Peripheral arterial disease

Synonym: peripheral vascular disease

What is peripheral arterial disease?

Peripheral arterial disease (PAD) occurs when there is significant narrowing of arteries distal to the arch of the aorta, most often due to atherosclerosis. Symptoms vary from calf pain on exercise (intermittent claudication) to rest pain (critical limb ischaemia), skin ulceration and gangrene. Patients diagnosed as having PAD - including those who are asymptomatic - have an increased risk of mortality, myocardial infarction and stroke.¹

It should be noted that the term 'peripheral arterial diseases' encompasses all arterial diseases other than coronary arteries and the aorta. This should be clearly distinguished from the term 'peripheral artery disease', which is often used for lower extremity artery disease (LEAD).²

Critical limb ischaemia is a chronic condition and is the most severe clinical manifestation of PAD affecting a limb. It is defined as the presence of ischaemic rest pain, and ischaemic lesions or gangrene objectively attributable to arterial occlusive disease. Acute limb ischaemia is a sudden decrease in arterial perfusion in the limb, due to thrombotic or embolic causes.²

Upper extremity artery disease²

• The subclavian artery and brachiocephalic trunk are the most common locations for atherosclerotic lesions in the upper extremities.

• Clinical features include pulse deficit, arm pain, pallor, paraesthesia, coldness and unequal arm pressures.

• The most common presentation for subclavian arterial occlusive disease is unequal arm pressures. A difference of 15 mm Hg or more indicates possible subclavian stenosis.

• Ischaemia affecting the arm causes cramp-like pain on exercise (arm claudication). More severe cases cause rest pain and ischaemia of the fingers with gangrene.

• Examination should include bilateral blood pressure measurement and assessment of the axillary, brachial, radial and ulnar artery pulses. Auscultation is important and should begin in the supraclavicular fossa.

• Investigations include duplex ultrasonography, CT angiography, MR angiography and digital subtraction angiography.

• Management includes control of cardiovascular risk factors. Revascularisation may be indicated, either endovascular or surgical interventions. Other therapies, including prostanoid infusion and thoracocervical sympathectomy, may be considered when revascularisation is not possible.

This rest of this article mainly discusses PAD affecting the legs (LEAD). See the separate Carotid artery stenosis, Renovascular disease and Bowel ischaemia articles.

How common is peripheral arterial disease? (Epidemiology)

• PAD affects over 200 million adults worldwide and the incidence of PAD increases to as high as 20% in people over the age of 70.³

• Although PAD has traditionally been perceived as a disease affecting men, the prevalence of PAD appears to be equal among senior men and women.

• With respect to upper limb artery disease, the prevalence of subclavian stenosis is approximately 2% in the general population, increasing to 9% in the case of concomitant LEAD.⁴

• The frequency of LEAD is strongly age-related, rising steeply after 50 years of age.

• Each year, 500-1,000 new cases of critical limb ischaemia are diagnosed per million of the population, with an estimated cost of £200 million to the NHS.⁵

• In the Framingham Study, the incidence of intermittent claudication in men rose from 0.4 per 1,000 aged 35-45 years to 6 per 1,000 aged 65 years and older. The incidence in women was about half that in men but was more similar at older ages.⁶

Risk factors

• Smoking³: smoking increases the risk of developing PAD fourfold and has the greatest impact on disease severity. Compared to non-smokers, smokers with PAD have shorter life spans and progress more frequently to critical limb ischaemia and amputation.

• Diabetes mellitus.

• Hypertension.

• Hyperlipidaemia: high total cholesterol and low high-density lipoprotein (HDL) cholesterol are independent risk factors.

• Physical inactivity.

• Obesity.

Peripheral arterial disease symptoms

A full cardiovascular history and examination are essential and should include assessment for coronary artery disease, cerebrovascular disease, all areas of possible PAD (eg, kidney, bowel, and upper and lower limbs) and any clinical features suggesting an aortic aneurysm.

