Dr Melas Nikolaos Vascular & Endovascular Surgeon MD, MSc, PhD

Peripheral artery disease (PAD), or Peripheral vascular disease (PVD), or peripheral artery occlusive disease (PAOD), refers to the obstruction of large arteries not within the coronary, aortic arch vasculature, or brain. PAD can result from atherosclerosis, inflammatory processes leading to stenosis, an embolism, or thrombus formation. It causes either acute or chronic ischemia (lack of blood supply). Often PAD is a term used to refer to atherosclerotic blockages found in the lower extremity. PAD also includes a subset of diseases classified as microvascular diseases resulting from episodal narrowing of the arteries (Raynaud’s phenomenon), or widening thereof (erythromelalgia), i.e. vascular spasms.

Epidemiology

The prevalence of peripheral vascular disease in the general population is 12–14%, affecting up to 20% of those over 70; 70%–80% of affected individuals are asymptomatic; only a minority ever require revascularisation or amputation. Peripheral vascular disease affects 1 in 3 diabetics over the age of 50. In the USA peripheral arterial disease affects 12–20 percent of Americans age 65 and older. Approximately 10 million Americans have PVD. Despite its prevalence and cardiovascular risk implications, only 25 percent of PAD patients are undergoing treatment. The incidence of symptomatic PVD increases with age, from about 0.3% per year for men aged 40–55 years to about 1% per year for men aged over 75 years. The prevalence of PVD varies considerably depending on how PAD is defined, and the age of the population being studied. Diagnosis is critical, as people with PAD have a four to five times higher risk of heart attack or stroke. The Diabetes Control and Complications Trial and U.K. Prospective Diabetes Study trials in people with type 1 and type 2 diabetes, respectively, demonstrated that glycemic control is more strongly associated with microvascular disease than macrovascular disease. It may be that pathologic changes occurring in small vessels are more sensitive to chronically elevated glucose levels than is atherosclerosis occurring in larger arteries

Classification

Peripheral artery occlusive disease is commonly divided in the Fontaine stages, introduced by René Fontaine in 1954 for ischemia:

• Stage I: Asymptomatic, incomplete blood vessel obstruction
• Stage II: Mild claudication pain in limb

Stage IIA: Claudication at a distance of greater than 200 metres

Stage IIB: Claudication distance of less than 200 metres

• Stage III: Rest pain, mostly in the feet
• Stage IV: Necrosis and/or gangrene of the limb

Symptoms

About 20% of patients with mild PAD may be asymptomatic; other symptoms include:

• Claudication—pain, weakness, numbness, or cramping in muscles due to decreased blood flow during walking or excersise.
• Sores, wounds, or ulcers that heal slowly or not at all
• Noticeable change in color (blueness or paleness) or temperature (coolness) when compared to the other limb (termed unilateral dependent rubor; when both limbs are affected this is termed bilateral dependent rubor)
• Diminished hair and nail growth on affected limb and digits

Causes

Risk factors contributing to PAD are the same as those for atherosclerosis:

– Smoking – tobacco use in any form is the single most important modifiable cause of PVD internationally. Smokers have up to a tenfold increase in relative risk for PVD in a dose-related effect. Exposure to second-hand smoke from environmental exposure has also been shown to promote changes in blood vessel lining (endothelium) which is a precursor to atherosclerosis.Smokers are 2 to 3 times more likely to cause lower extremity peripheral arterial disease than coronary artery disease. More than 80%-90% of patients with lower extremity peripheral arterial disease are current or former smokers. The risk of PAD increases with the number of cigarettes smoked per day and the number of years smoked.

– Diabetes mellitus – causes between two and four times increased risk of PVD by causing endothelial and smooth muscle cell dysfunction in peripheral arteries. The risk of developing lower extremity peripheral arterial disease is proportional to the severity and duration of diabetes. Diabetics account for up to 70% of nontraumatic amputations performed, and a known diabetic who smokes runs an approximately 30% risk of amputation within 5 years.

– Dyslipidemia (high low density lipoprotein [LDL] cholesterol, low high density lipoprotein [HDL] cholesterol) – elevation of total cholesterol, LDL cholesterol, and triglyceride levels each have been correlated with accelerated PAD. Correction of dyslipidemia by diet and/or medication is associated with a major improvement in rates of heart attack and stroke. This benefit is gained even though current evidence does not demonstrate a major reversal of peripheral and/or coronary atherosclerosis.

– Hypertension – elevated blood pressure is correlated with an increase in the risk of developing PAD, as well as in associated coronary and cerebrovascular events (heart attack and stroke).Hypertension increased the risk of intermittent claudication 2.5- to 4-fold in men and women,respectively

– Risk of PAD also increases in individuals who are over the age of 50, male, obese, heart attack, or stroke or with a family history of vascular disease.

– Other risk factors which are being studied include levels of various inflammatory mediators such as C-reactive protein, fibrinogen, homocysteine, hyperviscosity, hypercoagulable state.

