Peripheral arterial disease (PAD) is defined as a pathological narrowing of the non-cardiac vessels which is primarily atherosclerotic in nature. PAD and atherosclerosis have a close biological relationship; sharing many of their classical determinants, so much so that the severity of peripheral vascular damage closely correlates with the likelihood of cardiovascular related death. Therefore, in recent years, the identification of PAD has gained increasing attention as a reliable marker of advanced atherosclerosis and a predictor of death by vascular causes (Al-Omran 2012). However, although the diagnosis and treatment of PAD is relatively simple, it remains fairly undiagnosed and undertreated (Gandhi, Weinberg et al. 2011).

Despite this, PAD is the third leading cause of atherosclerotic cardiovascular morbidity with a worldwide prevalence of 3-12% – a number that has seen a staggering increase of 155% between 1990-2013 (Conte and Vale 2017)(Fowkes, Rudan et al. 2013). The incidence of PAD is 2:1 in males living in high income countries compared to females, but prevalence also increases with age; reaching as high as 25% in patients older than 70 years being detected in some studies up to 25% of patients older than 70 years as depicted in Figure 1 (Hirsch, Criqui et al. 2001).

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Figure 1. Prevalence of PAD by age and genders in adults 40 years and older. Taken from (Selvin and Erlinger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

 

 

 

Classification of PAD & Risk factors

Upon assessment of a patient’s symptom severity, they are classified according to the table below. Asymptomatic patients account for more than 50% of diagnoses, but still carry a 20% risk of an MI or stroke, with a 15-30% mortality risk at 5 years (Peach, Griffin et al. 2012).  In those diagnosed, 95% were found to have at least one modifiable risk factor, and 72% had two of them – these are risk factors that are strongly implicated in the underlying pathophysiology of PAD initiation and progression (Libby, Ridker et al. 2009). Aggressive control of such risk factors is most effective in this group at preventing progression to CLI and so early identification of asymptomatic PAD and rapid management of these risk factors is crucial (Selvin and Erlinger 2004).

 

Table 1. NICE guideline definitions of Peripheral arterial disease (National Institute for Health and Clinical Excellence, 2012)
 

 

 

Smoking

Of all the risk factors, cigarette smoking is the most culpable in the pathobiology underlying peripheral arterial disease, but they are also the most modifiable for both sexes (Fig.3). The incidence of symptomatic PAD is directly proportional to the dose of exposure; the Edinburgh artery study has suggested that current smokers are almost 4 times more likely to develop PAD than non-smokers with an 11-fold increase in the risk of developing CLI/ALI (Conte and Vale 2017).

 

Smoking cessation is the cornerstone of PAD management as it slows the rate of progression and in some patients can improve the walking distance during exercise, therefore all patients at risk should be strongly encouraged and repeatedly advised to abstain from smoking (Willigendael, Teikink et al. 2005). Psychological counselling should be implemented to support and engage the patient during the programme alongside Nicotine replacement therapy (NRT) through the use of Nicotine gum, patches, nasal spray or sublingual lozenges (Ruger and Lazar 2012). However, adherence to the programme is low and so to maximise the programme’s success, the non-nicotine-based antidepressant Bupropion can be given alone or in combination with NRT to ease the withdrawal symptoms and emotions experienced during the programme (Fig.2).

 

 

 

 

 

Figure 2. Success rates of patients engaged in a smoking cessation programme with either placebo, Nicotine Replacement (NRT), Bupropion or a combined of both NRT and Bupropion. Taken from (Jorenby, et al. 1999)
 

 

 

 

Lipids and statin therapy

The Framingham study of 1985 was the first to highlight hyperlipidaemia as an independent risk factor for the development of PAD, demonstrating that patients with a fasting cholesterol concentration of greater than 7mmol/L had a 2-fold increase in their risk of claudication.

 

In recent years, the advent of 3-hyrox-3-methylglutaryl-coenzyme A reductase inhibitors, commonly known as ‘Statins’ to reduce low density lipoprotein (LDL) levels has become a commonplace therapy in the treatment of cardiovascular disease patients and those at high risk of PAD. In the Heart Protection Study, the use of statins lowered LDL levels, and reduced the risk of cardiovascular events including PAD by 25%, and there is now overwhelming evidence to back this (HPS Group. 2002)(HPS Group. 2007).

 

Statins are pleiotropic in their benefit to cholesterol-independent outcomes in PAD patients as they are shown to improve the 6 minute walking distance of patients and reduce claudication by 38% in a 5-year follow up (McDermott, Guralnik et al. 2003)(Pedersen, Kjekshus et al. 1998). Considering this, all patients with symptomatic PAD should have their diet modified initially, followed by statins such as Atorvastatin or Rosuvastatin to lower LDL cholesterol levels to <2.59 mmol/L. Figure 3. The approximate odds radios for risk factors in the development of symptomatic PAD. As discussed, both smoking and diabetes present with the largest risk, but there is a multiplicity of factors contributing to PAD, some of which are non-modifiable such as race and gender. Hyperhomocysteinemia and CRP are novel risk factors suggested to have implications upon PAD progression. Taken from (Norgren, et al. 2007)                             Diabetes Mellitus management Diabetes mellitus (DM) is a common co-morbidity of PAD and in a similar way to smoking, the duration and severity of DM correlates with the risk of developing PAD which is estimated to be 20-30% higher than in any other matched population. A positive diagnosis in men increases the intermittent claudication 3.5-fold, and 8.6-fold in women and those diagnosed have a less favourable outcome for both the disease and its treatment, with a 5-10 fold increased incidence of amputation (Kannel and McGee 1985)(Leibson, Ransom et al. 2004).   Diabetes is a state of insulin resistance that influences a clustering of cardiometabolic risk factors such as hyperglycaemia and dyslipidaemia – which if not managed properly, causes the dysfunctional pathobiology of DM. When glycaemia is uncontrolled, blood levels of glycated haemoglobin (Ghb) levels increase, and just a 1% increase in Ghb confers a 26% increase in the risk of developing PAD and other cardiovascular events (Thiruvoipati, Kielhorn et al. 2015). However it remains unclear whether tightly controlling glycaemia reduces cardiovascular outcomes in PAD patients, but it has proven effective in reducing arterial calcification and common microvascular complications such as retinopathy (Selvin and Erlinger 2004)(Patel, MacMahon et al. 2008).   Diabetes is also associated with peripheral sensory neuropathy and a decreased resistance to infection within the foot, and so alongside close monitoring of blood glucose levels, patients should be encouraged to inspect their feet daily to ensure they are cleansed and moisturised, attend regular podiatric foot & nail care appointments and wear appropriate footwear to prevent ulceration (Norgren, et al. 2007). However, to help reduce macrovascular complications, clinicians should focus their therapies towards aggressive management of the other risk factors.

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