US Pharm. 2012;37(3):HS-16-HS-18.

Peripheral artery disease (PAD) is caused by a buildup of fatty materials (atheroma) in the arteries that carry blood from the heart to the head, internal organs, and limbs. Over time, these fatty deposits reduce blood flow to the organs, resulting in a narrowing of the arteries and circulatory problems. Other causes of PAD include injuries to blood vessels, blood-clotting disorders, tissue ischemia, congenital heart disease, and inflammation of the blood vessels (vasculitis).¹

PAD is a warning sign for a more problematic and widespread accumulation of fatty deposits or plaques in major arteries that will cause hardening of the artery walls. This condition reduces blood flow to heart and brain and increases the risk for heart attack or stroke.¹

Approximately 8 to 12 million people in the United States have PAD, including 12% to 20% of individuals older than age 60. In the U.S., general population awareness of PAD is estimated at 25%, and many people with PAD are undiagnosed.² Recent research funded by the National Heart, Lung, and Blood Institute revealed only one third of people with PAD took their medications to control high blood pressure and high cholesterol. This noncompliance leaves them at risk for heart disease.³

The reduction of blood flow to the extremities (usually legs) causes claudication during walking that manifests itself in the form of pain, fatigue, aching, tightness, weakness, and cramping or tingling in the legs. It can also increase skin ulcerations and, in severe cases, tissue death in limbs that will require leg amputation. PAD leg pain occurs in the muscles, not the joints. The non–PAD causes of leg pains are deep vein thrombosis (DVT), infection of the bones (osteomyelitis), skin and soft tissue infection (cellulitis), and varicose veins.⁴

As stated earlier, PAD often goes undiagnosed. Untreated PAD can be dangerous and can cause loss of a leg and increased risk of coronary artery disease and carotid atherosclerosis. The American Heart Association encourages people at risk to discuss PAD symptoms with their health care professional to ensure early diagnosis and treatment to prevent major complications.

CLINICAL SYMPTOMS

It is reported that half of people with PAD do not show any symptoms. In the other half, the most common symptom of PAD is a painful muscle cramping in the hips, thighs, or calves when walking, climbing stairs, or exercising. This is because during exercise the muscles need oxygen-rich blood and they do not get it efficiently.⁵

Other symptoms are a weak pulse in the legs, cold hands, wounds on toes that heal slowly, color changes in skin, lower temperature in one leg compared to the other leg, and poor nail and hair growth on toes and legs. PAD is normally distinguished from other leg conditions by the fact that the PAD-associated pain usually goes away when one rests or stops exercising, although this may take a few minutes.⁵

Many people think leg pain is a normal sign of aging and do not take it seriously enough to treat it. Those with diabetes might confuse PAD pain with a neuropathy, a common diabetic symptom that is a burning or painful discomfort of the feet or thighs.⁵ Both symptomatic and asymptomatic patients with PAD have a markedly increased rate of myocardial infarction, stroke, and cardiovascular events.

RISK FACTORS

People have certain habits and conditions that can raise their chance of developing PAD. People over the age of 50 are at risk. Smokers or people who have a history of smoking have up to four times the risk of developing PAD. Patients with diabetes over the age of 50 and people with high blood pressure, high cholesterol, high C-reactive protein, and high homocysteine levels in blood have a high risk for developing PAD. Any person with a family history for heart disease is at risk for PAD.⁶

Men and women are equally affected by PAD; however, African Americans have twice the chance of developing PAD. People of Hispanic origin may have similar to slightly higher rates of PAD compared to non–Hispanic whites.⁶

DIAGNOSIS AND MANAGEMENT

The first step in diagnosing PAD is a physical examination to see if there are weak pulses in the legs. This can be done with the following test.^7,8

Ankle-Brachial Index (ABI): This is a painless exam that compares the blood pressure in the feet to that in the arms to determine how well the blood is flowing. This is a quick and inexpensive test and can be done at the doctor’s office. Ankle pressure should be at least 90% of the arm pressure, but with severe narrowing it can be as low as 50%. The ABI result can help diagnose PAD. A normal resting ABI is 0.9 to 1.3. This means that the blood pressure at the ankle is the same or greater than the pressure at the arm and suggests that the person does not have significant narrowing or blockage of blood flow.

A resting ankle-brachial index of less than 0.9 is abnormal. If the ABI is 0.41 to 0.9, there is a chance of mild-to-moderate PAD. If the ABI is 0.4 or below, the person likely has severe PAD. If the ABI test result is abnormal, other tests must be done to confirm PAD.

Ultrasound and Doppler Analysis: This is a noninvasive method that visualizes the artery with sound waves and measures the blood flow in an artery to indicate the presence of a blockage. This is especially important for the carotid arteries in the neck, which supply the brain with blood.

