VSITE Review - Peripheral Arterial Occlusive Disease (Part One)


Written by Nedal Katib



Welcome back to the VSITE review series here at audible bleeding today, we're excited to bring you part one of a two part series on peripheral arterial, occlusive disease, discussing medical management and intermittent claudication with Dr. Nedal Katip and Dr. Danielle Bajakian.   Dr. Natal Katib is a recently graduated vascular surgeon having just been a fellowship at the Royal Australian college of surgeons.  He is now working at Prince of Wales university hospital and st. Vincent's hospital in Sydney, Australia  And Dr. Danielle Bajakian is an assistant professor of surgery at Columbia university medical center. Where she's also the Columbia site director of the vascular surgery fellowship at the New York Presbyterian Hospitals Cornell and Columbia program in vascular surgery Finally, she’s the site director of the clinical limb Ischemia program at Columbia university medical center. Thanks again for being with us Dr. katib and Dr. Bajakian.


What is PAD and what does it encompass?

Peripheral Arterial Disease encompasses extremity arterial disease but generally is used to describe lower limb arterial occlusive disease. PAOD is a more specific term and this encompasses atherosclerotic disease of the lower limb arteries.

The disease has various presentations on a spectrum of asymptomatic disease to intermittent claudication and finally chronic limb threatening ischemia (CLTI) formerly known as Critical Limb Ischemia (CLI)[1].


What is the underlying pathophysiology of PAOD?

The underlying pathophysiology which results in occlusive arterial disease of the lower limb has somewhat evolved over the last 50 years. While atherosclerosis remains, the main pathological process resulting in occlusive disease, smoking related atherosclerosis has in the last 30 years been confounded with the rising incidence of diabetes and in addition an aging population with progressive arterial disease.

Atherosclerosis, in summary, begins with an injury to the intimal lining of the arterial wall, which can result from smoking, hypertension or advanced age and ultimately a chronic inflammatory reaction resulting in plaque build up and calcification that may result in progressive stenosis and occlusion or plaque rupture with acute occlusion.


What are the risk factors for atherosclerosis?

The best way to categorise risk factors for peripheral arterial disease is into:

1.     Modifiable

2.     Non-Modifiable


·       Smoking

o   The most significant modifiable risk factor for developing peripheral arterial disease

o   Causes Endothelial dysfunction by reducing nitric oxide and triggering reactive-oxygen species.[2]

o   Causes a prothrombotic environment by causing an increase in thromboxane A2 and decreasing Prostacyclin thus overall resulting in an increased prothrombotic environment for platelets.

o   Smoking has a stronger association with Intermittent claudication than with Coronary Artery Disease![3]

·       Diabetes , Metabolic Syndrome and Insulin Resistance

o   Diabetes Mellitus, after smoking, is the most significant modifiable risk factor for developing peripheral arterial disease. Both insulin resistance and hyperinsulinemia are independent risk factors for developing peripheral arterial disease.

o   The Odds Risk for developing PAD in patients with DM ranges from 1.89 to 4.05.

o   An increase in HbA1C by 1% correlates with a 28% increase risk of developing PAD.[4]

·       Hypertension

o   The most common cardiovascular risk factor worldwide.

o   The Incidence of PAD increases to 2.5-fold in patients with Hypertension.[5]

·       Dyslipidemia 

o   A strong association has long been identified as a risk factor for cardiovascular disease.

o   25% cardiovascular event reduction for each 39 mg/dL (1mmol/L) reduction in LDL.[6]

Non Modifiable:

o   Age

o   Age is identified as a risk factor for PAD regardless of gender.

o   Prevalence of PAD increases with age: 15% > 70 years of age.

o   Gender

o   The Framingham Study has found that the risk of developing PAD is doubled in men.

o   Ethnicity

o   The MESA -2000- study showed a higher prevalence of PAD (ABPI <0.9) in African Americans compared to Whites. 7.2% versus 3.6%.


o   Allison et al 2006 JACC. Cross Sectional analysis 6653 subjects all with ABPI assessment revealed a prevalence of PAD (<0.9) of 4%. Non-Hispanic Whites: 3.6%, Asian: 2%, African American: 7.2% and Hispanic: 2.4%. (p<0.01) 



What are the some of the major population-based trials looking at the natural history?

o   The Framingham Heart Study: The original Cohort from the town of Framingham, n=5183 patients followed over time for over 30 years. There have been multiple subsequent recruited populations since. The majority of information we have about risk factors related to cardiovascular health comes from this study.[7]

o   The Rotterdam Study: 1990, Longitudinal Study, >7000 particpants.

o   CVHS – 1989-1999 Longitudinal Study : n>5000 Multicentre Study.

o   MESA – Allison et al 2006 JACC. Cross Sectional analysis 6653 subjects all with ABPI assessment revealed a prevalence of PAD (<0.9) of 4%. Non-Hispanic Whites: 3.6%, Asian: 2%, African American: 7.2% and Hispanic: 2.4%. (p<0.01)

o   The Edinburgh Study: The EAS began as a cross sectional study of 1592 men and women in Edinburgh with the goal of examining the frequency of risk factors for peripheral arterial disease. The subjects were followed over 20 years.[8]


What are the clinical findings of PAOD?

o   Historical data shows the majority of patients with PAD to be Asymptomatic (defined as an ABPI <0.9).

