15  Medical Management and Claudication

Authors: Nedal Katib and Danielle Bajakian

Contributors: Eilidh Gunn

15.1 Pathogenesis of peripheral arterial disease

What is Peripheral Artery Occlusive Disease (PAD)?

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

The disease has a step-wise spectrum of presentations from asymptomatic disease to intermittent claudication and finally chronic limb threatening ischemia (CLTI) formerly known as Critical Limb Ischemia (CLI) (Aboyans et al. 2018)

What is the underlying pathophysiology of PAD?

The understanding of the underlying pathophysiology which results in occlusive arterial disease of the lower limb has evolved over the last 50 years. Atherosclerosis remains the main pathological process resulting in occlusive disease with smoking being the primary modifiable risk factor.
Although with the rising incidence of diabetes a second population of patients with a significant PAD burden has developed.

Atherosclerosis begins with an injury to the intimal lining of the arterial wall, which, for example, can result from smoking, hypertension, hyperglycemia, or advanced age. Repeated injury leads to a chronic inflammatory process resulting in the uptake and oxidation of LDL, resulting in foam cells.(Hiltunen et al. 1998; Tsimikas et al. 2005; Witztum 1994) Foam cells result when unregulated scavenger receptors promote uptake of oxidized LDL by macrophages and smooth muscle cells. These foam cells become necrotic and then create the central core of the atheroma.(Owens 2019) This oxidized LDL form into intimal plaque, build up and calcification that may result in progressive vessel stenosis and subsequent occlusion, or plaque rupture with acute occlusion.

Atherosclerosis is particularly prone to developing at sites of arterial bifurcation (i.e. carotid bifurcation, femoral bifurcation) because turbulent flow and low laminar shear stress results in the down regulation of eNOS and NO production. This in turn increases V-CAM-1 and reduces inhibition of KF-kB (resulting in it’s elevation.(Owens 2019)

Take a Listen

Check out our episode with Dr. Melina Kibbe, who is actively researching the role of nitric oxide in vascular pathology.

AHA lesion classification - defines plaque risk for rupture/thrombosis. Extrapolated from the coronary artery disease literature.(McGill et al. 2000)
Classification Description
0 Normal artery
1 Initial atherosclerotic lesion
2 Fatty streak
3 Fatty plaque/raised fatty streak
4 Atheroma
5 Fibroatheroma - development of fibrotic cap, vascularization or calcium
6 Complicated lesion

Since the publication of WIfI in 2014 a lot has changed in the way we view PAD leading up to last years new Global Vascular Guidelines on CLTI, which as a term has replaced CLI (see Chapter 16). (Mills et al. 2014; Conte et al. 2019)

15.1.1 Risk Factors

What are the risk factors for atherosclerosis?

Modifiable:

  1. Smoking

    • The most significant modifiable risk factor for developing peripheral arterial disease.

    • Causes endothelial dysfunction by reducing nitric oxide and triggering reactive-oxygen species, platelet adhesion, and permeability of endothelial surface to fibrinogen.(United States Surgeon General 2014; Hackam and Anand 2003).

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

    • Smoking has a stronger association with Intermittent claudication than with Coronary Artery Disease(Gordon and Kannel 1972)

  2. Diabetes, Metabolic Syndrome, and Insulin Resistance

    • 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. Increasing Incidence of Diabetes world-wide.(Boulton et al. 2005)

      • 2.8% of the global population affected by diabetes in 2000, estimated to be 4.4% by 2030.

      • 25% of patients with diabetes develop a diabetic foot ulcer (DFU), at some stage in their lives.

      • Diabetic foot ulcers have a very high rate of recurrence with 40% of patients developing a new ulcer within 12 months of healing a previous ulcer. (D. G. Armstrong, Boulton, and Bus 2017)

      • Limb Loss occurs every 20 seconds world-wide to due to Diabetes related PAD or infection.

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

    • Factors associated with developing PAD in diabetics include female gender, chronicity/severity of DM, insulin dependence, African American race or Hispanic ethnicity.(Regensteiner et al. 2015; Selvin et al. 2006; Wattanakit et al. 2005) An increase in HbA1C by 1% correlates with a 28% increase risk of developing PAD. (Amanda I. Adler et al. 2002)

    • The following mechanisms may lead to PAD in diabetics

      • Hyperglycemia reduces bioavailability of NO, which is a vasodilator, enhances endothelial function, and inhibits both platelet activation and smooth muscle migration.(Higashi et al. 2009)

      • Hyperglycemia activates protein kinase C and thus accumulation of mitochondrial ROS and prostanoids.(Geraldes and King 2010)

      • Endothelial dysfunction leads to increased endothelin-1 and vasoconstriction.(Ahlborg et al. 2007)