Computed Tomographic Angiography: This is a noninvasive test that can show the arteries in the abdomen, pelvis, and legs. This test is particularly useful in patients with pacemakers or stents.

Magnetic Resonance Angiography: Magnetic resonance angiography is an MRI exam of the blood vessels. Unlike traditional angiography that involves placing a catheter into the body, MRI is considered noninvasive. Some exams require a special dye or contrast to be given before the test. The dye helps the radiologist see certain areas more clearly.

Angiography of the Arteries in the Legs: An angiogram is a special form of x-ray that permits the diagnosis of blockages (occlusions) or narrowings (stenosis) in the arteries of the body. A special radio-opaque dye (contrast medium) is injected down the tube, and x-ray pictures are taken as the solution passes along the blood vessels. The entire procedure usually lasts approximately 1 hour and is performed by a specialist interventional radiologist or a vascular surgeon.

Electrocardiogram: This test records the heart’s activity by measuring electrical currents through the heart muscle.

In addition to all of these procedures, a special blood test called the D-dimer test may also be performed. This test can quickly rule out a DVT or pulmonary embolism and determine if a patient needs additional tests.

TREATMENT

The goal of treatment is to reduce the patient’s symptoms, prevent complications, and improve quality of life. Currently, there are four classes of drugs that are used for PAD.⁹

Antiplatelet Agents

Clopidogrel: Clopidogrel works by preventing blood coagulation so that clots do not form in the arteries. This drug should not be taken by patients with a blood-clotting disorder or patients who are simultaneously taking aspirin or any other nonsteroidal anti-inflammatory drugs. The oral dose is 75 mg, once daily. The ACCF/AHA guidelines for PAD recommend clopidogrel as an alternative to aspirin or in conjunction with aspirin for those who are not at an increased risk of bleeding, but are of high cardiovascular risk. These recommendations also pertain to those with intermittent claudication or critical limb ischemia, or prior amputation for lower extremity ischemia. Some side effects of clopidogrel are potentially serious complications such as uncontrolled bleeding; coughing that produces blood, numbness, chest pain, pale skin or easy bruising.

Cilostazol: Cilostazol is a quinolone derivative that inhibits cellular phosphodiesterase. Phosphodiesterase inhibition is believed to result in increased cyclic adenosine monophosphate in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation. Cilostazol is an antiplatelet medication and a vasodilator that is used to improve the symptoms of a blood flow problem in the legs or intermittent claudication.¹⁰

The FDA approved cilostazol in 1999 for the treatment of intermittent claudication and to improve walking distance. In four trials including more than 1,500 patients, 100 mg of cilostazol administered twice daily improved both maximal and pain-free walking distance when compared with placebo. In a study of patients with intermittent claudication, cilostazol demonstrated a significant benefit, compared with both pentoxifylline and placebo.

Some common side effects associated with cilostazol therapy are headache, diarrhea, palpitations, and dizziness. Cilostazol should not be administered to patients with congestive heart failure of any severity. This contraindication is due to earlier evidence of increased mortality with the use of phosphodiesterase inhibitors in patients with heart failure.¹⁰

Pentoxifylline

Pentoxifylline is a methylxanthine derivative that enhances red blood cell flexibility and decreases blood viscosity, thereby improving blood flow through the arteries. The FDA approved pentoxifylline in August 1984. This drug has been proven to benefit patients with PAD. Several reports have indicated statistical benefits versus placebo on pain-free walking distance; however, due to the limited benefit observed in clinical trials, pentoxifylline is not widely used. The recommended dose of pentoxifylline is 400 mg three times daily with meals. Pentoxifylline is excreted in breast milk and may cause adverse effects in infants.¹¹

Statins  

Statins such as atorvastatin or simvastatin are used for reducing total cholesterol, LDL cholesterol, and triglycerides, and for increasing HDL cholesterol. This will help patients with PAD and its complications. Statins are also prescribed for reducing the risk of mortality by reducing death from coronary heart disease. Patients with coronary heart disease, diabetes, PAD, or history of stroke or other cerebrovascular disease benefit from simvastatin due to a reduced need for coronary and noncoronary revascularization procedures.¹²

Vasodilators

Vasodilators such as naftidrofuryl, a 5-hydroxytryptamine serotonin receptor inhibitor, and inositol nicotinate have been used to relieve leg pain. Inositol nicotinate is a compound made of niacin and inositol and is used to treat blood circulation problems, including pain when walking due to poor circulation. This drug releases a form of niacin when it is metabolized. The niacin can widen blood vessels and also lower blood levels of fats. Vasodilators can lower systemic pressure and lead to a reduction in perfusion of the lower limbs. Although these drugs were among the first class of drugs used for intermittent claudication, they are not currently widely used. Naftidrofuryl oxalate is used at a dose of 100 mg to 200 mg three times/day in PAD.¹²