How does Diabetes confound the clinical picture of PAOD?

o   Increasing Incidence of Diabetes world-wide.

o   2.8% in 2000, 4.4% in 2030[9]

o   25% of patients with diabetes develop a DFU at some stage in their lives[10]

o   Limb Loss every 20 seconds world-wide to Diabetes[11]


What’s the pathophysiology of Diabetes and PAOD[12]:

o   Sensory Neuropathy, Motor Neuropathy and Autonomic Neuropathy

o   Structural and Gait abnormalities

o   Arterial disease

§  Large Vessel

§  Small Vessel

§  Both

Given this diverse and confounding pathology the normal progressive history of PAD is somewhat different. What’s most concerning is the neuropathy resulting in initial presentation being ulceration. This results in a lack of a ‘safety net’ where presenting with progressive claudication allows for a period of detection, management and and risk factor modification before they develop tissue loss and are at risk of amputation.


Since 2014 and the publication of WIfI[13] a lot has changed in the way we view PAD leading up to last years new Global Vascular Guidelines on CLTI[14], which as a term has replaced CLI.


What is Intermittent Claudication and the classic patient presentation?

                  The original population studies we mentioned determined the epidemiology and natural history of Intermittent Claudication based on historically validated and widely accepted questionnaires, namely the Rose[15] (which later was adopted by the WHO) and subsequently the Edinburgh questionnaire[16].

All questionnaires are based on a number of key diagnostic clinical factors that define claudication., they are:

o   Onset

o   Calf involvement

o   Reproducibility

o   Relief with Rest

o   Not occurring at Rest

The progression historically graded by Fontaine (1954)[17] followed by the Rutherford Grading System (1986)[18]


Rutherford et al. Ad Hoc Committee on Reporting Standards, SVS/North American Chapter ISCVS:


Clinical Description


Asymptomatic -no haemodynamic significant occlusive disease


Mild Claudication


Moderate Claudication


Severe Claudication


Ischaemic Rest Pain


Minor Tissue Loss


Major Tissue Loss




What is involved in the work up of patients with PAOD/Intermittent Claudication?

o   History / Clinical Examination

SVS Guidelines:

“We recommend using ABI as the first-line non-invasive test to establish a diagnosis of PAD in individuals with symptoms or signs suggestive of disease. When the ABI is borderline or normal (>0.9) and symptoms of claudication are suggestive, we recommend an exercise ABI.” –

Grade 1 Level of Evidence A

o   ABPI

o   Exercise ABPI

o   Ultrasound


What is an ABPI and how is it measured?

The AHA came out with guidelines on how to perform an ABI and to standardise the method to allow for more comparable results from studies.

Divide the higher of the PT or DP pressure by the higher of the right or left Brachial SBP (Class 1 Level of Evidence A)[19]

Sensitivity and Specificity both >95% (when ABPI cut off </=0.9 – in detecting >/= 50% stenosis)[20] [21]


Interpreting ABPI






Mild to Moderate PAD


Severe PAD



What is Exercise ABPI studies?

Constant Load Testing – (unlike the Graded Test – Bruce Protocol)

Walking distance has been shown to correlate with level and severity of POAD.[22]


What is the ultrasound duplex criteria for defining PAOD?


Stenosis Category

Peak Systolic Velocity

Velocity Ratio

Distal Artery Spectral Waveform




Triphasic, Normal PSV




Triphasic, Normal PSV




Monophasic, reduced PSV




Damped, monophasic, reduced PSV


No Flow – B -mode, Terminal Thump



(above taken from Rutherford 9th edition – JP Eiberg et al – Duplex Ultrasound Scanning of peripheral arterial disease in the lower limb. Eur J Vasc Endovasc Surg. 2010)


What Guidelines are there pertaining to PAD Management.

SVS Guidelines (2015)

o   The SVS published the SVS practice guidelines for atherosclerotic occlusive disease of the lower extremities: Management of asymptomatic disease and claudicationConte and Pomposelli et al. JVS 2015

Other Guidelines:

o   TASC 1 -2

o   European Guidelines (2017)

o   AHA Guidelines (last update 2016)

What is the initial management of Asymptomatic Patients with PAD?