    • Given the pathological effect of diabetes upon multiple structures and systems the normal progressive history of diabetes related PAD is somewhat different to smoking related PAD. Clinically due to the combined effect of peripheral neuropathy and microvascular arterial disease, foot ulceration for many patients tends to be the initial presentation. 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, leading to poor outcomes and greater morbidity and mortality. (D. L. Armstrong et al. 2012)

      • Neuropathy. The loss of the basic nociceptive mechanisms in the foot among diabetics, presents as a loss of protective sensation (LOPS). Neuropathy can be divided into three types:

        • Sensory: “stocking-glove” distribution

        • Motor: Intrinsic muscle wasting – resulting in deformities

        • Autonomic: Sympathetic nervous system pathology

      • Structural deformities and gait disturbances

      • Arterial disease of large and small vessels.

        • Large Vessel

        • Small Vessel

        • Both

      • Foot infection(Bandyk 2018; KAYSSI, ROGERS, and NEVILLE 2019; Lepäntalo et al. 2011)

  3. Hypertension

  4. Dyslipidemia

Non-Modifiable:

  1. Age

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

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

  2. Gender

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

  3. Race and Ethnicity

    • The MultiEnthic Study on Atherosclerosis (MESA) study showed a higher prevalence of PAD (ABPI <0.9) in African Americans compared to Whites. 7.2% versus 3.6%. (Bild 2002)

    • 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) (Allison et al. 2006)

  4. Family History

    • Family history of atherosclerotic disease increases an individuals risk of atherosclerotic disease themselves.

15.1.2 Landmark Studies

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

  1. 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. (Mahmood et al. 2014)

  2. The Rotterdam Study: 1990, Longitudinal Study, >7000 participants.(Ikram et al. 2017)

  3. CVHS: 1989-1999 Longitudinal Study : n>5000 Multicenter Study.

  4. MESA: 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) (Allison et al. 2006)

  5. 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. (F. G. R. Fowkes et al. 1991)

15.2 Intermittent Claudication

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 (Rose 1962) (which later was adopted by the WHO) and subsequently the Edinburgh questionnaire. (Lend and Fowkes 1992).

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

  • Onset

  • Calf Involvement

  • Reproducibility

  • Relief with Rest

  • Not Occurring at Rest

The progression of intermittent claudication was historically graded by Fontaine (1954) (Fontaine, Kim, and Kieny 1954) followed by the Rutherford Grading System (1986, Revised 1997) (Rutherford et al. 1997)

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

Grade Category Clinical Description
0 0 A symptomatic - no hemodynamic significant occlusive disease
I 1 Mild Claudication
I 2 Moderate Claudication
I 3 Severe Claudication
II 4 Ischemic Rest Pain
III 5 Minor Tissue Loss
III 6 Major Tissue Loss

Leriche Syndrome - Is a clinical triad of: claudication (buttock, thigh, and calf), impotence, and decreased lower limb pulses, which signifies aortoiliac occlusive disease. (Frederick, Newman, and Kohlwes 2010; Leriche and Morel 1948; Setacci et al. 2012)

Neurogenic Claudication - Differentiating neurogenic claudication from vasculogenic claudication can be difficult. Vasculogenic claudication is relieved by cessation of ambulation and mostly affects a unilateral calf. Neurogenic improves with postural changes, more often bilateral and affects the thighs. (Nadeau et al. 2013)

15.2.1 Evaluation

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

SVS Guidelines:

“We recommend using ABPI 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 ABPI.”(Conte, Pomposelli, Clair, Geraghty, McKinsey, Mills, Moneta, Murad, Powell, Reed, and al. 2015)

Grade 1 Level of Evidence A

  • ABPI

  • Exercise ABPI

  • Ultrasound

What is an ABPI and how is it measured?

The AHA released guidelines on how to perform an ABPI in an attempt to standardize 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) (Aboyans et al. 2012)

Sensitivity and Specificity both >95% (when ABPI cut off </=0.9 – in detecting >/= 50% stenosis) (Yao, Hobbs, and Irivne 2005; Ouriel et al. 1982)

Interpretation of ABPIs.
ABPI Interpretation
>1.4 Non-compressible
>0.9-1.39 Normal
0.5-0.9 Mild to Mod PAD
0.0-0.5 Severe PAD

Patients with diabetes may have non-compressible tibial vessels and therefore toe pressures can be particularly useful in this population.

Segmental pulse volume recordings (PVR) can provide information about the quality of perfusion at the level of the thigh or calf helping to localize the likely level of occlusive disease.

What are Exercise ABPI studies?

Constant Load Testing – (unlike the Graded Test – Bruce Protocol used in testing for coronary artery disease).

