Clinical review: Peripheral vascular disease

The diagnosis and management of peripheral vascular disease in primary care, including methods to manage cardiovascular risk for these patients and optimal therapies to reduce side-effects.

Atherosclerosis: Coloured light micrograph of a cross-section through an artery obstructed with atheroma plaque (Picture: SPL)
Atherosclerosis: Coloured light micrograph of a cross-section through an artery obstructed with atheroma plaque (Picture: SPL)

The prevalence of peripheral vascular disease (PVD) ranges from 3 to 10%, rising to 15 to 20% in the elderly.1 One in five people aged 65 to 75 years in the UK have clinical evidence of PVD, although only a quarter of them are symptomatic.2

Of patients asymptomatic at baseline, 9% will develop symptoms of intermittent claudication (IC) over 5 years.3 In addition, 40 to 60% of patients with PVD also have coronary artery and cerebral artery disease,1 and 20 to 30% of those with IC will die within five years, mainly due to cardiovascular events.4 This is why the most vital goal of PVD treatment is the reduction of the patient's cardiovascular risk.

Aetiology

PVD, also known as peripheral arterial disease, is an occlusive disease of the large peripheral arteries (especially of the legs), excluding the coronary and intracranial vessels. It is associated with a resting ankle brachial pressure index (ABPI) of ≤0.90, which is indicative of a haemodynamically significant arterial stenosis.

Traditional risk factors include age, diabetes, smoking, obesity, and hypertension, and non-traditional risk factors include race, chronic kidney disease, and hypercoagulable states.5

PVD is primarily caused by atherosclerosis and results in either acute or chronic limb ischaemia. The latter presents as IC, which is defined as pain in the leg muscles on walking.

Accumulated atheroma in the walls of arteries eventually leads to inadequate tissue perfusion. Atherosclerosis is a complex process involving endothelial dysfunction, thrombosis, platelet activation, lipid disturbances, oxidative stress, and genetic factors.

Other less common causes of PVD include thrombus formation, emboli, and inflammatory processes resulting in vessel stenosis.1 In the late stages of the disease, long-term tissue hypoperfusion progresses to critical limb ischaemia.

Classification systems

PVD can be categorised using the Fontaine or Rutherford classification systems. Each system grades PVD from no symptoms to major tissue loss and can be used at diagnosis, and to evaluate the progression or improvement of symptoms.

Fontaine classification system of PVD
Stage History
I Asymptomatic
IIa Mild claudication (>200 m)
IIb Moderate-severe claudication (<200m)
III Ischaemic rest pain
IV Tissue loss or ulceration

Rutherford's classification system of PVD
Grade Category History
0 0 Asymptomatic
I 1 Mild claudication
I 2 Moderate claudication
I 3 Severe claudication
II 4 Ischaemic rest pain
III 5 Tissue ulceration (minor)
III 6 Tissue loss/gangrene

Making the diagnosis

Most patients with PVD present with the classic symptoms of IC, particularly in the calf, although the thigh or buttocks may also be affected. Pain is stimulated by exercise and relieved by rest.1

The location of the pain represents the anatomical level of the disease. Pain in the calf reflects a diseased femoropopliteal segment, whereas pain in the buttock, hip, or thigh reflects disease at the aortoiliac level. Patients may have weak or absent femoral pulses if there is aortoiliac disease. The latter can be associated with erectile dysfunction.

Patients often complain of muscle fatigue, pain, or cramps in these areas. Pain can be reproduced after the same mobilising distance. Furthermore, patients with PVD can report a reduced quality of life because of limited exercise and walking ability. Hence it is vital to determine the impact of symptoms on a patient's daily activities.

Less commonly, acute limb ischaemia - defined as a reduction in limb perfusion which could threaten limb viability - may be the first presentation of arterial disease in previously asymptomatic patients with PVD. These patients may present with one of five symptoms referred to as the 'five Ps': pain, pulselessness, pallor, paralysis, and paraesthesia.

Examination

Clinical examination should consist of a vascular examination (see box) which includes abdominal palpation for an aortic aneurysm. The patient should also be examined for lower extremity ulcers, gangrene, and signs of alopecia, dry skin, and muscle atrophy.

Checklist of PVD investigations in primary care
  • Examination of peripheral pulses
  • Examination for ulcers
  • Palpation of the abdomen for an aortic aneurysm
  • Measurement of ABPI

The first investigation in primary care should be the measurement of the ABPI. This consists of the ratio of the ankle to brachial systolic pressure and is determined using a sphygmomanometer and a handheld Doppler device.

The ratio is calculated by dividing the higher pressure reading at the ankle by the higher systolic pressure reading of the right and left brachial arteries. A normal ABPI is greater than one. Patients with long-standing diabetes mellitus or renal failure may have calcified tibial arteries, rendering them incompressible and causing a falsely raised ABPI, which is defined as an ABPI >1.40.1

Imaging techniques consist of a Duplex scan or angiography, which could be in the form of an MRI (magnetic resonance angiogram) or a computerised axial tomogram (CT) angiogram. It is important to check for renal function and history of iodine allergy before ordering an MR or CT angiogram as both need contrast injection which can be nephrotoxic. Catheter angiography is rarely performed as a first-line investigation.