1.     Smoking Cessation – Multidisciplinary comprehensive smoking cessation interventions – repeatedly until tobacco use has stopped (Grade A – 1)

2.     Intervention is not only not recommended, but invasive treatment is recommended against, in the absence of symptoms (Grade A -1)



How can we medically (non-invasively) manage Asymptomatic PAOD based on the SVS Guidelines?

o   Antiplatelet Therapy

o   The Aspirin for Asymptomatic Atherosclerosis Trial – n=3350, aspirin versus placebo. 8 years follow up no difference in events[23] – therefore benefit unknown

o   Statin Therapy

o   The Heart Protection Study[24] - this study looked at Statins in patients with PAD but not completely asymptomatic, they had other risk factors such as diabetes, IHD, cerebral disease or hypertension. Without these risk factors Statin therapy benefit unsure.

o   However, the AHA from the Framingham Study does recommend using Statins if 10-year risk based on risk calculators >7.5% (which would be positive if PAD present).

o   Exercise and Limb Function

o   No clear evidence that physical therapy improves QoL

o   Surveillance

o   No benefit from US surveillance, unclear benefit of ABPI surveillance.


How can we medically manage Intermittent Claudication based on the SVS Guidelines?

o   Smoking Cessation – Multidisciplinary comprehensive smoking cessation interventions – repeatedly until tobacco use has stopped (Grade A – 1)

o   Dyslipidaemia: Statin Therapy Recommended – most recent evidence on lipid therapy has suggested focussing on reducing 10-year cardiovascular event risk rather than specifically reducing lipid levels. (Grade 1-A)

o   Statin Therapy – Aspirin therapy (75-325mg daily) is recommended to reduce cardiovascular events in patients with PAD (Grade 1-Level A)

o   This is based on Antithrombotic Trialists’ Collaboration. Collaborative Meta-analysis – BMJ 2002

o   There is evidence that Clopidogrel 75mg compared to Aspirin is better in event reduction (CAPRIE)[25] – replacing Aspirin with Clopidogrel Grade 1-Level B)

o   Diabetes Mellitus – Optimisation of HbA1C < 7% (Grade 1-Level B)

o   Hypertension – Indicated B-Blockers for hypertension (Grade 1-Level B) (there’s no evidence that Beta Blockers worsens IC)

o   Homocysteine – Recommendation against Folic Acid and Vit B12 ( Grade 2 – C)


To improve Limb Function in patients with IC:

o   Cilostozol use – IC without CHF – 3-month Trial (Grade 2 - A)

o   If unable to tolerate Cilostozol – Pentoxifylline (400mg TDS) (Grade 2 – B)

o   Based on Meta-analysis 26 trials[26]

o   Exercise Therapy

o   First Line Therapy recommended SEP: minimum three times / week (30-60 min/session) for at least 12 weeks (Grade 1 Level A)

o   Meta-analysis of 22 RCT’s[27]: Placebo versus exercise: Walking Time, Walking Ability, Pain Free Walking and maximum walking distance improves. BUT no difference in ABPI, Mortality or amputation.

o   Meta- Analysis of 14RCT’s[28]: SEP better than Non-Supervised Programs.


What is the management for patients with Intermittent Claudication?

o   Patient Selection for Intervention:

o   20-30% of patients with IC who adhere to risk factor modification will have progressive symptoms that will eventually be treated with intervention.

o   Patient selection should be based on QoL and functional impairment in an active person (loss of ability to perform occupation or that limits basic activities of daily living) rather than haemodynamic (ABPI or US) or anatomical disease progression/severity.

o   Always remember multifactorial causes of immobility – particularly in the elderly.

o   SVS recommends that invasive therapy for IC have a >50% likelihood of sustained clinical improvement for at least 2 years.

o   Anatomical Selection:

o   Aortoiliac Disease:

§  Previous TASC Classification has attempted to categorise anatomy of disease and subsequent recommendation of Endovascular versus open surgery. But as the authors of the SVS guidelines highlight, “improvements in technology and endovascular techniques have resulted in EVT replacing open surgical bypass as a primary treatment for both focal and advanced AIOD in many cases.”

§  The majority of evidence is non randomized and meta analyses of non-randomized series.

§  Endovascular procedures over open surgery for focal AIOD causing IC. (Grade 1 Evidence B)

§  Endovascular interventions as first line for CIA or EIZ occlusive disease-causing IC. (Grade 1 Level B)

§  Hybrid recommended for Iliac disease involving CFA. (Grade 1 Level B)

§  Direct Surgical reconstruction (bypass, endarterectomy) in patients with reasonable surgical risk and diffuse AIOD not amenable to endovascular approach, after one or more failed attempts at EVT, or combined occlusive and aneurysmal disease. (Grade 1 Evidence B)

o   Infrainguinal Disease:

§  When you look at the historical data comparing all EVT together they are less durable than surgical bypass, especially when there’s diffuse or long segments of occlusion/multilevel infra inguinal disease.