The physiological changes in ABPI related to exercise are due to the fact that exercise increases SBP and decreases SVR and, therefore, will affect flow through a stenosis making it more physiologically relevant during exercise and result in a decreased pressure in the lower extremity. (Nicolaï et al. 2009; Alqahtani et al. 2018)

Walking distance has been shown to correlate with level and severity of POAD. (Strandness and Sumner 1975)

Furthermore patients with single level iliac disease may present with buttock/thigh claudication with preserved pulses. Exercise treadmill ABPI is particularly useful in determining the severity of disease in these patients. (Aboyans et al. 2010) For more on exercise testing see Section 20.5

What is the ultrasound duplex criteria for defining PAD?

Stenosis Category Peak Systolic Velocity Velocity Ratio Distal Artery Spectral Waveform
Normal <150 <1.5 Triphasic, Normal PSV
30-49% 150-200 1.5-2 Triphasic, Normal PSV
50-75% 200-400 2-4 Monophasic, reduced PSV
>75% >400 >4 Damped, monophasic, reduced PSV
Occlusion No Flow – B -mode, Terminal Thump NA NA

Adapted from Stone and Hass. Vascular Laboratory: Arterial Duplex Scanning. Rutherford’s Vascular Surgery and Endovascular Therapy. 2019.(Stone and Hass 2019)

What Guidelines are there pertaining to PAD Management.

SVS Guidelines (2015)

The SVS published the SVS practice guidelines for atherosclerotic occlusive disease of the lower extremities: Management of asymptomatic disease and claudication. Conte and Pomposelli et al. JVS 2015 (Conte, Pomposelli, Clair, Geraghty, McKinsey, Mills, Moneta, Murad, Powell, Reed, Schanzer, et al. 2015)

Additional Guidelines

Take a Listen

Check out our episode with Dr. Leila Mureebe, where we briefly discuss her role in the multidisciplinary development of the AHA/ACC guidelines.

15.2.2 Management

15.2.2.1 Medical Management

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) First line therapy is behavioral therapy + varenicline/bupropion or nicotine replacement therapy (NRT) per EAGLES trial.(Anthenelli et al. 2016; Vogeler, McClain, and Evoy 2016)

    • Preloading with varenicline (4 weeks) or bupropion (5-7d) prior to quitting has demonstrated higher abstinence at 12w.(Ratchford and Black 2011)

    • NRT is preferred if rapid onset of action is needed.(Thomsen, Villebro, and Møller 2014) However, contraindicated in setting of recent MI, severe angina, or life threatening arrhythmias.

  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 manage asymptomatic PAD based on the SVS and AHA Guidelines?

  • Anti-Platelet Therapy

    • The Aspirin for Asymptomatic Atherosclerosis Trial – n=3350, aspirin versus placebo. 8 years follow up no difference in events (F. Gerald R. Fowkes 2010) – therefore benefit unknown

  • Statin Therapy

    • The Heart Protection Study (H. P. S. C. Group 2007) - this study looked at statins in patients with PAD but not completely asymptomatic, they had other risk factors such as diabetes, IHD, cerebrovascular disease, or hypertension. Without these risk factors the benefit of Statin therapy remains unclear.

    • 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).

    • Statins are particularly useful for risk reduction of cardiovascular events in diabetics.(Collaborators et al. 2008; Colhoun et al. 2004; Stamler et al. 1993)

    • Statin-associated muscle symptoms (SAMS) is the most common side effect and occurrence has been reported as high as 30% in some cohorts.(Keen et al. 2014) Other side effects are rare (1.5-5% of patients) and include DM2 new onset, neurocognitive effects, hepatotoxicity, renal toxicity and pancreatitis.(Bitzur et al. 2013; Saxon and Eckel 2016; Ward, Watts, and Eckel 2019)

  • Exercise and Limb Function

    • No clear evidence that physical therapy improves the patient outcomes or quality of life.

  • Surveillance

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

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

  • Smoking Cessation: As in with asymptomatic disease above, multidisciplinary comprehensive smoking cessation interventions – repeatedly until tobacco use has stopped (Grade A – 1)

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

  • Anti-Platelet Therapy: Aspirin therapy (75-325mg daily) is recommended to reduce cardiovascular events in patients with PAD (Grade 1-Level A) (Antithrombotic Trialists’Collaboration 2002; Antithrombotic Trialists’(ATT) Collaboration et al. 2009)

