Peripheral arterial disease (PAD) is an important public health problem in the United States and worldwide. PAD affects 8 to 12 million men and women in the United States, and prevalence is increasing with the aging of the U.S. population. PAD is also a marker for more widespread atherosclerotic disease and is associated with other adverse cardiovascular (CV) events. Patients with PAD are at high risk for myocardial infarction (MI), stroke, and CV death. Functional impairment and diminished quality of life are important consequences of PAD, and in severe cases, limb amputation may be necessary. These limb events, as well as the heightened risk for other CV events, contribute to the substantial increase in healthcare costs associated with PAD. It is estimated that annual costs for PAD-related hospitalizations in the U.S. exceed $1.8 billion. With an increasingly aged population and greater prevalence of risk factors such as diabetes and smoking, the burden of PAD will continue to grow, leading to an even greater impact on patients and the healthcare system. Despite the importance of PAD, there remains a relative lack of public awareness and understanding of the disease. This may be due to the fact that PAD is often asymptomatic in its early stages or that patients and healthcare providers may attribute leg symptoms to normal aging. In addition, the focus of both patients and providers on treatment of other atherosclerotic conditions (e.g. coronary artery disease and cerebrovascular disease) may lead to insufficient attention to the diagnosis and management of PAD. Recognition of the impact of PAD and its status as a global health issue has spurred efforts by the American Heart Association (AHA) and other organizations to increase awareness of PAD and its complications. Our growing understanding of the mechanisms of atherosclerosis and the role of various risk factors in the development and progression of PAD has also raised hopes that preventive and therapeutic interventions to reduce the burden of PAD may be successful.
Definition of Peripheral Arterial Disease (PAD)
PAD is a chronic, lifestyle-limiting disease and is an underdiagnosed marker for widespread atherosclerosis. The clinical manifestations of PAD are highly variable and many patients are asymptomatic. At one end of the spectrum, PAD may present as atypical leg discomfort on walking, whereas in severe cases, critical limb ischemia may supervene and this represents the end stage of occlusive atherosclerotic disease in the lower limb. Most patients with PAD have an elevated risk of coronary, cerebrovascular, and renal artery disease and cardiovascular events. The economic burden of PAD is high, and costs for managing patients with PAD increase exponentially with disease severity. Accurate data on the annual cost of PAD in the UK are not available, but a US database registry estimates the cost of care to be over $21,000 per year for patients with intermittent claudication and $32,000 per year for patients with critical limb ischemia. This definition and the subsequent sections that deal with the clinical manifestations, epidemiology, and prognosis of PAD all focus on atherosclerotic PAD and potential risk factors for the disease. Nonatherosclerotic etiologies of PAD should also be considered as part of the differential diagnosis, but this lies outside the scope of the present guidelines.
Prevalence and Impact of PAD
It is also noteworthy that the relative risk for cardiovascular events associated with PAD is higher than the risk for those same events occurring in patients who have known coronary artery disease. However, it is not until the onset of limb-threatening ischemia that the risk of mortality becomes equal for patients with PAD and those with coronary artery disease. This increase in mortality is a reflection of the added effect of systemic atherosclerosis in the PAD population.
Symptomatic and asymptomatic PAD each have an associated heightened risk for acute cardiovascular events and the continued progression of atherosclerosis. Patients with PAD are also at increased risk for functional decline and limb loss, which can have a profound impact on quality of life.
The economic burden and impact of PAD is comparable to that of coronary heart disease and significantly exceeds expenditure for similar cerebrovascular events. It is of great public health interest that a disease that is both as common as coronary artery disease and associated with such increased cardiovascular morbidity and mortality has not been as well recognized in physicians or the lay public. The dramatic advances in the detection and treatment of coronary artery disease that have occurred in the past 40 years have not been paralleled for the early diagnosis of PAD or its effective medical management.
In comparison to prevalent knowledge, PAD is five to six times more common in adults above 60 years of age than intermittent claudication. In fact, PAD affects approximately 20% of adults above 50 years of age and 15-20% of older adults. The economic burden due to hospitalized treatment for PAD has tripled over 10 years, from $4.2 billion to $12.4 billion.
Risk Factors for Peripheral Arterial Disease
Diabetes is a potent risk factor for PAD in all populations studied, and the relative risk is greater in women than in men. PAD in diabetic patients is often more severe and extensive than in non-diabetic patients. These patients have an increased prevalence of atypical leg symptoms and a lower classic symptom threshold. They are also at increased risk of developing critical limb ischemia and have a higher rate of amputation and worse prognosis than non-diabetic PAD patients. The increased risk of PAD in diabetic patients has been attributed to the coexistent risk factors seen in these patients, such as hypertension and hyperlipidemia, and the frequent occurrence of microvascular disease.
