Peripheral Arterial Disease (PAD)

Peripheral arterial disease (PAD), also known as peripheral artery disease, is usually a sign of atherosclerosis. It’s a major cardiovascular disease (CVD) that often overlaps with ischaemic heart disease^[1]. This progressive disorder is characterized by partial or complete obstruction of one or more of the peripheral arteries. The resulting reduction in blood flow can impair walking, and in severe cases, can lead to tissue loss, infection, and limb amputation^[2].

Peripheral arterial disease (PAD) was estimated in 2015 to affect more than 236 million adults aged 25 years and older worldwide^[3], but the true prevalence of PAD is unknown. More than 50% of people with a low ankle brachial index (ABI) (see below) have either no symptoms or atypical ones, such as pain beginning at rest^[4]. The occurrence of PAD also increases sharply with age^[5]. 

The most characteristic symptom of PAD is leg pain brought on by walking and relieved by rest. Known as intermittent claudication (IC), the pain can occur in the buttock, hip, thigh or calf, and varies from mild to debilitating^[7]. 

Other symptoms of PAD include^[8]:

• Leg numbness or weakness
• Coldness in the lower leg or foot
• Sores on the toes, feet or legs that won't heal
• Changes in leg colour
• Hair loss or slower hair growth on the feet and legs
• Slower toenail growth
• Shiny skin on legs
• No pulse or a weak pulse in legs or feet
• Erectile dysfunction
• Pain using arms

The ankle brachial index (ABI) is a simple tool for diagnosing lower extremity PAD. An ABI of <0.90 is indicative of obstructive disease, while an elevated ABI (<0.9) suggests arterial stiffening. 

Imaging with ultrasound, MRI or angiography are used for diagnosis^[9].

The risk factors for PAD are similar to those for other CVD and include: 

• Smoking
• Diabetes
• Advanced age
• Hypertension
• Hypercholesterolemia
• High serum homocysteine
• Chronic kidney disease

The most strongly associated of the above risk factors are smoking and diabetes mellitus^[10,11].

Someone with PAD caused by atherosclerosis is also at risk of critical limb ischemia (CLI). This begins with open sores that don't heal, or an injury/infection of the legs or feet, and may progress to tissue death and amputation. 

• More than 10% of patients with PAD develop CLI^[13]
  
• 56% of patients hospitalised with CLI are readmitted within ~1 year^[14]
• Patients aged ≥50 years have a 25% risk of death after one year and a 30% chance of amputation^[15,16]

Patients with symptomatic PAD initially manage the disease with medical and structured exercise therapies^[17]. The patient should be assessed for previously undiagnosed cardiovascular disease (CVD) conditions or risk factors and treated for secondary prevention of CVD, including^[18]:

• Smoking cessation
• Obesity – diet, weight management, exercise
• Hypercholesterolemia – lipid modification and statin therapy
• Diabetes – glycemic control
• Hypertension – antihypertensives
• Thrombus prevention – antiplatelet therapy

Patients with debilitating symptoms that don’t respond to risk factor modification, exercise or medical therapy may be offered endovascular and/or surgical intervention. Endovascular treatment is the first line therapy in most cases^[19]. 

Although percutaneous transluminal angioplasty (PTCA) initially had a high success rate, its use was limited by high, short-term restenosis rates of
up to 60%^[20]

The development of modern bare metal stents, nitinol self-expanding stents, and cobalt-chromium balloon-expanding stents resulted in superior patency rates. However, there remained a high restenosis rate of 30-50% within 12-24 months. In addition, there were long-term complications of thrombus and stent fracture^[21,22]

The introduction of antiproliferative drug-coated balloons (DCB) and drug-eluting stents (DES) aimed to generate long-term patency without the drawbacks of PTCA and bare metal stents.

Drug-coated balloons, such as Ranger,^TM deliver the antiproliferative therapy - paclitaxel - in a single burst to the arterial wall at the time of intervention, with paclitaxel remaining long enough in the tissue to impact patency^[23]. 

Ranger achieved similar patency at 2 years in the first head-to-head comparison trial of two DCBs (Figure 3), in which low-dose DCB Ranger (2 μg/mm²) was compared to higher-dose IN.PACT DCB (3.5 μg/mm²). 

However, balloon-based drug delivery is unable to scaffold the artery, which is often required for long lesions or calcified femoropopliteal disease^[25]. Drug-eluting stents combine the advantage of the mechanical scaffold of the stent with the antiproliferative effect of paclitaxel in inhibiting post-intervention inflammation and neointimal hyperplasia^[26]. 

Compared with the DES Zilver PTX, Eluvia^TM provides the additional benefit of providing sustained-release paclitaxel over the long term. In this way, Eluvia ensures paclitaxel is present at the time of peak restenosis^[27], contributing to the consistently low 2-year clinically driven target lesion revascularization rate (CD-TLR) across complex lesions (Figure 4).

Following concern about the long-term safety of paclitaxel in drug-coated devices (DCDs) - arising from a meta-analysis of first-generation DCBs and DES - initial results from the SAFE-PAD study, designed with FDA involvement, have shown that DCDs are not inferior to non-DCDs, in respect to mortality through a median follow-up of 2.72 years^[28,29].