Endovascular Procedures

There are many highly successful procedures that can help improve circulation, increase walking distance, heal foot ulcers, and prevent amputation. These are typically recommended after a thorough evaluation of the vascular lab results combined with the patient’s age and health history. The primary care physician will refer the patient to a vascular surgeon or interventional radiologist. The advantages, risk of complications, and recovery time should be discussed in detail with all medical staff involved. Endovascular procedures are performed in a hospital or outpatient center by doctors with special training. Two common endovascular procedures are balloon angioplasty and stenting.¹³

Balloon Angioplasty: To open a narrowed artery, a catheter with a very small balloon on its tip is placed in the artery and is threaded to reach the narrowed or blocked artery. The balloon is then inflated inside the artery, pushing the plaque that has built up against the artery walls. The surgeon inflates and deflates the balloon several times to push away the plaque and open the artery. Once the artery is opened, the doctor lets the air out of the balloon and removes it.¹⁴

Stenting: Sometimes, angioplasty is not enough to restore blood flow in the legs. In this case, the surgeon may recommend placing a stent in the artery. A stent is a small, flexible wire mesh tube that is placed inside an artery and is intended to keep the blood vessel open. Over time, the healthy lining of the artery will grow over the stent, making it a part of the artery wall.¹⁴

Bypass Surgery: Graft bypass surgery uses a vessel from another part of the body or a blood vessel made of synthetic fabric. This technique allows blood to flow around or bypass the blocked or narrowed artery.¹⁴

Thrombolytic Therapy: If a blood clot is blocking an artery, the surgeon may inject a clot-dissolving drug such as alteplase or reteplase into the artery at the point of the clot to break it up.

Lifestyle Changes

The patients must make long-lasting lifestyle changes. These include quitting smoking and lowering the following numbers: high blood pressure, high cholesterol, and high blood glucose levels. Smoking is the single most important modifiable risk factor for the development of PAD. It is unknown why the association between PAD and smoking is about twice as strong as that between PAD and coronary artery disease (CAD). Smokers have a risk of PAD that is four times that of nonsmokers and experience onset of symptoms almost a decade earlier. A healthy diet and more physical activity, with the goal of a healthy weight if the patient is obese or overweight, can also decrease PAD risk. Attentive foot care and proper treatment of foot injuries is very important for patients with diabetes.

REFERENCES

1. Arain FA, Cooper LT Jr. Peripheral arterial disease: diagnosis and management. Mayo Clin Proc. 2008;83(8):944-949.
2. Allison MA, Ho E, Denenberg JO, et al. Ethnic-specific prevalence of peripheral arterial disease in the United States. Am J Prev Med. 2007;32:328-333.
3. Murphy TP, Hirsch AT, Cutlip DE, Claudication: exercise vs endoluminal revascularization (CLEVER) study update. J Vasc Surg. 2009;50(4):942-945.
4. Creager MA, Loscalzo J. Vascular diseases of the extremities. In: Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 17th ed. New York, NY: McGraw Hill, 2008.
5. Rooke TW, Wennberg PW. Diagnosis and management of diseases of the peripheral arteries and veins. In: Walsh RA, Simon DI, Hoit BD, et al, eds. Hurst’s The Heart. 12th ed. New York, NY: McGraw Hill, 2007.
6. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart Disease and Stroke Statistics 2011 Update: A Report From the American Heart Association. Circulation. 2011;123:e189-e209.
7. Met R, Bipat S, Legemate DA, et al. Diagnostic performance of computed tomography angiography in peripheral arterial disease: a systematic review and meta-analysis. JAMA. 2009;301(4):415-424.
8. Collins R, Burch J, Cranny G, 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;16:334-341.
9. Kikano GE, Brown MT. Antiplatelet therapy for atherothrombotic disease: an update for the primary care physician. Mayo Clin Proc. 2007;82(5):583-593.
10. O’Donnell ME, Badger SA, Sharif MA, et al. The vascular and biochemical effects of cilostazol in patients with peripheral arterial disease. J Vasc Surg. 2009;49(5):1226-1234.
11. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 Practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): Circulation. 2006;113:463-654.
12. Thomson Reuters Micromedex Health Series. www.micromedex.com.
13. Rooke TW, Hirsch AT, Misra S, et al, 2011 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Peripheral Artery Disease (Updating the 2005 Guideline): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011 [epub ahead of print].
14. Bradbury AW, Adam DJ, Bell J, et al. Multicentre randomised controlled trial of the clinical and cost-effectiveness of a bypass-surgery-first versus a balloon-angioplasty-first revascularisation strategy for severe limb ischaemia due to infrainguinal disease. The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial. Health Technol Assess. 2010;14:1-236.

To comment on this article, contact rdavidson@uspharmacist.com.