The most well recognized risk factor for peripheral artery disease (PAD) is cigarette smoking. Smokers have a 3-5 fold increased risk of developing PAD. There is a direct dose-response relationship between the amount of smoking and the extent of PAD. Among patients with claudication, current smokers have more severe walking impairment and a greater likelihood of progression to limb loss than former smokers or non-smokers. The mechanism by which smoking causes atherosclerosis is not well understood, but studies have shown that smoking increases platelet aggregation and adhesiveness, blood viscosity, and LDL cholesterol, all of which are directly related to the development of atherosclerosis. In patients with PAD, cessation of smoking delays the progression of the disease and reduces symptoms and adverse cardiovascular events. Unfortunately, the effects of smoking cessation are not as well sustained in preventing PAD as they are in coronary artery disease.
Smoking and Tobacco Use
The mechanisms by which smoking induces atheroma are not fully understood, but may include increased platelet aggregation, damage to the endothelium leading to smooth muscle proliferation, an adverse effect on serum lipids, and increased oxidative stress. The harmful effects of smoking encapsulate all stages of atheroma development and low extremity ischemia and extend to an increased systemic cardiovascular atherothrombotic events and death. Even though many patients recognize that there are adverse health effects due to smoking, the specific understanding that they may cause damage necessitating amputation is considerably less prevalent.
Smoking and tobacco use have emerged as the strongest and most consistently reported independent risk factor for lower extremity atherosclerotic disease. Separating the effect of tobacco itself from that of other variables is difficult because smokers tend to have more comorbidity than non-smokers, in terms of other cardiovascular risk factors such as diabetes, hypertension, and hyperlipidemia. However, where attempts have been made to adjust for these confounders, smoking often emerges as the most significant risk factor. Smokers tend to develop claudication up to a decade earlier than non-smokers, and the relative risk for symptomatic PAD in smokers compared with non-smokers ranges from 1.8 to 7.03.
Diabetes Mellitus
From the result of an observational cohort study of 30,000 men older than 50 years without previous cardiovascular disease and type 2 DM, it showed that type 2 DM patients with no previous myocardial infarction have the same cardiovascular risk compared with non-DM patients with previous myocardial infarction. This condition is often underestimated by DM patients and healthcare practitioners. Data from the same study also showed that adequate prophylaxis of antiplatelet and lipid-lowering therapy is still inadequate for type 2 DM patients with or without CAD history. 16.4% of DM patients with CAD history and 9.6% of DM patients without CAD history are still not taking aspirin therapy, while 4.1% of DM patients with CAD history and 2.6% of DM patients without CAD history are not taking lipid-lowering therapy. Only 1 in 5 type 2 DM patients without previous myocardial infarction recognize their cardiovascular disease risk and take adequate preventive therapy. High cardiovascular disease in DM patients causes around two-thirds of DM mortality. This case will cause an increase in peripheral arterial disease (PAD) incidence in DM patients with the same or greater magnitude compared to CAD incidence. From a study by Criqui et al., PAD incidence in DM patients and non-DM patients has no significant difference. The most striking fact from this study is that the relative risk of intermittent claudication in DM patients compared to non-DM patients is equal to the relative risk of intermittent claudication in non-DM patients with previous myocardial infarction compared to non-DM patients without previous myocardial infarction. In some cases of myocardial infarction or stroke, simultaneous leg amputation in DM patients is still performed because of unawareness of a better treatment, for example, revascularization. This fact brings to the surface an awareness of high cardiovascular disease and CAD in DM patients and its equivalent risks to the same CAD in non-DM patients.
Diabetes mellitus is a metabolic disorder that affects carbohydrate, protein, and fat metabolism. The most common atherosclerotic disease in DM patients is coronary artery disease (CAD), which leads to a substantial increase in mortality in both type 1 and type 2 DM patients, myocardial infarction, or stroke. Some possible explanations for this phenomenon are hyperglycemia, insulin resistance, and dyslipidemia characteristic of DM patients, effects of genetic predisposition, and the coexistence of hypertension. DM patients have an approximately 2-4 fold increase in CAD risk compared to non-DM patients, and since a CAD event is a potent predictor for cerebrovascular ischemic events, it practically brings CAD risk equivalence to DM and non-DM patients. The exact mechanism for the high CAD in DM patients is complex and multifactorial. Some contributing factors are endothelial dysfunction, which leads to reduced production and bioavailability of vasodilation, and/or anti-thrombotic and fibrinolytic activity. This condition is more marked for type 2 DM patients, which is caused by insulin resistance. Other pathways are increased oxidation of LDL cholesterol and protein kinase C activation, or endothelial growth factor due to chronic hyperglycemia. It is proven that each 1% decrease in HbA1c level reduces the risk for microvascular and macrovascular complications of DM. Primary and secondary prevention of CAD in DM patients are according to the Diabetes Care 2007 on the basis of aspirin therapy use with aspirin dosage recommendation 75-162mg/day in patients over 30 years of age. Control of high blood pressure and dyslipidemia, and quitting smoking.