Individuals at Risk for Lower Extremity Peripheral Arterial Disease

• All patients who have Leg symptoms with exertion (suggestive of claudication) or ischemic rest pain.
• All patients aged 65 years and over regardless of risk factor status.
• All patients between the age of 50 to 69 and who have a cardiovascular risk factor (particularly diabetes or smoking).
• Age less than 50 years, with diabetes and one other atherosclerosis risk factor (smoking, dyslipidemia, hypertension, or hyperhomocysteinemia).
• Abnormal lower extremity pulse examination.
• Known atherosclerotic coronary, carotid, or renal artery disease.
• All patients with a Framingham risk score 10%-20%
• All patient who has a previous chest pain

Diagnosis

Upon suspicion of PVD, the first-line study is the ankle brachial pressure index (ABPI/ABI). When the blood pressure readings in the ankles is lower than that in the arms, blockages in the arteries which provide blood from the heart to the ankle are suspected. Normal ABI range of 1.00 to 1.40.The patient is diagnosed with PAD when the ABI is ≤ 0.90 . ABI values of 0.91 to 0.99 are considered ‘‘borderline’’ and values >1.40 indicate noncompressible arteries. PAD is graded as mild to moderate if the ABI is between 0.41 and 0.90, and an ABI less than 0.40 is suggestive of severe PAD. These relative categories have prognostic value. In patients with suspected PAD but normal resting ABIs, exercise testing of ABI can be done. A base line ABI is obtained prior to exercise. The patient is then asked to exercise (usually patients are made to walk on a treadmill at a constant speed) until claudication pain occurs (or a maximum of 5 minutes), following which the ankle pressure is again measured. A decrease in ABI of15%-20%would be diagnostic of PAD .

It is possible for conditions which stiffen the vessel walls (such as calcifications that occur in the setting of chronic diabetes) to produce false negatives usually, but not always, indicated by abnormally high ABIs (> 1.40). Such results and suspicions merit further investigation and higher level studies. If ABIs are abnormal the next step is generally a lower limb doppler ultrasound examination to look at site and extent of atherosclerosis. Other imaging can be performed by angiography,^[1] where a catheter is inserted into the common femoral artery and selectively guided to the artery in question. While injecting a radiodense contrast agent an X-ray is taken. Any flow limiting stenoses found in the x-ray can be identified and treated by atherectomy, angioplasty or stenting. Contrast angiography is the most readily available and widely used imaging technique.

Modern multislice computerized tomography (CT) scanners provide direct imaging of the arterial system as an alternative to angiography. CT provides complete evaluation of the aorta and lower limb arteries without the need for an angiogram’s arterial injection of contrast agent. Magnetic resonance angiography (MRA) is a noninvasive diagnostic procedure that uses a combination of a large magnet, radio frequencies, and a computer to produce detailed images to provide pictures of blood vessels inside the body. The advantages of MRA include its safety and ability to provide high-resolution three-dimensional (3D) imaging of the entire abdomen, pelvis and lower extremities in one setting.

Treatment

Dependent on the severity of the disease, the following steps can be taken:^[23]

• Smoking cessation (cigarettes promote PVD and are a risk factor for cardiovascular disease).
• Management of diabetes.
• Management of hypertension.
• Management of cholesterol, and medication with antiplatelet drugs. Medication with aspirin, clopidogrel and statins, which reduce clot formation and cholesterol levels, respectively, can help with disease progression and address the other cardiovascular risks that the patient is likely to have.
• Regular exercise for those with claudication helps open up alternative small vessels (collateral flow) and the limitation in walking often improves. Treadmill exercise (35 to 50 minutes, 3 to 4 times per week) has been reviewed as another treatment with a number of positive outcomes including reduction in cardiovascular events and improved quality of life.
• Cilostazol or pentoxifylline treatment to relieve symptoms of claudication.

Treatment with other drugs or vitamins are unsupported by clinical evidence, “but trials evaluating the effect of folate and vitamin B-12 on hyperhomocysteinaemia, a putative vascular risk factor, are near completion”.

After a trial of the best medical treatment outline above, if symptoms remain unnacceptable, patients may be referred to a vascular or endovascular surgeon; however, “No convincing evidence supports the use of percutaneous balloon angioplasty or stenting in patients with intermittent claudication”.

• Angioplasty (PTA or percutaneous transluminal angioplasty) can be done on solitary lesions in large arteries, such as the femoral artery, but angioplasty may not have sustained benefits. Patency rates following angioplasty is highest for iliac Arteries, and decrease with artery towards toes.other criteria that affect out come following revascularization are length of the lesion, number of lesion.
• Plaque excision, in which the plaque is scraped off of the inside of the vessel wall.
• Occasionally, bypass grafting is needed to circumvent a seriously stenosed area of the arterial vasculature. Generally, the saphenous vein is used, although artificial (Gore-Tex) material is often used for large tracts when the veins are of lesser quality.
• Rarely, sympathectomy is used – removing the nerves that make arteries contract, effectively leading to vasodilatation.
• When gangrene of the toes has set in, amputation is often a last resort to stop infected dying tissues from causing septicemia.
• Arterial thrombosis or embolism has a dismal prognosis, but is occasionally treated successfully with thrombolysis.

Prognosis

Individuals with PAD have an “exceptionally elevated risk for cardiovascular events and the majority will eventually die of a cardiac or cerebrovascular etiology”; prognosis is correlated with the severity of the PAD as measured by the Ankle brachial pressure index (ABPI). Large-vessel PAD increases mortality from cardiovascular disease significantly. PAD carries a greater than “20% risk of a coronary event in 10 years”. There is a low risk that an individual with claudication will develop severe ischemia and require amputation, but the risk of death from coronary events is three to four times higher than matched controls without claudication. Of patients with intermittent claudication, only “7% will undergo lower extremity bypass surgery, 4% major amputations, and 16% worsening claudication”, but stroke and heart attack events are elevated, and the “5-year mortality rate is estimated to be 30% (versus 10% in controls)”.

References

• TASC II Guidelines

• ACC-AHA 2005 Guidelines
• ACC-AHA 2011 focused update of the guideline