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.¹

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 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.

This rest of this article mainly discusses peripheral arterial disease (PAD) affecting the legs (lower extremity arterial disease (LEAD)). There are separate articles on Carotid Artery Occlusion, Renovascular Disease and Bowel Ischaemia.

Epidemiology²

• Peripheral arterial disease (PAD) affects 4% to 12% of people aged 55 to 70 years and 20% of people over 70 years.³
• The frequency of lower extremity arterial disease (LEAD) is strongly age-related, rising steeply after 50 years of age.
• 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 factors²

• Smoking.
• Diabetes mellitus.
• Hypertension.
• Hyperlipidaemia: high total cholesterol and low high-density lipoprotein (HDL) cholesterol are independent risk factors.
• Physical inactivity.
• Obesity.

Presentation

A full cardiovascular history and examination are essential and should include assessment for coronary artery disease, cerebrovascular disease, all areas of possible peripheral arterial disease (PAD), e.g. kidney, bowel, 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):⁴
  • Walking impairment, e.g. 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 buttocks and thighs, associated with absent femoral pulses and male impotence (Leriche's syndrome; caused by aorto-iliac obstruction).
  • Lower extremity arterial disease (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.⁵

Signs

• Examination of the lower limbs should include auscultation of the femoral arteries at the groin level.
• The affected leg may be pale, cold and with a loss of hair and 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 factors

Any patient suspected or diagnosed as having peripheral arterial disease (PAD) should have a full cardiovascular risk assessment.¹

• Blood pressure.
• FBC (anaemia will aggravate PAD), ESR (inflammatory process, e.g. 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.

Confirm diagnosis

• 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.²
• 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.²
• Digital subtraction arteriography is not recommended as the primary imaging modality and is essentially a preoperative investigation. Its use is limited to an adjuvant of endovascular management, surgical planning or the management of an acute ischaemic limb.

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.

Referral

Patients with suspected peripheral arterial disease (PAD) should be referred to secondary care if:¹

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

Management

Most patients' symptoms improve with optimal medical treatment and invasive intervention is often not required.⁴ Beta-blockers are not contra-indicated in patients with lower extremity arterial disease (LEAD), and should be considered in the case of concomitant coronary artery disease and/or heart failure.²

Modification of cardiovascular risk factors

See also separate article Secondary Prevention of Cardiovascular Disease.

• Smoking cessation.
• Promote regular exercise: walking through discomfort is not damaging and promotes the collateral circulation leading to an improvement in walking capacity. A supervised exercise programme has been shown to be a very important part of management.^6,7
• 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 peripheral arterial disease (PAD), with and without coronary artery disease. Lowering total cholesterol and low-density lipoprotein (LDL) cholesterol by 25% with a statin reduces cardiovascular mortality and morbidity in patients with PAD by around a quarter.⁸ Lipid-lowering therapy with a statin is recommended, aiming to maintain LDL cholesterol level below 2.5 mmol/L and ideally below 1.8 mmol/L.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.⁴
• Angiotensin-converting enzyme (ACE) inhibitors (ramipril in the HOPE study (= the Heart Outcomes Prevention Evaluation study)⁹) have been shown to reduce cardiovascular morbidity and mortality in patients with PAD by about 25%. This reduced risk is greater than that just due to blood pressure control.
• 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 atherothrombotic vascular diseases.¹⁰ There is currently insufficient evidence to support the treatment of hyperhomocysteinaemia with folate and vitamin B12.

Antiplatelet drugs

• 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.¹¹
• Clopidogrel is at least as effective as aspirin in patients with PAD and has a better side-effect profile. However, it is much more expensive and is generally reserved for those who cannot take or tolerate aspirin or who continue to have events on aspirin. The small benefits of combining clopidogrel and aspirin do not justify its recommendation in patients with lower extremity arterial disease (LEAD), due to an increased bleeding risk.²

Peripheral vasodilators¹²

• Naftidrofuryl oxalate is recommended by the National Institute for Health and Clinical 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.^3,13

Surgical

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.²

• 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. 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.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.¹⁴
• 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.² 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.¹⁵
  • Amputation rates range from 5% to 20%, mainly in patients unsuitable for revascularisation, who are neurologically impaired or non-ambulatory.²

Complications

• 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.
• Gangrene.
• Amputation.

