Peripheral Arterial Disease

Peripheral arterial disease is atherosclerotic obstruction of the arteries of the lower limbs, and rarely upper limbs. It affects roughly 10% of people over 60 and up to 20% over 70, though many are asymptomatic.

Risk factors and associations

• Smoking (the strongest, with a risk of 3 to 4 fold), diabetes (2 to 4 fold, with distal tibial disease), hypertension, dyslipidaemia, chronic kidney disease, older age and a family history.
• Coexisting coronary and cerebrovascular disease is present in half of patients. Five year risk of myocardial infarction, stroke or vascular death is 20 to 30%.

Anatomical patterns

• Aortoiliac: buttock and thigh claudication, erectile dysfunction, and absent femoral pulses (Leriche syndrome).
• Femoropopliteal: calf claudication, the most common pattern.
• Tibial and pedal: common in diabetes and renal disease, producing rest pain and tissue loss.

Other causes of arterial occlusion should be considered in young patients: fibromuscular dysplasia, popliteal entrapment, Buerger disease, vasculitis, adventitial cystic disease and radiation arteritis.

Clinical staging

• Fontaine: I asymptomatic, IIa mild claudication, IIb moderate to severe claudication, III ischaemic rest pain, IV ulceration or gangrene.
• Rutherford: grades 0 to 6, from asymptomatic to major tissue loss.

Chronic limb-threatening ischaemia is rest pain, or ulceration or gangrene present for more than 2 weeks, with objective evidence of ischaemia (ankle pressure below 50 mmHg, toe pressure below 30 mmHg, or transcutaneous oxygen pressure below 30 mmHg). One year mortality is 20 to 25% and major amputation 15 to 20% without revascularisation.

Intermittent claudication

• Reproducible cramping pain in a muscle group during walking, relieved by 1 to 10 minutes of standing rest, without needing to sit or flex the spine.
• Up to half of patients have atypical leg symptoms or none at all.

Chronic limb-threatening ischaemia

• Rest pain in the forefoot, worse at night and relieved by hanging the leg over the bed. Ulcers on toes, heels and pressure points that are painful, punched out, with a pale base and little bleeding, and gangrene.

Signs

• Diminished or absent pulses, femoral or abdominal bruits, cool pale shiny skin, hair loss, thick nails, dependent rubor with elevation pallor (Buerger test), and capillary refill over 3 seconds.
• Foot ulcers in diabetes may be neuro-ischaemic and painless.

Differential diagnosis for leg pain on walking

• Neurogenic claudication from lumbar stenosis (relief on sitting or flexion), venous claudication (bursting pain relieved by elevation), hip or knee arthritis, chronic compartment syndrome, popliteal cyst, and diabetic neuropathy.

Red flags are acute onset of pain, pallor, pulselessness, paraesthesia or paralysis, which indicate acute limb ischaemia, and wet gangrene or spreading infection in a diabetic foot.

Ankle brachial index (highest ankle systolic pressure divided by highest brachial pressure) at rest:

• 1.00 to 1.40 is normal. 0.91 to 0.99 is borderline.
• 0.90 or lower confirms PAD. 0.41 to 0.90 is mild to moderate. 0.40 or lower is severe.
• Above 1.40 indicates non-compressible calcified vessels, and toe brachial index (abnormal below 0.70) or toe pressure is used instead.
• Exercise testing: a fall of more than 20% in index, or more than 30 mmHg in ankle pressure after treadmill exercise, makes the diagnosis in patients with normal resting values.

Further testing

• Arterial duplex ultrasound: peak systolic velocity ratio above 2 indicates 50% stenosis and above 4 indicates over 75% stenosis, with monophasic downstream waveforms.
• Toe pressures, transcutaneous oxygen measurement and skin perfusion pressure for tissue healing potential.
• CT angiography or MR angiography (gadolinium group II agent, with caution when eGFR is below 30) for planning. Catheter angiography is used for therapeutic access.
• Laboratory evaluation: lipid profile, HbA1c, creatinine, CBC, CRP.
• Cardiovascular assessment: ECG, carotid duplex when indicated, and abdominal ultrasound for aortic aneurysm.
• Wound assessment with the WIfI classification (wound, ischaemia, foot infection), and probe-to-bone test and foot radiograph or MRI for osteomyelitis.

