Synonym: peripheral vascular 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.
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.
Clinical Editor's comments (September 2017)
Dr Hayley Willacy recommends the recently released European Society of Cardiology's Guidelines for the diagnosis and treatment of peripheral arterial diseases. In this guideline 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). The modern management of LEAD includes statin therapy (improves walking distance) and supervised exercise therapy.
Upper extremity artery disease
- 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.
- PAD affects 4-12% of people aged 55-70 years and 15-20% of people aged over 70 years.
- 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.
- 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.
Risk factors 
- Diabetes mellitus.
- Hyperlipidaemia: high total cholesterol and low high-density lipoprotein (HDL) cholesterol are independent risk factors.
- Physical inactivity.
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, upper and lower limbs) and any clinical features suggesting an aortic aneurysm.
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.
- The most common symptom is muscle pain in the lower limbs on exercise (intermittent claudication):
- 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 been shown to be a specific and sensitive diagnostic tool.
- 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.
- 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.
- 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 - ankle-brachial pressure index (ABPI) - 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 ABPI 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.
- 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.
- 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. 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.
Patients with suspected PAD should be referred to secondary care if:
- 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.
Most patients' symptoms improve with optimal medical treatment and invasive intervention is often not required.Approximately 20% will deteriorate and develop critical limb ischaemia.
See also the separate Cardiovascular Risk Assessment article. Risk factors for peripheral arterial disease are typical of those predisposing to atherosclerotic disease.
- Smoking cessation.
- Promote regular exercise.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.This should comprise two hours of exercise per week for a three-month period.
- 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.
- 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.
- 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.There is currently insufficient evidence to support the treatment of hyperhomocysteinaemia with folate and vitamin B12.
See also separate Antiplatelet Drugs article.
- Antiplatelet therapy is recommended for those with symptomatic PAD.
- 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.
- 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.
- Naftidrofuryl oxalate is recommended by the National Institute for Health and Care Excellence (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.
Although revascularisation is essential in patients with critical limb ischaemia, the evidence of any long-term benefit of endovascular treatment over supervised exercise and best medical treatment is inconclusive, especially in patients with mild-to-moderate claudication.
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.
There is currently no evidence for superiority of atherectomy over angioplasty on any outcome.
- 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.
- The major drawback of endovascular interventions compared with surgery is the lower long-term patency. There is currently no established method, apart from inserting a stent, to improve at least the medium-term patency of angioplasty. 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.
- 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.
- 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.However, despite positive results regarding rest-pain relief, ulcer healing and amputations, there is no conclusive evidence of the long-term effectiveness and safety of different prostanoids in patients with critical limb ischaemia.
- Amputation rates range from 5-20%, mainly in patients unsuitable for revascularisation, who are neurologically impaired or non-ambulatory.Amputation should not be considered unless all other options for revascularisation have been considered by a multidisciplinary team.
- Quality of life is often significantly impaired, particularly as a result of reduced mobility.
- 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.
- Multiorgan dysfunction - may occur, especially in people with acute limb ischaemia.
- The mortality rate in people with PAD is approximately 50% at 5 years and 70% at 10 years.
- Patients with PAD are at increased risk for all-cause mortality and from cardiovascular mortality.Coronary heart disease is present in about 90% of people with severe PAD.
- 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.
- Critical limb ischaemia requires a major lower-limb amputation 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 may be necessary in up to 40% of people and the 30-day mortality can be up to 30%.
- Lower-limb artery bypass surgery is associated with up to 3% perioperative mortality and a mortality rate of almost 20% at one year.
- The prognosis following amputation is poor. Two years following a below-knee amputation, 30% are dead, 15% have an above-knee amputation, 15% have a contralateral amputation and only 40% have full mobility.
Further reading and references
Peripheral arterial disease; NICE Quality Standard, Jan 2014
Diagnosis and management of peripheral arterial disease; Scottish Intercollegiate Guidelines Network - SIGN (2006)
Diagnosis and Treatment of Peripheral Artery Diseases; European Society of Cardiology (2011)
Aboyans V, Ricco JB, Bartelink MEL, et al; 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteriesEndorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). Eur Heart J. 2017 Aug 26. doi: 10.1093/eurheartj/ehx095.
Peach G, Griffin M, Jones KG, et al; Diagnosis and management of peripheral arterial disease. BMJ. 2012 Aug 14345:e5208. doi: 10.1136/bmj.e5208.
Lower limb peripheral arterial disease; NICE Clinical Guideline (August 2012, updated 2018)
Peripheral Arterial Disease; NICE CKS, April 2014 (UK Access Only)
Ray KK, Kastelein JJ, Boekholdt SM, et al; The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011. Eur Heart J. 2014 Apr35(15):960-8. doi: 10.1093/eurheartj/ehu107. Epub 2014 Mar 17.
Lane R, Ellis B, Watson L, et al; Exercise for intermittent claudication. Cochrane Database Syst Rev. 2014 Jul 187:CD000990. doi: 10.1002/14651858.CD000990.pub3.
Mazari FA, Gulati S, Rahman MN, et al; Early outcomes from a randomized, controlled trial of supervised exercise, Ann Vasc Surg. 2010 Jan24(1):69-79. Epub 2009 Sep 17.
Ganguly P, Alam SF; Role of homocysteine in the development of cardiovascular disease. Nutr J. 2015 Jan 1014:6. doi: 10.1186/1475-2891-14-6.
Marti-Carvajal AJ, Sola I, Lathyris D; Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2015 Jan 151:CD006612. doi: 10.1002/14651858.CD006612.pub4.
Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events; NICE Technology Appraisal Guidance, December 2010
Peripheral arterial disease - cilostazol, naftidrofyryl oxalate, pentoxifylline and inositol nicotinate; NICE Technology Appraisal Guidance, May 2011
Bedenis R, Stewart M, Cleanthis M, et al; Cilostazol for intermittent claudication. Cochrane Database Syst Rev. 2014 Oct 3110:CD003748. doi: 10.1002/14651858.CD003748.pub4.
Ambler GK, Radwan R, Hayes PD, et al; Atherectomy for peripheral arterial disease. Cochrane Database Syst Rev. 2014 Mar 173:CD006680. doi: 10.1002/14651858.CD006680.pub2.
Percutaneous atherectomy of femoropopliteal arterial lesions with plaque excision devices; NICE Interventional Procedure Guidance, February 2011
Ruffolo AJ, Romano M, Ciapponi A; Prostanoids for critical limb ischaemia. Cochrane Database Syst Rev. 2010 Jan 20(1):CD006544.
Aronow WS; Office management of peripheral arterial disease. Am J Med. 2010 Sep123(9):790-2.
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