Prognosis

• Patients with peripheral arterial disease (PAD) are at increased risk for all-cause mortality and from cardiovascular mortality.¹⁶
• Very variable: intermittent claudication may resolve spontaneously, remain stable or progress rapidly to critical limb ischaemia. About 15% of people with intermittent claudication eventually develop critical leg ischaemia, which endangers the viability of the limb. 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
• Coronary heart disease is the major cause of death in people with PAD. The mortality rate, mainly from coronary and cerebrovascular events, is three to four times greater than age-sex matched controls without claudication. The risk is similarly increased in those who have asymptomatic disease as well as those with intermittent claudication.
• Outcome for patients presenting with intermittent claudication over five years:⁴
  • 50% will improve, 25% will stabilise and 25% will worsen. Of those who worsen, 20% (5% of total) will need intervention and 8% (2% of total) will need a major limb amputation.
  • 5-10% will have a non-fatal cardiovascular event.
  • 30% will die: cardiac 16%, cerebral 4%, other vascular 3%, non-vascular 7%.
  • 55-60% will survive with no cardiovascular event.
• 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.²

Prevention

See separate articles: Primary Prevention of Cardiovascular Disease and Secondary Prevention of Cardiovascular Disease.

Document references

1. Diagnosis and management of peripheral arterial disease, Scottish Intercollegiate Guidelines Network - SIGN (2006)
2. Diagnosis and Treatment of Peripheral Artery Diseases, European Society of Cardiology (2011)
3. Robless P, Mikhailidis DP, Stansby GP; Cilostazol for peripheral arterial disease. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD003748. [abstract]
4. Burns P, Gough S, Bradbury AW; Management of peripheral arterial disease in primary care. BMJ. 2003 Mar 15;326(7389):584-8.
5. The Edinburgh Claudication Questionnaire.
6. Mazari FA, Gulati S, Rahman MN, et al; Early outcomes from a randomized, controlled trial of supervised exercise, Ann Vasc Surg. 2010 Jan;24(1):69-79. Epub 2009 Sep 17. [abstract]
7. Watson L, Ellis B, Leng GC; Exercise for intermittent claudication. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD000990. [abstract]
8. No authors listed; MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.; Lancet. 2002 Jul 6;360(9326):7-22. [abstract]
9. Yusuf S, Sleight P, Pogue J, et al; Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000 Jan 20;342(3):145-53. [abstract]
10. Weiss N, Hilge R, Hoffmann U; Mild hyperhomocysteinemia: risk factor or just risk predictor for cardiovascular diseases? Vasa. 2004 Nov;33(4):191-203. [abstract]
11. Vascular disease - clopidogrel and dipyridamole, NICE Technology Appraisal Guideline (December 2010); Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events
12. Peripheral arterial disease - cilostazol, naftidrofyryl oxalate, pentoxifylline and inositol nicotinate, NICE Technology Appraisal Guideline (May 2011); Cilostazol, naftidrofyryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease
13. Mangiafico RA, Fiore CE; Current management of intermittent claudication: the role of pharmacological and Curr Vasc Pharmacol. 2009 Jul;7(3):394-413. [abstract]
14. Percutaneous atherectomy of femoropopliteal arterial lesions with plaque excision devices, NICE Interventional Procedure Guideline (February 2011)
15. Ruffolo AJ, Romano M, Ciapponi A; Prostanoids for critical limb ischaemia. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD006544. [abstract]
16. Aronow WS; Office management of peripheral arterial disease. Am J Med. 2010 Sep;123(9):790-2. [abstract]