking cessation also 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 trans fatty 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. Vitamin E has also not been shown to help with symptoms.
Herbs and Supplements
Generally, manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products. Always check with your health care provider before using any herbal remedies or dietary supplements.
The following herbs and supplements are relevant for patients with PAD:
- 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. This herbal remedy is reported to have blood-thinning properties, although studies have not indicated it provides any extra benefit when added to exercise therapy for patients with intermittent claudication.
Although the risks for gingko appear to be low, there is an increased risk for bleeding at high doses and harmful interaction with high doses of vitamin E and anti-clotting medications. (This is particularly important because patients with PAD often use these types of medications.) Commercial gingko preparations have also been reported to contain colchicine, a chemical that can be harmful in pregnant women and people with kidney or liver problems.
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 antiplatelet drugs) or improve blood flow.
Doctors 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 reduce the risk for blood clots. Most patients with peripheral artery disease should receive antiplatelet medication. For the most part, this recommendation is made to prevent future death from heart attack or stroke. Antiplatelet drugs may or may not provide benefit for PAD symptoms and progression.
Aspirin is usually the recommended first-line choice. Clopidogrel (Plavix) is recommended as an alternative.
Dipyridamole (Persantine) 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.
Research indicates that adding an anticoagulant drug, such as warfarin (Coumadin), to antiplatelet therapy does not help prevent heart complications of PAD, and can increase the risks for life-threatening bleeding.
[For more information on these drugs, see In-Depth Report #03: Coronary artery disease.]
Phosphodiesterase Inhibitors
Phosphodiesterase inhibitors are drugs that help improve blood flow.
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 recommended only 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 these patients 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.
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
ACE Inhibitors. ACE inhibitors are a type of drug used to treat high blood pressure. The ACE inhibitor ramipril (Altace) is often recommended for patients with symptomatic peripheral artery disease, primarily to reduce the risk of cardiovascular events.
Investigational Drugs and Treatments
Growth Factors. Growth factors help new blood vessels grow, an action called angiogenesis. The results of high-quality clinical trials have been disappointing. Growth factors may have severe side effects, and long-term safety is unknown.
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.
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, 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. They also raise HDL levels, but not as much as some 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.
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 the 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. Anyone with liver problems or women who are pregnant or breastfeeding should not take statins.
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, prescription formulations may have fewer side effects. It is important to take this medication under a doctor's direction, to ensure its safety and effectiveness. Combinations with other drugs, particularly statins, may add significant benefits.
Many patients cannot tolerate the side effects of crystalline (rapid-release) 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 anywhere from 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 may diminish. 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. Combination therapy with a fibrate and a statin poses a significantly higher risk for myopathy than either drug alone.
Managing High Blood Pressure
Evidence suggests that the 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, an extreme reduction in white blood cells.
Rarely (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 potassium-sparing diuretics or potassium supplements.
ACE inhibitors can harm a developing fetus and should not be used during pregnancy.
[For more information, 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 performed. These include open bypass procedures, which connect an artery before the location of the obstruction to an artery below the obstruction, or minimally invasive endovascular techniques such as angioplasty and stenting. The location of the lesions and how many other risk factors and illnesses patients have often determine which procedure is chosen.
Surgery is generally performed for claudication that has become disabling despite full medical and exercise therapy. Surgery may also be necessary for patients with rest pain, and to save a limb when a patient develops critical limb ischemia and is in danger of amputation.
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. Possible bypass connections between arteries include aorta to iliac arteries, aorta to femoral arteries, and bypass between the femoral artery and popliteal, tibial, and peroneal arteries.
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 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. Some studies suggest that laser therapy may be particularly useful in patients with PAD who are not good candidates for bypass surgery.
PolarCath. A 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. An 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
References
Aboyans V, Criqui MH, Denenberg JO, Knoke JD, Ridker PM, Fronek A. Risk factors for progression of peripheral arterial disease in large and small vessels. Circulation. 2006 Jun 6;113(22):2623-9.
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.
Aung PP, Maxwell HG, Jepson RG, Price JF, Leng GC. Lipid-lowering for peripheral arterial disease of the lower limb. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD000123.
Collins R, Burch J, Cranny G, Aguiar-Ibáñez R, Craig D, Wright K, et al. Duplex ultrasonography, magnetic resonance angiography, and computed tomography angiography for diagnosis and assessment of symptomatic, lower limb peripheral arterial disease: systematic review. BMJ. 2007 Jun 16;334(7606):1257. Epub 2007 Jun 4
Creager MA and Libby P. Peripheral arterial disease. In: Libby P, Bonow RO, Mann DL, Zipes DP, eds. Libby: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 8th ed. Saunders; 2007:chap 57.
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.
Kikano GE, Brown MT. Antiplatelet therapy for atherothrombotic disease: an update for the primary care physician. Mayo Clin Proc. 2007 May;82(5):583-93.
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.
Warfarin Antiplatelet Vascular Evaluation Trial Investigators, Anand S, Yusuf S, Xie C, Pogue J, Eikelboom J, et al. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med. 2007 Jul 19;357(3):217-27.
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.
Review Date:
4/17/2008
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.
The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies. Links to other sites are provided for information only -- they do not constitute endorsements of those other sites. © 1997-
A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.