Risk factor and cardiovascular modification (all patients)

• Smoking cessation, with behavioural support plus varenicline (0.5 mg daily for 3 days, 0.5 mg twice daily for 4 days, then 1 mg twice daily for 12 weeks), bupropion SR 150 mg daily for 3 days then twice daily, or nicotine replacement.
• High-intensity statin: atorvastatin 40 to 80 mg or rosuvastatin 20 to 40 mg daily, targeting LDL cholesterol below 55 mg/dL (1.4 mmol/L) with at least 50% reduction. Add ezetimibe 10 mg, then a PCSK9 inhibitor (evolocumab 140 mg SC every 2 weeks or alirocumab 75 to 150 mg every 2 weeks) if not at target.
• Antiplatelet: aspirin 75 to 100 mg daily or clopidogrel 75 mg daily.
• Rivaroxaban 2.5 mg twice daily with aspirin 100 mg daily reduces major cardiovascular and limb events in stable symptomatic disease and after revascularisation, with higher bleeding risk. Avoid with high bleeding risk or creatinine clearance below 15 mL/min.
• Blood pressure below 130/80 mmHg, with ACE inhibitor (ramipril 5 to 10 mg daily) as an appropriate first agent.
• Diabetes: HbA1c around 7%, with GLP-1 receptor agonists and SGLT2 inhibitors for cardiovascular benefit. Review SGLT2 inhibitors in patients with active foot ulcers or gangrene.
• Foot care education, daily inspection and appropriate footwear.

Claudication

• Supervised exercise therapy, at least 30 to 60 minutes, three times weekly for 12 weeks or longer, walking to moderate-to-maximal pain, improves maximal walking distance by 50 to 200%. Home-based structured programmes are an alternative.
• Cilostazol 100 mg twice daily, taken 30 minutes before or 2 hours after food, improves walking distance by about 40 to 50%. It is contraindicated in heart failure of any severity, and the dose is 50 mg twice daily with CYP3A4 or CYP2C19 inhibitors such as omeprazole or diltiazem.
• Naftidrofuryl oxalate 100 to 200 mg three times daily, where available. Pentoxifylline 400 mg three times daily has marginal benefit.
• Revascularisation for lifestyle-limiting claudication after 3 months of optimal medical and exercise therapy, where the anatomy offers a durable result.

Chronic limb-threatening ischaemia

• Urgent referral to a vascular team (within days), with revascularisation whenever feasible to save the limb.
• Treatment of infection: amoxicillin-clavulanate 875/125 mg twice daily for mild infection, or piperacillin-tazobactam 4.5 g IV every 6 to 8 hours (with vancomycin if MRSA risk) for moderate to severe infection, with debridement and drainage of abscess before revascularisation.
• Offloading, wound care, glycaemic control, nutrition and pain control with opioids and gabapentin 300 mg at night titrated to 1800 mg/day.
• Intravenous prostanoids (iloprost) or spinal cord stimulation for non-reconstructable disease with rest pain.

Revascularisation

• Endovascular: angioplasty with drug-coated balloons, drug-eluting or bare metal stents. Aortoiliac stenting has excellent patency and is first line for most iliac disease. Infrainguinal disease in short lesions is also treated endovascularly.
• Open surgery: aortobifemoral bypass for extensive aortoiliac disease, femoral to popliteal or tibial bypass using autologous great saphenous vein (patency superior to PTFE), endarterectomy of the common femoral artery, and hybrid procedures.
• Post-procedure antithrombotics: dual antiplatelet therapy (aspirin 75 to 100 mg with clopidogrel 75 mg) for 1 to 6 months after endovascular intervention, then single antiplatelet, or aspirin with rivaroxaban 2.5 mg twice daily. Aspirin or warfarin after vein bypass.
• Surveillance duplex at 1, 3, 6 and 12 months after vein graft, then annually.

Amputation

• Primary amputation for unsalvageable limbs: extensive necrosis, uncontrollable sepsis, or non-reconstructable disease with intractable pain. Below-knee level is preferred when the knee can be preserved. Rehabilitation with prosthesis fitting.
• Minor amputation (toe or transmetatarsal) after revascularisation, with wound healing expected in 3 to 6 months.

Follow-up

• Annual review for symptoms, ABI, foot examination, lipid and glycaemic targets, and cardiovascular events.