Differential diagnosis

IC must be differentiated from leg pain occurring as a result of non-vascular causes. The differential diagnosis of IC includes nerve root compression, compartment syndrome, venous claudication, and spinal stenosis.

True claudication starts after a reproducible length of walking and resolves within a few minutes of rest. In contrast, pain from nerve impingement resulting from spinal stenosis, for instance, does not resolve after rest and might even get worse after long periods of standing or sitting.

Measuring the ABPI

ABPI = ankle systolic pressure divided by brachial systolic pressure

0.9 – normal

0.5-0.9 - moderate claudication

Managing the condition

Treatment of PVD depends on the severity of the disease. IC, the commonest presentation of PVD, is associated with an increased risk of morbidity and mortality from cardiovascular events such as myocardial infarction and stroke.6

Initial management should therefore be aggressive and aimed at reducing the patient's risk of cardiovascular complications and improving function by including risk factor modification, exercise, and pharmacological therapy.

Endovascular procedures and surgery are usually reserved for patients who have impaired functional status with a poor quality of life.7

Risk factor modification measures include:

  • Smoking cessation
  • Weight reduction
  • Blood pressure control
  • Glycaemic control
  • Supervised exercise
  • Antiplatelet therapy
  • Cholesterol lowering

Lifestyle measures

Smoking is associated with a considerably increased risk of cardiovascular events. It is the critical risk factor modification measure in the management of PVD.6

Smoking cessation methods include counselling and nicotine replacement therapy.

Guidelines recommend that the BP control in patients with diabetes associated with hypertension should aim for 130/80 mmHg instead of 140/90 mmHg.8

Contrary to a long-held belief, beta blockers are not contraindicated in PAD and any suitable combination of medication is safe.

Patients with type 2 diabetes have three to four times the risk for PVD and intermittent claudication. They also tend to develop this at a younger age, with an increase in the risk of complications. Therefore, glycaemic control has to be very accurate.

The BARI trial (bypass versus angioplasty revascularisation investigation trial for type 2 diabetes) patients who received insulin-sensitising therapy like metformin had lower frequencies of lower-extremity revascularisation (1.1% versus 2.6%), of low ankle-brachial index (16.5% versus 22.7%), and of amputation (0.1% versus 1.6%) than patients who received insulin-providing therapy.9,10

Anti-thrombotic trials have shown a significant reduction in cardiovascular events in patients with peripheral vascular disease and all patients should be on aspirin, or clopidogrel if they are aspirin intolerant.

Management of cholesterol levels is also vital. The Heart Protection Study randomised 20,536 patients with a total cholesterol level of at least 3.5 mmol/l to either 40 mg simvastatin daily or matching placebo tablets. Results demonstrated that patients on simvastatin with no history of CHD at baseline had a relative risk reduction of 25% in the first occurrence of a major vascular event.11

Supervised exercise

Exercise has been shown to improve total walking distance and optimal exercise time in patients with IC.6 Although exercise has been proven to have significant benefits, it requires a considerable amount of motivation and may be difficult for some patients with comorbidities.

All patients should have access to supervised exercise in order to achieve optimal results. It has been suggested that most effective exercise regimens should involve walking on a treadmill for approximately 30 to 60 minutes, three times per week for a period of 3 months.7

A Cochrane review of 22 RCTs that investigated the efficacy of exercise therapy in PVD patients with IC showed that exercise programmes benefited patients compared with placebo or usual care. In particular, improvements in walking time and patients' overall quality of life were observed.12 Advice to ‘go home and walk’ is unlikely to improve pain-free walking distance.

Pharmacotherapy

Several drugs have been developed without clear benefit, except for naftidrofuryl, cilostazol, and pentoxyfylline.

Naftidrofuryl oxalate is a peripheral vasodilator that blocks vascular and platelet 5-hydroxytryptamine receptors. It is contraindicated in patients with hyperoxaluria or recurrent renal stones.13 At a dose of 100 mgs three times a day, the monthly cost is around £9.

Cilostazol is a phosphodiesterase III inhibitor and works by vasodilatory and antiplatelet activity. It is contraindicated in patients with severe renal impairment, unstable angina, congestive cardiac failure, and hepatic impairment, as well as in patients who are predisposed to bleeding problems or have a history of ventricular tachycardia fibrillation or ventricular ectopic beats.14

Prescribers should assess any benefit after three months of treatment and stop if there is no improvement in walking distance. At a dose of 100 mgs twice a day the monthly cost is about £35.