    • Literature reviews find benefits in secondary prevention with antiplatelet monotherapy (aspirin or clopidogrel) in symptomatic PAD.(Banerjee et al. 2015) Some initial studies did demonstrate benefit from vorapaxar as well.(Rooke et al. 2013)
    • There is evidence that Clopidogrel 75mg compared to Aspirin is better in event reduction. (CAPRIE)(Committee 1996)– replacing Aspirin with Clopidogrel (Grade 1-Level B)
    • Recent evidence from the COMPASS trial has suggested that the addition of low dose rivaroxaban (2.5mg BID) to aspirin (100mg daily) has lower MALE, composite endpoint of cardiovascular death, stroke and MI. Subgroup analysis suggested clopidogrel may be better with reduced risk of GI bleed and MACE.(Anand et al. 2018; Eikelboom et al. 2017)

  • Diabetes Mellitus: Optimization of HbA1C < 7% (Grade 1-Level B)(Lajoie 2019)

  • Hypertension: Indicated B-Blockers for hypertension. (Grade 1-Level B)

    • There’s no evidence that beta blockers worsen the symptoms of intermittent claudication, but the patients should be monitored for episodes of hypotension

    • Initiation of beta-blockers in the immediate preoperative period is associated with worse outcomes.(Blessberger et al. 2018; P. S. Group et al. 2008)

    • ACE Inhibitors are first line in patients with heart failure, diabetes or kidney disease but should be avoided in patients with renal artery stenosis (RAS).(Barrons and Woods 2016)

  • Homocysteine: While higher homocysteine levels are associated with PAD and risk of venous and arterial thrombosis.(D’Angelo and Selhub 1997; Khandanpour et al. 2009; Liebman 2019) Recommendation against Folic Acid and Vit B12(Grade 2 – C)

  • Patients are at higher risk of depression (almost 20%), therefore PHQ-9 and -2 are good screening tools and should be use in these patients.(Jha et al. 2019; McDermott et al. 2016; Ramirez, Drudi, and Grenon 2018)

To improve Limb Function in patients with Claudication:

  • Cilostozol use – Claudication without CHF – 3-month Trial (Grade 2 - A)

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

    • Based on Meta-analysis 26 trials (Stevens et al. 2012)

  • Supervised Exercise Therapy

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

    • More durable functional improvements than angioplasty alone, however no current data demonstrating impact on need for revascularization or amputation rate.(F. Fakhry et al. 2013; Farzin Fakhry et al. 2015; Murphy et al. 2012, 2015)

    • Meta-analysis of 32 RCTs: Placebo versus exercise: Walking Time, Walking Ability, Pain Free Walking and maximum walking distance improves. BUT no difference in ABPI, Mortality or amputation. (Lane et al. 2017)

    • Meta-analysis of 14 RCTs: Supervised better than Non-Supervised Programs. (Hageman et al. 2018)

15.2.2.2 Open and Endovascular Management

What is the surgical management for patients with Intermittent Claudication?

  • With appropriate medical management and risk modification, 25% of patients will improve, 50% will remain stable and 25% will progress and requiring intervention. (Conte, Pomposelli, Clair, Geraghty, McKinsey, Mills, Moneta, Murad, Powell, Reed, and al. 2015; Norgren et al. 2007)

  • Patient Selection for Intervention:

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

    • 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 hemodynamic (ABPI or US) or anatomical disease progression/severity.

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

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

  • Anatomical Selection:

    • Aortoiliac Disease: Previous TASC Classification has attempted to categorize 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 is preferred as primary thearpy over open surgery for focal aortoiliac, common Iliac and external iliac disease causing Claudication. (Grade 1 Evidence B)

      • Hybrid approaches are recommended for Iliac disease involving CFA with the addition of an open femoral endarterectomy. (Grade 1 Level B)

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

      • Bilateral external iliac occlusion may be best treated with end to side aorto-bifemoral bypass to allow for continued perfusion of the pelvis. (Jaquinandi et al. 2008; Akker et al. 1992; Brewster and Darling 1978)

    • Infrainguinal Disease: Reviewing historical data comparing all EVT compared with surgical bypass EVTs are less durable, especially when there’s diffuse or long segments of occlusion/multilevel infrainguinal disease. Most recommendations are based on low level evidence when comparing EVT versus Open Surgery

      • Endovascular therapy has become first line therapy for focal SFA disease not involving the vessel origin. (Grade 1 Level C)

      • Endovascular therapy with self-expanding stent (with or without paclitaxel) is recommended for SFA disease 5-15cm (Grade 1 Level B)

      • Recommend against treatment of isolated infrapopliteal disease for claudication (Grade 1 Level C)

      • Initial Surgical Bypass (with vein: Grade 1 Level A) is recommended in the following clinical scenarios.

        • Diffuse femoropopliteal disease

        • Small caliber vessels <5mm

        • Extensive diffuse calcification in SFA

        • Average or Low Operative Risk (Grade 1 Level B)

Take a Listen

Check out our episode where we discuss overuse of early peripheral interventions in patients with claudication with Dr. Caitlin Hicks.