Peripheral Artery Disease: Diagnosis, Ankle–Brachial Index and Risk Management

Definition and pathophysiology

Peripheral artery disease (PAD) is a clinical disorder caused by stenosis or occlusion of the aorta or arteries supplying the limbs. In adults over 40 years of age, atherosclerosis is the predominant cause. Other mechanisms include thrombosis, embolism, vasculitis, fibromuscular dysplasia, arterial entrapment, cystic adventitial disease and trauma.

Atherosclerotic PAD is a manifestation of systemic arterial disease rather than an isolated disorder of the lower limbs. Patients frequently have concomitant coronary, cerebrovascular or other peripheral arterial disease, and management should therefore address the entire arterial circulation. PAD is associated with increased cardiovascular morbidity and mortality, as well as limb complications.

Atherosclerotic lesions generally affect large and medium-sized arteries. Pathological features include plaque formation with calcium deposition, medial thinning, destruction of muscular and elastic tissue, fragmentation of the internal elastic lamina, and superimposed platelet- and fibrin-rich thrombus. Lesions preferentially occur at arterial branch points, where disturbed flow, altered shear stress and intimal injury promote atherosclerosis.

The principal anatomical distributions are:

• Abdominal aorta and iliac arteries, involved in approximately 30% of symptomatic patients.

• Femoral and popliteal arteries, involved in approximately 80–90%.

• Tibial and peroneal arteries, involved in approximately 40–50%.

Distal disease is particularly common in older people and in patients with diabetes. The haemodynamic consequences depend on lesion location, severity, length, the presence of multilevel disease and collateral circulation. Flow limitation may be clinically silent, manifest as exertional symptoms, or progress to chronic limb-threatening ischaemia (CLTI).

Clinical presentation and symptoms

Asymptomatic and atypical disease

Fewer than half of patients with PAD have typical symptoms. Many have impaired walking or a slow gait without describing classic claudication. In older adults, approximately 40% are asymptomatic, 50% report atypical leg symptoms and fewer than 10% have classic claudication.

Asymptomatic or atypical PAD remains clinically important. Reduced activity may lead to progressive functional decline, sedentary behaviour and loss of independence. Identification of PAD also provides an opportunity to recognise atherosclerosis in other arterial territories and to initiate secondary prevention.

Clinical assessment should include functional status and walking capacity, because these may reveal “masked” PAD in patients who do not exert themselves sufficiently to provoke symptoms.

Intermittent claudication

Intermittent claudication is exertional discomfort in a limb muscle that improves with rest. The symptom may be described as pain, aching, cramping, numbness or fatigue. The symptomatic territory is usually distal to the arterial obstruction:

• Buttock, hip or thigh symptoms suggest aortoiliac disease.

• Calf symptoms are typical of femoropopliteal disease.

• More distal disease may cause foot symptoms, although lower-extremity symptoms are much more common than upper-extremity symptoms.

The severity of symptoms should be described by their effect on walking distance, daily activities, work and independence. Exercise testing can quantify both the time to initial claudication and the maximum tolerated exercise time.

Chronic limb-threatening ischaemia

CLTI occurs when resting perfusion is insufficient to meet the basal nutritional requirements of tissue. Typical symptoms include:

• Ischaemic rest pain.

• Coldness or numbness of the foot and toes.

• Pain that is worse at night or when the limb is horizontal.

• Improvement when the leg is placed in a dependent position.

With advanced disease, rest pain may become persistent. Tissue loss, ulcers and gangrene may develop. In patients with CLTI, early recognition and referral to a vascular team are essential for limb salvage.

Acute limb ischaemia

Acute limb ischaemia requires urgent evaluation by an experienced vascular clinician. The source material emphasises assessment of limb viability, the presence of neurological deficit, and identification of thrombosis or embolisation as the underlying mechanism. A neurological deficit indicates the need for urgent revascularisation.

Evaluation and physical examination

Evaluation should combine:

• A detailed history.

• Cardiovascular risk-factor assessment.

• Functional and quality-of-life assessment.

• Comprehensive vascular examination.

• Haemodynamic testing.

History

The history should establish:

• Exertional symptoms, their location and reproducibility.

• Walking limitation and its effect on activities and independence.

• Rest pain, nocturnal symptoms and positional relief.