§  Most recommendations are based on low level evidence when comparing EVT versus Open Surgery

§  Focal + Not involving SFA origin = EVT (Grade 1 Level C)

§  SFA 5-15cm, self-expanding stent (with or without paclitaxel) (Grade 1 Level B) – NB: (This was in 2015 pre Katsanos Paper)

§  Recommend against infrapopliteal treatment for IC (Grade 1 Level C)

§  Initial Surgical Bypass (with vein: Grade 1 Level a): If

·       Diffuse FP disease

·       Small Calibre <5mm

·       Extensive calcification in SFA

·       Average or low operative risk

o   (Grade 1 Level B)



[1] Aboyans V. Ricco JB, Bartelink MEL, Bjorck N, Brodmann M, Cohnert T, et al. Editors choice – 2017 ECS guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European society of vascular surgery (ESVS). Eur J Vasc Endovasc Surg 2018;55:305-68

[2] The Health Consequences of Smoking-50 Years of Progress: A Report of the Surgeon General. Atlanta

[3] T GordonWB KannelPredisposition to atherosclerosis in the head, heart, and legs. The Framingham study. JAMA. 221 (7):661-666 1972

[4] Adler A. UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral arterial disease in type 2 diabetes. Diabetes care 2002;25:894-9.

[5] Kannel WB, McGee DL. Update on some epidemiologic features of intermittent claudication: the Framingham study. J Am Geriatric Soc 1985;33:13-18.

[6] The Heart Protection Study excerpt from Rutherford Vascular 7th Edition section 58.

[7] https://www.framinghamheartstudy.org/fhs-about

[8] https://www.ed.ac.uk/usher/molecular-epidemiology/our-studies/the-edinburgh-artery-study

[9] DFCon 11 Bakker DFCon.com, Boulton, The Lancet Nov 2005

[10] Singh, Armstrong Lipsy, J Amer Med Assoc 2005

[11] DFCon11, Bakker (after Boulton), DFCon.com ,Boulton, The Lancet (cover), Nov. 2005

[12] Chapter 26 Pathophysiology and Principles of Management of the Diabetic Foot. Armstrong, Fisher, White and Mills. Mechanisms of Vascular Disease Fitridge and Thompson. 

[13] Joesph Mills et al. The Society for Vascular Surgery Lower Extremity Limb Classification System: Risk stratification based on Wound, Ischemia and foot Infection (WIfI) JVS Jan 2014.

[14]Conte MS et al. Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia Eur J Vasc Endovasc Surg 2019

[15] Rose G.A. et al. The Diagnosis of Ischaemic Heart Pain and Intermittent Claudication in Field Surveys. Bull. Wld. Hlth. Org. 1962

[16] Leng G, Fowkes F. The Edinburgh claudication questionnaire: an improved version of the WHO/Rose questionnaire for use in the epidemiological surveys. J Clin Epidemiol 1992; 45: 1101-1109

[17] Fontaine R et al Surgical treatemnet of peripheral circulation disorders. Held Chir Acta. 1954.

[18] Ad Hoc Committee on Reporting Standards, SVS/North American Chapter ISCVS. Rutherford et al J Vasc Surg 1986.

[19] Aboyans and Criqui et al AHA Scientific Statement Measurement and interpretation of the Ankle-Brachial Index 2012

[20] Yao et al Ankle Systolic Pressure Measurements in the Arterial Disease Affecting the Lower Extremities.

[21] Ouriel et al Critical evaluation of stress testing in the diagnosis of peripheral vascular disease. Surgery 1982

[22] Rutherford Eight Edition-modified from Strandness DE Jr et al Hemodynamics for Surgeons, 1975

[23] Fowler FG et al Aspirin for prevention of cardiovascular events in general population screened for a low ankle brachial index: a randomised controlled trial. JAMA 2010;303:841-8

[24] Heart Protection Study Collaborative Group. 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

[25] CAPRIE steering committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events. Lancet 1996;348:1329-39

[26] (J.W. Steven et al. Systematic review of the efiicacy of cilostozol, naftidrofuryl oxalate and pentoxifylline for the treatment of intermittent claudication. BJS October 2012)

[27] Watson L, Ellis B, Leng GC. Exercise for intermittent claudication. Cochrane Database Syst Rev 2008;(4):CD000990

[28] Fokkenrood HJ, Bendermacher BL, Lauret GJ, Willigendael EM, Prins MH, Teijink JA. Supervised exercise therapy versus non-supervised exercise therapy for intermittent claudication. Cochrane Database Syst Rev 2013;8:CD005263