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Peripheral Arterial Disease (PAD)

Causes and risk factors for peripheral arterial disease (PAD), as well as diagnosis and current treatments including the Ranger™ drug-coated balloon (DCB).

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].

Epidemiology of peripheral arterial disease

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]

Regional number of people with PAD and contributing age groups in 2015

(Figure 1)

Figure 1: Regional number of people with PAD and contributing age groups in 2015[6]
People with peripheral artery disease were restricted to those older than 25 years given the study context. AFR=African Region. AMR=Region of the Americas. EMR=Eastern Mediterranean Region. EUR=European Region. HICs=high-income countries. LMICs=Low-income and middle-income countries. PAD=peripheral artery disease. SEAR=South-East Asia Region. WPR=Western Pacific Region.

Symptoms of peripheral arterial disease (PAD)

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

Diagnosis of peripheral arterial disease (PAD) 

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].

Risk factors for peripheral arterial disease (PAD)

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].

Diagnostic algorithm for peripheral arterial disease

Diagnostic algorithm for peripheral arterial disease

(Figure 2)

ABI indicates ankle-brachial index; CLI, critical limb ischemia; CTA, computed tomography angiography; GDMT, guideline-directed management and therapy; MRA, magnetic resonance angiography; PAD, peripheral artery disease; and TBI, toe-brachial index. 
Green = Strong guideline recommendation; Yellow = Moderate guideline recommendation.

Prognosis for peripheral arterial disease (PAD)

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]

Management of peripheral arterial disease (PAD)

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

Revascularization for peripheral arterial disease (PAD)

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]

Paclitaxel treatments including the Ranger™ drug-coated balloon

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, 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). 

COMPARE trial: low-dose DCB Ranger vs. higher-dose DCB IN.PACT

COMPARE trial: low-dose DCB Ranger vs. higher-dose DCB IN.PACT

(Figure 3)

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 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].

IMPERIAL trial at 2 years: reduced stenosis in complex PAD

IMPERIAL trial at 2 years: reduced stenosis in complex PAD

IMPERIAL trial at 2 years: reduced stenosis in complex PAD

IMPERIAL trial at 2 years: reduced stenosis in complex PAD

Do you have more questions about peripheral arterial disease? Check out our FAQ


[1] Tran B. Assessment and management of peripheral arterial disease: what every cardiologist should know. Heart 2021;0:1-9.

[2] Curry SJ, Krist AH, Owens DK, et al. Screening for peripheral artery disease and cardiovascular disease risk assessment with the ankle-brachial index. JAMA 2018;320:177.

[3]  Song P, Rudan D, Zhu Y, Fowkes FJI, Rahimi K, Fowkes FGR, Rudan I. Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis. Lancet Glob Health 2019;7:e1020-30.

[4] Curry et al., Screening.

[5] Criqui MH, Aboyans V. Epidemiology of peripheral artery disease. Circulation Res 2015;116:1509-26.

[6] Song P, Rudan D, Zhu Y, et al. Global, regional, and national prevalence and risk factors for peripheral artery disease in 2015: an updated systematic review and analysis. Lancet Glob Health 2019;

[7]: e1020–30.

[7] Criqui & Aboyans. Epidemiology.

[8] Mayo Clinic. Symptoms. In: Peripheral artery disease. Available from https://www.mayoclinic.org/diseases-conditions/peripheral-artery-disease/symptoms-causes/syc-20350557 (Last accessed 4 Oct 2021.)

[9] Tran, Assessment and Management.

[10] Criqui & Aboyans. Epidemiology.

[11] National Institute for Health and Care Excellence (NICE). (2012). What are the risk factors? In: Peripheral arterial disease. Clinical Knowledge Summaries. Available: https://cks.nice.org.uk/topics/peripheral-arterial-disease/background-information/risk-factors/ (Last updated: 11 December 2020.)

[12] Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: executive summary. Vasc Med 2017;22:NP1-N43.

[13] Nehler MR et al. J VascSurg. 2014;60(3):686-95.e2.

[14] Reed GW et al. J Am Heart Assoc. 2016 20;5(5). pii: e003168.

[15] Norgren L et al. J Vasc Surg 2007;45:S5A-S67A..

[16] Abu Dabrh AM et al. J Vasc Surg. 2015;62(6):1642-51.e3.

[17] Curry et al., Screening.

[18] Gerhard-Herman et al., 2016 AHA/ACC Guideline.

[19] Kokkinidis DG, Armstrong EJ. Current developments in endovascular therapy of peripheral vascular disease. J Thorac Dis 2020;12:1681-1694.

[20] Schillinger M, Minar E. Percutaneous treatment of peripheral artery disease: novel techniques. Circulation 2012;126:2433-40.

[21] Ibid.

[22] Lindquist J, Schramm K. Drug-eluting balloons and drug-eluting stents in the treatment of peripheral vascular disease. Semin Intervent Radiol 2018;35:443-52.

[23] Gray WA, Keirse K, Soga Y, Benko A, et al; IMPERIAL investigators. A polymer-coated, paclitaxel-eluting stent (Eluvia) versus a polymer-free, paclitaxel-coated stent (Zilver PTX) for endovascular femoropopliteal intervention (IMPERIAL): a randomised, non-inferiority trial. Lancet 2018;392:1541-51.

[24] Steiner S, Schmidt A, Zeller T, et al. COMPARE: prospective, randomized, non-inferiority trial of high- vs. low-dose paclitaxel drug-coated balloons for femoropopliteal interventions. Eur Heart J 2020;41:2541-2552.

[25] Gray et al., IMPERIAL investigators.

[26] Lindquist et al., Drug-eluting balloons.

[27] Gray et al., IMPERIAL investigators.

[28] Kokkinidis et al., Current developments.

[29] Secemsky EA, Shen C, Schermerhorn M, et al. Longitudinal assessment of safety of femoropopliteal endovascular treatment with paclitaxel-coated devices among medicare beneficiaries: The SAFE-PAD Study. JAMA Intern Med 2021;181:1071-80.

[30] Müller-Hülsbeck S, Benko A, Soga Y, et al. Two-year efficacy and safety results from the imperial randomized study of the Eluvia polymer-coated drug-eluting stent and the Zilver PTX polymer-free drug-coated stent. Cardiovasc Intervent Radiol 2021;44:368-75.

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