• Ulceration, tissue loss, gangrene or nonhealing wounds.

• Smoking and diabetes status.

• Hypertension, hypercholesterolaemia, renal insufficiency and other cardiovascular risk factors.

• Previous peripheral, coronary or cerebrovascular disease.

• Previous endovascular or surgical revascularisation.

• Possible embolic or thrombotic precipitants in acute presentations.

In patients with diabetes, assessment should specifically address foot wounds and neuropathy, because early recognition of PAD and foot neuropathy can help prevent wounds and amputation.

Vascular examination

The examination should include palpation of:

• Femoral pulses.

• Popliteal pulses.

• Dorsalis pedis pulses.

• Posterior tibial pulses.

The abdomen and groins should be auscultated for bruits. The legs and feet should be inspected for:

• Muscle wasting.

• Hair loss.

• Thickened nails.

• Smooth, shiny skin.

• Reduced skin temperature.

• Pallor or cyanosis.

• Ulceration and gangrene.

• Dependent rubor.

• Oedema related to prolonged dependency in severe ischaemia.

Elevation of the legs and repeated calf flexion may produce pallor of the soles. When the legs are returned to a dependent position, reactive hyperaemia may produce rubor. The time required for rubor to develop or for foot veins to refill relates to the severity of ischaemia and the adequacy of collateral circulation.

Ischaemic neuropathy may cause numbness and reduced reflexes.

Bilateral arm blood-pressure measurement is recommended in patients with peripheral arterial and aortic disease. This is particularly relevant when upper-extremity or subclavian disease is possible.

Diagnostics

Ankle–brachial index

The ankle–brachial index (ABI) is the preferred first-line non-invasive test for PAD screening, diagnosis and surveillance. It is inexpensive, widely available and can be measured at rest or after exercise.

The ABI is calculated from ankle and brachial systolic pressures. Ankle pressure is measured using a cuff and Doppler assessment of arterial flow, usually in the dorsalis pedis and posterior tibial arteries. Oscillometric and Doppler approaches have shown good concordance, although reproducibility is better when the measurement is performed by trained physicians.

Resting ABI has reported sensitivity of 68–84% and specificity of 84–99% for PAD diagnosis. An ABI ≤0.90 confirms PAD.

The ABI also contributes to cardiovascular risk assessment and can reclassify individuals initially considered to be at low or intermediate risk.

Non-compressible arteries

An ABI >1.40 should be described as indicating non-compressible arteries rather than as a normal result. This finding reflects arterial stiffness and is encountered particularly in diabetes, severe kidney failure and advanced age. It is associated with increased cardiovascular-event and mortality risk.

When ankle arteries are non-compressible, additional assessment is recommended using:

• Toe pressure.

• Toe–brachial index (TBI).

• Doppler waveform analysis.

Toe–brachial index

The TBI evaluates pressure in medium-calibre digital arteries and is useful when ankle arteries cannot be compressed reliably. Toe pressure may be measured at the hallux, second toe or third toe using laser Doppler or plethysmography.

A TBI ≤0.70 is generally considered abnormal. Reported sensitivity and specificity vary substantially, ranging from 45–100% and 17–100%, respectively.

In patients with diabetes or renal failure, toe pressure or TBI should be measured even when the resting ABI is normal, because arterial stiffness may obscure lower-extremity disease.

Exercise testing and post-exercise ABI

Exercise testing is useful when symptoms suggest claudication but the resting ABI is borderline or normal. It can:

• Support the diagnosis of PAD.

• Characterise flow limitation.

• Objectively measure functional impairment.

• Assess response to treatment.

Exercise may be performed using a graded treadmill protocol. The time to onset of claudication and the maximum tolerated exercise time should be documented. A six-minute walk test can also assess time and distance to initial and maximum calf pain.

The post-exercise ABI is measured after standardised treadmill exercise, generally one minute after exercise cessation in the vascular-examination protocol. Bilateral ankle pressures should be obtained, beginning with the symptomatic leg, and brachial systolic pressure should be measured concurrently.

In healthy individuals, exercise produces a mild ABI reduction that normally resolves within one to two minutes. In PAD, ankle pressure falls more substantially and recovery is prolonged.

Proposed diagnostic criteria include:

• A post-exercise ABI fall of 20% from the resting value.