History

The history should include a history of cardiovascular disease and an assessment of risk factors, including hypertension, dyslipidaemia, diabetes mellitus and smoking status. Any family history of cardiovascular disease is also important. Many patients with PAD are asymptomatic but still at high risk of cardiovascular events.²

• The most common symptom is muscle pain in the lower limbs on exercise (intermittent claudication):⁷

  • Walking impairment - eg, fatigue, aching, cramping or pain in the buttock, thigh, calf or foot, particularly when symptoms are quickly relieved at rest. Pain comes on more rapidly when walking uphill than on the flat. Claudication can occur in both legs but is often worse in one leg.

  • Similar pain may occur in the buttocks and thighs, associated with absent femoral pulses and male impotence (Leriche's syndrome; caused by aorto-iliac obstruction).

  • LEAD is often under-recognised in patients who also suffer with coronary artery disease, as patients are largely asymptomatic, possibly because these patients exercise to a degree insufficient to cause intermittent claudication.

• Ischaemic rest pain:

  • Severe extensive PAD can lead to a severe unremitting pain in the foot, particularly at night.

  • It is partially relieved by hanging the foot out of the bed.

The Edinburgh Claudication Questionnaire has low accuracy as a diagnostic tool and it should not be relied on as the only diagnostic method. ⁸

The ankle-brachial index (ABI) is a low-cost, easy, and largely used tool, used both at rest or after exercise for PAD diagnosis and surveillance.⁹ Both oscillometric and Doppler methods have shown good concordance..

Signs³

• Examination of the lower limbs should include auscultation of the femoral arteries at the groin level.

• The affected leg may be pale and cold, with a loss of hair and with skin changes.

• Inspection of the feet, noting the colour, temperature and integrity of the skin, and the presence of ulcerations. There may be poorly healing wounds of the extremities. Patients with severe PAD or critical lower-limb ischaemia may have ulceration or gangrene.

• Palpation of the femoral, popliteal, dorsalis pedis and posterior tibial pulses. Examination usually reveals weak or absent pulses.

Differential diagnosis

The differential diagnosis of pain in the lower limb when walking includes sciatica and spinal stenosis, deep vein thrombosis, entrapment syndromes and muscle/tendon injury.

Investigations

Adverse/risk factor assessment

Any patient suspected of, or diagnosed as, having PAD should have a full cardiovascular risk assessment.¹⁰

• Blood pressure.

• FBC (anaemia will aggravate PAD), ESR (inflammatory process - eg, giant cell arteritis), thrombophilia screen.

• Fasting blood glucose.

• Lipid levels.

• ECG: 60% of patients with intermittent claudication have ECG evidence of pre-existing coronary heart disease.

• Patients under 50 years of age should also have a thrombophilia screen and serum homocysteine levels taken.

Confirm diagnosis¹⁰

• The main method to confirm the diagnosis is Doppler ultrasonography (duplex scanning). The ratio of systolic blood pressure at the ankle and in the arm - ABI - provides a measure of blood flow at the level of the ankle (as a general guide, normal = 1, claudication 0.6-0.9, rest pain 0.3-0.6, impending gangrene 0.3 or less). The ABI is a strong marker of cardiovascular disease and is predictive of cardiovascular events and mortality.

• Duplex ultrasonography is also able to determine the site of disease and indicate the degree of stenosis and length of an occlusion.

• ABI is not recommended by the National Institute for Health and Care Excellence (NICE) as an accurate method of diagnosing LEAD in diabetes as the assessment is affected by the hardening of the arterial wall in this condition. NICE advises that further research is needed to identify the best investigative options in this patient group.

• Other methods of investigation now include MR angiography and CT angiography. MR angiography may be offered prior to revascularisation.

• Digital subtraction arteriography is not recommended as the primary imaging modality and is essentially a pre-operative investigation. Its use is limited to an adjuvant of endovascular management, surgical planning or the management of an acute ischaemic limb. It has been superseded somewhat by computerised tomography angiography.¹¹

Associated diseases

• Coronary heart disease: because of the probability of significant coronary artery disease, patients who require vascular surgery to the lower limb(s) may need coronary artery revascularisation as a prelude.

• Cerebrovascular disease.

• Up to 20% of patients with intermittent claudication have diabetes.⁷ Those with diabetes who have a new foot ulcer should be seen by a multidisciplinary foot clinic within 24 hours, as the ulcer can rapidly become severely infected and require amputation.

Referral

Patients with suspected PAD should be referred to secondary care if:¹⁰

• There is any doubt about the diagnosis or there is concern that the symptoms may have an unusual cause.

