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
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
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
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.
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
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
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
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
embolism and determine if a patient needs additional tests.
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
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.
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
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 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 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 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
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
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.
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.
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