• A post-exercise ABI below 0.90.

• A fall in ankle systolic pressure exceeding 30 mmHg.

However, a fall of more than 20% may produce false-positive results in healthy individuals. Exercise criteria should therefore be interpreted in conjunction with symptoms and other haemodynamic findings.

Segmental pressure and pulse-volume assessment

Pneumatic cuffs placed at sequential levels of the limb permit measurement of segmental systolic pressures. Pressure gradients between adjacent cuffs suggest the presence and level of haemodynamically significant stenosis.

Pulse-volume recordings provide additional physiological information. Significant PAD produces blunting of the pulse-volume contour.

Duplex ultrasonography

Duplex ultrasonography combines B-mode imaging with Doppler flow assessment and is recommended as the first-line imaging technique for confirming PAD lesions. It can identify stenoses in native arteries and assess bypass grafts.

Anatomical imaging should not be interpreted in isolation. Symptoms, physical findings and haemodynamic testing should be considered alongside imaging before an invasive procedure is undertaken.

Computed tomographic and magnetic resonance angiography

Computed tomographic angiography (CTA) and magnetic resonance angiography (MRA) are not routine initial diagnostic tests. They are used when more detailed anatomical definition is needed, particularly before possible revascularisation.

In symptomatic patients with aortoiliac, multisegmental or complex disease, CTA and/or MRA are recommended as adjunctive imaging for procedural planning. The choice of modality should consider renal function, pregnancy, age, contrast allergy and radiation exposure, except when emergency circumstances require rapid imaging.

Catheter angiography

Conventional catheter-based angiography is reserved for defining anatomy when revascularisation is being considered. It is not recommended as a routine diagnostic test.

Tissue viability and transcutaneous oxygen pressure

Transcutaneous oxygen pressure (TcPO2) can be used to assess tissue viability and has been proposed as a diagnostic measure in CLTI. Values are influenced by skin thickness, probe temperature, inflammation and oedema and may therefore be misleading.

A resting TcPO2 above 30 mmHg is a favourable indicator for wound healing. A value below 10 mmHg is associated with poor wound-healing and amputation prognosis in patients with CLTI treated with bone marrow-derived stem cells. Serial measurements at different levels of an ischaemic limb may assist in determining an appropriate amputation level.

Exercise transcutaneous oximetry may help identify proximal, including buttock, claudication and unsuspected exercise-induced hypoxaemia.

Biomarkers and laboratory findings

A thorough cardiovascular risk-factor laboratory evaluation is recommended in patients with peripheral arterial and aortic disease. The material specifically identifies the following areas:

• Lipid assessment, particularly low-density lipoprotein cholesterol (LDL-C).

• Glycaemic assessment, including HbA1c.

• Evaluation relevant to renal function.

• Broader cardiovascular risk-factor assessment.

In patients with atherosclerotic PAAD, the recommended LDL-C goal is below 1.4 mmol/L (55 mg/dL), together with a reduction of more than 50% from baseline. In diabetes, tight glycaemic control with HbA1c below 53 mmol/mol (7%) is recommended to reduce microvascular complications, while targets should be individualised according to comorbidities, duration of diabetes and life expectancy.

Inflammatory biomarkers, metabolomics and proteomics may have prognostic value in PAD, but the source material does not provide specific biomarkers, thresholds or validated clinical applications.

Treatment and management

The goals of treatment are to:

• Reduce cardiovascular events and death.

• Prevent acute limb ischaemia and progression to CLTI.

• Reduce the risk of major amputation and other major adverse limb events.

• Improve walking ability, function and quality of life.

• Preserve limb viability and independence.

Management should be lifelong and multidisciplinary, with shared decision-making and patient involvement in the selection of treatment options.

Comprehensive risk-factor management

PAD should be managed as systemic atherosclerotic disease. Risk-factor treatment includes:

• Smoking cessation and continued abstinence from all forms of smoking.

• A healthy diet.

• Regular aerobic activity or structured exercise.

• Blood-pressure control.

• Lipid lowering.

• Diabetes management.

• Adherence to antithrombotic treatment when indicated.

• Education and empowerment of patients and caregivers.

A Mediterranean-style diet rich in legumes, dietary fibre, nuts, fruits and vegetables, with a high flavonoid intake, is recommended for cardiovascular prevention.