Pentoxyfylline is an oral peripheral vasodilator derived from methylxanthine. Research tools are often confounding, and compare and measure improvement in maximum walking distance (MWD), pain free walking distance (PWD), absolute walking distance (AWD), and initial improvement in walking distance, as well as quality of life indices (quality adjusted life years - QALYs).

In one of the largest systemic Cochrane reviews, Stevens et al identified 1,876 citations and noted that naftidrofuryl oxalate was the best medication for MWD - which improved by 60% as compared to 25% for cilostazol and 11% for pentoxyfylline - and PWD, which improved by 49% for naftidrofuryl, and 13% and 9% for cilostazol and pentoxyfylline, respectively.15

Current NICE guidelines suggest that naftidrofuryl is the best and most cost-effective drug for medical management of intermittent claudication.13

Radiological intervention

There has been a rapid expansion of endovascular treatment for symptomatic PAD. TASC II (TransAtlantic inter-society consensus group) has classified lesions of the aortoiliac and femoropopliteal segments based on their anatomy into grades A-D, with surgery recommended for grade C and D lesions that are long and complex.

However, a recent revision to the TASC guidelines incorporates infrapopliteal lesions and recommends endovascular treatment first, even for complex anatomical lesions.16

Surgery

Surgery is indicated for short distance disabling claudication affecting the patient’s lifestyle, or for critical leg ischaemia.

A bypass operation for an occlusion of the iliac segment is usually done with a prosthetic material like dacron or PTFE (polytetrafluoroethylene). For occlusions of the femoropopliteal segment, bypass should be carried out using the long saphenous vein from the same or opposite leg. The arm veins may also be used, especially if the bypass is to a below knee popliteal or anterior or posterior tibial vessels.

Prognosis

The prognosis is variable depending on the cause and severity of the disease. Evidence suggests that the majority of patients with IC who are on conservative treatment have a reasonably favourable outlook over 5 years, with only 25% of patients developing severe symptoms.6

Of the 25% whose symptoms appear to deteriorate, 20% will require some form of intervention, while 8% (2% of the total) will require an amputation.2

  • Mr Vish Bhattacharya is consultant general and vascular surgeon, Queen Elizabeth Hospital, Gateshead and associate clinical lecturer, Newcastle University

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This is an updated version of an article that was first published in February 2011.

References

  1. Norgren L, Hiatt WR, Dormandy JA et al. Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg 2007; 45: Suppl S5-67
  2. Burns P, Gough S, Bradbury AW et al. Management of peripheral arterial disease in primary care. BMJ 2003; 326(7389): 584-8
  3. Leng GC, Lee AJ, Fowkes FG et al. Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. Int J Epidemiol 1996; 25(6): 1172-81
  4. Stansby G. The patient with intermittent claudication. Practitioner 2005; 249(1670): 318
  5. Bartholomew JR, Olin JW. Pathophysiology of peripheral arterial disease and risk factors for its development. Cleve Clin J Med 2006; 73(Suppl 4): S8-14
  6. Scottish Intercollegiate Guidelines Network. Diagnosis and management of peripheral arterial disease. A national clinical guideline. SIGN 2006. www.sign.ac.uk/pdf/sign89.pdf
  7. Antoniou GA, Ibrahim R, Ahmad N, Torella F. TASC II anatomic classification for infrapopliteal arterial disease: a framework for clinical practice and future research. J Endovasc Ther 2015; 22: 678-80
  8. Mancia G, De Backer G, Dominiczak A et al. 2007 guidelines for the management of arterial hypertension: The task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25: 1105-87
  9. Althouse AD, Abbott JD, Sutton-Tyrrell K et al. Favorable effects of insulin sensitizers pertinent to peripheral arterial disease in type 2 diabetes: Results from the bypass angioplasty revascularization investigation 2 Diabetes (BARI 2D) trial. Diabetes Care 2013; 36: 3269-75
  10. Busko M. Insulin sensitizers halve PAD risk, amputations in BARI 2D. Medscape Medical News June 10, 2013. http://www.medscape.com/viewarticle/805540
  11. MRC/BHF. Heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7-22
  12. Watson L, Ellis B, Leng GC. Exercise for intermittent claudication. Cochrane Database Syst Rev 2008; 8(4): CD000990
  13. National Institute of Health and Care Excellence. Peripheral arterial disease: diagnosis and management (CG147). NICE guidelines. August 2012 www.nice.org.uk
  14. Cilostazol (risk of cardiac and bleeding events) http://www.mhra.gov.uk/home/groups/dsu/documents/publication/con267913.pdf
  15. Stevens JW, Simpson E, Harnan S et al. Systematic review of the efficacy of cilostazol, naftidrofuryl oxalate and pentoxyfylline for the treatment of intermittent claudication. Br J Surg 2012; 99(12): 1630-8
  16. The TASC steering committee. An update on methods for revascularization and expansion of the TASC lesion classification to include below-the-knee arteries: a supplement to the Inter-society consensus for the management of peripheral arterial disease (TASC II). J Endovasc Ther 2015; 22: 657-71

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