• Symptoms are severe and inadequately controlled.

• Endovascular surgery needs to be considered - stenting, angioplasty or bypass surgery.

• Risk factors can't be managed to recommended targets.

• The patient has symptoms which limit lifestyle, and objective signs of arterial disease.

• Young and otherwise healthy adults, presenting prematurely with claudication, should be referred to exclude entrapment syndromes and other rare disorders.

Treatment for peripheral arterial disease

Most patients' symptoms improve with optimal medical treatment, and invasive intervention is often not required.¹⁰ Approximately 20% will deteriorate and develop critical limb ischaemia.

Beta-blockers are not contra-indicated in patients with LEAD, and should be considered in the case of concomitant coronary artery disease and/or heart failure.²

Modification of cardiovascular risk factors¹²

See also the separate Cardiovascular risk assessment article. Risk factors for PAD are typical of those predisposing to atherosclerotic disease.

• Smoking cessation.

• .Promote regular exercise.¹³ A supervised exercise programme has been shown to be a very important part of management and should be offered to all patients with intermittent claudication.¹⁴ This should comprise two hours of exercise per week for a three-month period.¹⁰

• Weight reduction for patients who are overweight or obese.

• Lipid-lowering drugs: statins reduce the risk of mortality, cardiovascular events and stroke in patients with PAD. Lipid-lowering therapy with a statin is recommended, aiming to maintain LDL cholesterol level ideally below 1.8 mmol/L or a 50% reduction.²

• Hypertension: long-term benefit but, in the short term, a reduction in blood pressure, whatever drug treatment has been used, may worsen intermittent claudication.

• Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce cardiovascular morbidity and mortality in patients with PAD. However, ACE inhibitors should be carefully monitored because more than 25% of patients with PAD have co-existent renal artery stenosis.⁵

• Management of diabetes mellitus: optimal control of glucose and all other cardiovascular risk factors.

• Elevated plasma levels of homocysteine (hyperhomocysteinaemia) are increasingly recognised as a potential risk for cardiovascular diseases.¹⁵ There is currently insufficient evidence to support the treatment of hyperhomocysteinaemia with folate and vitamin B12.¹⁶

Analgesia

Patients with critical limb ischaemia should be offered paracetamol plus an opiate. The strength of the opiate should be determined after a risk-benefit discussion is held with the individual patient.¹⁰

Antiplatelet drugs

See also the separate Antiplatelet drugs article.

• Antiplatelet therapy is recommended for those with symptomatic PAD.²

• The antiplatelet agents aspirin, clopidogrel, and aspirin plus dipyridamole have been shown to reduce major cardiovascular events. Antiplatelet agents reduce vascular death in patients with any manifestation of atherosclerotic disease.

• Clopidogrel is recommended as an option to prevent occlusive vascular events for people who have PAD or multivascular disease.¹⁷

• Clopidogrel is at least as effective as aspirin in patients with PAD and has a better side-effect profile. The small benefits of combining clopidogrel and aspirin do not justify its recommendation in patients with LEAD, due to an increased bleeding risk.²

Peripheral vasodilators¹⁸

• Naftidrofuryl oxalate is recommended by NICE as an option for the treatment of intermittent claudication in people with PAD for whom vasodilator therapy is considered appropriate.

• Cilostazol, pentoxifylline and inositol nicotinate are not recommended for the treatment of intermittent claudication in people with PAD. However, cilostazol has been shown to be of benefit in improving walking distance in people with intermittent claudication.¹⁹

Surgical

Cardiovascular risk factor management and supervised exercise are the mainstays of treatment, especially in patients with mild to moderate ischaemia. Revascularisation is essential in patients with critical limb ischaemia, and may also be considered in combination with supervised exercise in patients whose daily life activity is compromised.²

NICE states that angioplasty should be offered when risk factor modification has been discussed, supervised exercise has failed to improve symptoms and imaging shows angioplasty is suitable for the patient.¹⁰

There is currently no evidence for superiority of atherectomy over angioplasty on any outcome.²⁰