Behavioural counselling should support dietary improvement, smoking cessation and physical activity. Tailored education is intended to improve adherence, encourage regular exercise and reinforce the importance of ongoing risk-factor control.

Exercise therapy and rehabilitation

Low- to moderate-intensity aerobic exercise is recommended to increase total and pain-free walking distance; higher intensity may be used if tolerated.

Supervised exercise training (SET) is recommended in symptomatic PAD and should also be used as an adjunct after endovascular revascularisation. Structured exercise can improve walking performance and functional status. Cardiac rehabilitation programmes may be available for symptomatic PAD, including in older patients.

Exercise training is not recommended in patients with CLTI and wounds.

Blood-pressure management

For patients with PAAD and hypertension, an SBP target toward 120–129 mmHg is recommended if tolerated.

In unilateral renal artery stenosis, antihypertensive treatment should include an ACE inhibitor or angiotensin receptor blocker.

Lipid-lowering therapy

All patients with PAD should receive statin therapy. In atherosclerotic PAAD, the recommended ultimate LDL-C target is:

• LDL-C <1.4 mmol/L (55 mg/dL), and

• More than 50% reduction from baseline.

If the target is not reached:

• Add ezetimibe to maximally tolerated statin therapy.

• If LDL-C remains above target, add a PCSK9 inhibitor.

• In high-risk, statin-intolerant patients who do not achieve the target with ezetimibe, bempedoic acid may be added, either alone or with a PCSK9 inhibitor.

Fibrates are not recommended for cholesterol lowering in this setting.

Diabetes management

In patients with PAAD and type 2 diabetes mellitus:

• Tight glycaemic control is recommended, with HbA1c below 53 mmol/mol (7%) to reduce microvascular complications.

• SGLT2 inhibitors with established cardiovascular benefit are recommended to reduce cardiovascular events, independent of baseline or target HbA1c and concomitant glucose-lowering treatment.

• GLP-1 receptor agonists with established cardiovascular benefit are similarly recommended.

• Hypoglycaemia should be avoided.

• HbA1c targets should be individualised.

• Glucose-lowering agents with proven cardiovascular benefit, or at least established cardiovascular safety, should be prioritised over agents without evidence of benefit or safety.

Antithrombotic therapy

For symptomatic PAD, single antiplatelet therapy is recommended to reduce major adverse cardiovascular events:

• Aspirin 75–160 mg once daily, or

• Clopidogrel 75 mg once daily.

Long-term dual antiplatelet therapy is not recommended for PAD. Oral anticoagulant monotherapy should not be used solely for PAD unless there is another indication. Routine ticagrelor use is not recommended.

In asymptomatic PAD without clinically relevant atherosclerotic cardiovascular disease, antiplatelet treatment should not be instituted systematically.

Patients with atrial fibrillation generally require anticoagulation for the atrial fibrillation indication; anticoagulation alone is usually sufficient during the chronic phase, with direct oral anticoagulants preferred in the cited guidance. After recent peripheral endovascular revascularisation, a short period of combination treatment with an anticoagulant and single antiplatelet therapy may be considered, balancing thrombotic and bleeding risks and keeping the combination period as brief as possible. The cited material describes approximately one month for peripheral procedures.

Cilostazol

Cilostazol can improve claudication symptoms and walking distance. It is contraindicated in patients with heart failure. No dose is provided in the source material.

Revascularisation in stable PAD

Revascularisation should be considered according to:

• Lesion location.

• Lesion morphology.

• Extent of disease.

• Patient comorbidity and procedural risk.

• Response to optimal medical treatment and exercise therapy.

• Lifestyle limitation and quality-of-life impairment.

In symptomatic PAD, quality-of-life assessment is recommended after three months of optimal medical treatment and exercise therapy. Revascularisation should not be performed solely to prevent progression to CLTI, and it is not recommended in asymptomatic PAD.

Endovascular procedures include atherectomy, angioplasty and stenting. Surgical treatment may involve bypass. The choice should be individualised by a multidisciplinary vascular team. In older patients, endovascular therapy may be favoured because of the operative risks associated with age and comorbidity.

Chronic limb-threatening ischaemia

CLTI requires management by a vascular team. Revascularisation is recommended for limb salvage and should be performed as soon as possible.

Additional principles include:

• Offloading mechanical tissue stress in patients with ulcers.

• Antibiotic treatment of infection.

• Elimination of inflow obstruction when treating downstream lesions.

• Individual assessment of endovascular versus surgical procedural risk.

• Preference for autologous vein as the conduit for infra-inguinal bypass surgery.

• Regular post-revascularisation follow-up assessing clinical, haemodynamic and functional status, limb symptoms, treatment adherence and cardiovascular risk factors.

Amputation is appropriate when tissue loss is beyond salvage. The material emphasises that late recognition of PAD contributes to amputation in older adults and that amputation may reduce independence, particularly when adaptation to prosthetic devices is poor.

Acute limb ischaemia

Acute limb ischaemia requires urgent vascular assessment. Management should include:

• Immediate evaluation of limb viability.

• Urgent revascularisation in the presence of neurological deficit.

• Imaging to guide treatment when this does not delay therapy.

• Revascularisation within hours of initial imaging when severe neurological deficit is absent, with timing determined case by case.

• Prompt analgesia.

• Monitoring for compartment syndrome after revascularisation, with fasciotomy when required.

• Assessment of clinical and haemodynamic success.

• Investigation of the cause of thrombosis or embolisation.

Guideline recommendations

The principal recommendations are summarised below.

Prognosis and follow-up

PAD confers a substantial risk of cardiovascular death and limb events. Prognosis is determined principally by the extent of coexisting coronary and cerebrovascular disease and by the severity of lower-extremity ischaemia.

Patients with PAD have a reported five-year mortality of approximately 15–25% and a two- to fourfold higher risk of cardiovascular death. The ABI helps identify patients at increased risk of adverse cardiovascular and limb outcomes. Mortality is greatest in those with the most severe disease.

Over five years, the ABI worsens in approximately 40% of patients and symptoms progress in approximately 20–25%. Around 11% of patients with symptomatic PAD ultimately develop CLTI. Without revascularisation, approximately one quarter of patients with CLTI undergo amputation within one year. Prognosis is worse among patients who continue to smoke or who have diabetes.

Lifelong surveillance

Atherosclerotic lower-extremity PAD requires lifelong follow-up. At least annual review should assess:

• New or changing limb symptoms.

• Walking capacity and functional status.

• Ulcers, tissue loss and signs of CLTI.

• Cardiovascular risk factors.

• Medication adherence and tolerance.

• Need for duplex ultrasonography.

Following infra-inguinal autogenous vein bypass or endovascular intervention, ABI and arterial duplex ultrasound surveillance is considered reasonable at one to three months, then at six and twelve months, and annually thereafter, provided there are no new lower-extremity signs or symptoms. The effectiveness of the same surveillance strategy is uncertain after infra-inguinal prosthetic bypass.

Telehealth may be used for longitudinal assessment when appropriate to the urgency of symptoms, but it should not replace urgent face-to-face vascular evaluation when acute or limb-threatening symptoms are present.

Practical diagnostic and management pathway

A clinically useful sequence is:

• Identify possible disease: assess exertional symptoms, rest pain, wounds, walking limitation and cardiovascular risk factors.

• Examine the vascular system: palpate pulses, assess skin and tissue, auscultate for bruits, and measure blood pressure in both arms.

• Measure ABI: an ABI ≤0.90 confirms PAD.

• Address non-compressibility: if ABI is >1.40, obtain toe pressure, TBI or Doppler waveform analysis.

• Resolve diagnostic uncertainty: use exercise testing and post-exercise ABI when symptoms are suggestive but resting measurements are borderline or normal.

• Define anatomy when necessary: use duplex ultrasonography first; add CTA or MRA for complex disease or revascularisation planning.

• Begin comprehensive treatment: smoking cessation, Mediterranean-style diet, structured exercise, lipid lowering, blood-pressure control, diabetes management and appropriate antithrombotic therapy.

• Reassess function and quality of life: particularly after an initial three-month period of medical therapy and exercise.

• Refer urgently when limb viability is threatened: CLTI and acute limb ischaemia require vascular-team involvement and timely revascularisation.

• Continue lifelong surveillance: review symptoms, function, risk factors, adherence and limb status at least annually.