• The two options are endovascular revascularisation and surgery. Bypass surgery is the most common surgical approach for diffuse occlusive disease. Indications for surgical intervention in PAD include disabling claudication, critical limb ischaemia (urgent referral recommended) or weak or absent femoral pulses. Many centres now favour an endovascular approach, due to reduced morbidity and mortality, preserving the surgical option in case of failure.²

• The major drawback of endovascular interventions compared with surgery is the lower long-term patency. Stents do help to some degree, and several new endovascular solutions, such as atherectomy devices, drug-eluting balloons and new stent designs, have been shown to improve long-term patency. The patency after angioplasty is greatest for lesions in the common iliac artery and decreases distally, and with increasing length, multiple and diffuse lesions, poor-quality run-off, diabetes and chronic kidney disease.²

• Although symptoms are frequently unilateral, most people with claudication have bilateral disease and revascularising one leg often unmasks previously asymptomatic disease in the other leg.

• NICE currently considers that there is insufficient evidence to recommend the use of percutaneous atherectomy of femoropopliteal arterial lesions, using plaque excision devices.²¹

• Critical limb ischaemia:

  • Revascularisation should be attempted without delay in all patients presenting with critical limb ischaemia, whenever technically possible.

  • Prostanoids may be considered If revascularisation is not possible. There are small beneficial effects on rest-pain relief and ulcer healing but no evidence of a reduction in amputations. Patients should be made aware of the risks of adverse effects when considering this treatment. There is no evidence to support the use of one prostanoid over another in terms of long-term safety and effectiveness.²²

  • Amputation rates are 20-25%, mainly in patients unsuitable for revascularisation, who are neurologically impaired or non-ambulatory.² Amputation should not be considered unless all other options for revascularisation have been considered by a multidisciplinary team.¹⁰

Complications¹²

• Quality of life is often significantly impaired, particularly as a result of reduced mobility.

• Psychosocial complications in patients with advanced PAD such as depression.

• Acute limb ischaemia may result from thrombosis arising within a peripheral artery or from embolic occlusion.

• Infection and poor healing of tissue with reduced blood supply.

• Ulceration.

• Gangrene.

• Amputation.

• Complications secondary to invasive treatments.

• Vascular complications associated with generalised atherosclerosis - eg, myocardial infarction, stroke, vascular dementia, renovascular disease, and mesenteric disease.

• Multiorgan dysfunction - may occur, especially in people with acute limb ischaemia.

• Complications associated with acute limb ischaemia - eg:

  • Compartment syndrome - reperfusion of ischaemic muscles causing oedema and a rise in compartmental pressure.

  • Reperfusion injury - when blood flow to the ischaemic limb is restored products of cell death (for example, potassium, phosphate and myoglobin) are released. This can result in rhabdomyolysis, cardiac dysrhythmia, acute kidney injury, multiorgan failure, and disseminated intravascular coagulation.

Prognosis¹²

• The mortality rate from a cardiovascular cause in people with PAD presenting with intermittent claudication is approximately 10-15% over a five-year period.

• Most people with PAD will have atherosclerosis of the brain or heart and are three times more likely to die from a cardiovascular cause than people who do not.

• The course of PAD is variable from gradual progression to more sudden deterioration.

• For people with intermittent claudication over a five-year period:

  • Most people continue to have stable claudication.

  • 10-20% develop worsening symptoms.

  • 5-10% develop critical limb ischaemia.

  • Amputation is eventually required in 1-2% but this increases to 5% in people with diabetes.

• Critical limb ischaemia is also a marker for generalised, severe atherosclerosis, with a three-fold risk excess of future myocardial infarction, stroke, and vascular death compared with patients with intermittent claudication.²

• Critical limb ischaemia requires a major lower-limb amputation (LLA) in about 30% of people within one year of diagnosis.

• Acute limb ischaemia has a poor prognosis, especially if diagnosis and treatment are delayed. Amputation rates depend on the time between onset of ischaemia and reperfusion (20% in 24 hours). Mortality rate is 15-20%.

• The prognosis following amputation is poor. In one study of patients who had lower limb amputations, 11.4% had contralateral major lower-limb amputations. After ipsilateral major LLA, the incidence rate of death was 18.9 per 100 person-years, and after ipsilateral minor LLA it was 11.4 per 100 person-years.²³

Prevention

See the separate Prevention of cardiovascular disease and Cardiovascular risk assessment articles.