Hypertension
Hypertension, or high blood pressure, is a highly prevalent and potent risk factor for the development of symptomatic PAD. Hypertension has been considered to be a systemic atherogenic factor that causes generalized atherosclerosis, increasing the risk of PAD many folds. People with hypertension have a 2-4-fold increased risk of developing PAD. In a study, it was shown that every 20 mmHg increase in systolic blood pressure doubles the risk of PAD. The pathophysiology of how hypertension contributes to PAD is through damage to the endothelium. Increased pressure and shear stress leads to endothelial damage, allowing for LDL to accumulate in the vessel wall. This is the initial step in atherosclerosis formation. Hypertension also causes increased oxidative stress which potentiates damage to the vessel wall, especially in the presence of a high LDL concentration. Another mechanism by which hypertension exacerbates PAD is through increased coagulation of the blood. This is caused by increased platelet activation and adhesion as well as an increase in thrombin activity. The end result is an increased risk of formation of thrombi and emboli in the lower limb vessels, causing acute limb ischaemia and increasing the risk of CLI. Finally, hypertension is a major risk factor for the development of critical limb ischaemia in the presence of PAD. The low flow state caused by severe aortoiliac disease combined with microvascular disease in hypertensive patients often leads to tissue necrosis and ulceration.
Hyperlipidemia
Dyslipidaemias are a collection of conditions characterized by imbalances in the plasma lipoproteins, commonly referred to as high levels of “bad” cholesterol (low-density lipoprotein; LDL), normal or low levels of “good” cholesterol (high-density lipoprotein; HDL), and high levels of triglycerides. LDL is believed to be the most atherogenic of these lipoproteins and is taken up by macrophages within the arterial wall, leading to the formation of foam cells and the initiation of the atherosclerotic plaque. Conversely, HDL is thought to protect against cardiovascular disease by its role in reversing cholesterol transport out of the arteries and into the liver for excretion. The association between raised LDL levels and the development of atherosclerosis has been clearly established in numerous epidemiological studies and has subsequently been confirmed by randomized trials involving LDL-lowering drug therapy. Although the relationship between HDL levels and the development of atherosclerotic plaques is less clear, there is evidence to suggest that low levels of HDL are associated with an increased risk of coronary and peripheral artery disease. A similar association has been identified between levels of triglycerides and atheroma formation, thereby suggesting that all types of dyslipidaemia can contribute to the pathogenesis of PAD. This is supported by accumulating evidence from cross-sectional studies and clinical trials, which have consistently demonstrated a strong relationship between dyslipidaemias and the prevalence and incidence of PAD. Overall, the data indicates that hyperlipidaemia is an independent risk factor for both clinically overt and subclinical PAD and that the strength of this association is broadly comparable to that of coronary artery disease.
Prevention Strategies for Peripheral Arterial Disease
The risk factors for atherosclerosis are well defined, and treatment of these risk factors has been proven to reduce the risk of cardiovascular events. These risk factors include hyperlipidemia, hypertension, smoking, and diabetes. The control of these risk factors will be described in the context of the atherosclerosis risk factor and whether control of the risk factor has beneficial effects on the prevention of development of peripheral arterial disease or progression of the disease.
The key concept for prevention strategies for coronary artery disease and peripheral arterial disease rests in the control of atherosclerosis risk factors. Coronary heart disease can be prevented primary and secondary, while the prevention for peripheral arterial disease is primarily focused on making the patients with claudication function better, with the secondary aim to prevent disease progression to critical limb ischemia. Therefore, the available methods of preventing peripheral arterial disease will be described according to whether they are primary or secondary prevention.
Lifestyle Modifications
Atherosclerosis is known as a systemic disease because it can affect many different arterial beds. The same risk factor modifications that are used to prevent the progression of atherosclerosis in the coronary or cerebral vasculature can be used to prevent it in the peripheral arterial system. The benefit in the case of PAD is that when the disease is limited to the peripheral arteries, disease reversal is much more obtainable, and the symptoms of intermittent claudication and critical limb ischemia can be completely resolved.
A vast majority of peripheral arterial disease (PAD) is a direct result of atherosclerosis. For this reason, we base our prevention strategies on modifying the risk factors for atherosclerosis. This can be broadened to include all cardiovascular disease. There are risk factors that are non-modifiable, such as age, family history of cardiovascular disease, and comorbidities such as diabetes, renal disease, or active tobacco use. Although these are important to identify and address, the focus of prevention should be targeted toward those risk factors that are modifiable. Through extensive research, it has been determined that many lifestyle modifications, as well as using medication to control certain risk factors, can effectively prevent the progression of atherosclerosis. In some cases, it can even reverse the disease process.
Medications for Risk Factor Control
The use of lipid-lowering medications, mainly HMG CoA reductase inhibitors, as a secondary preventive measure in patients with PAD is an area that has shown some benefit. Data from the Heart Protection Study showed a 29% reduction in major vascular events in patients with PAD who took 40 mg of simvastatin daily. This randomized controlled trial included 6748 patients with PAD, of which 20% of the vascular disease was symptomatic. Although this was a subgroup analysis, the 29% reduction was nearly identical to the 30% reduction seen in the main HPS article. This is consistent with similar cholesterol-lowering trials which also showed about a 1% reduction in relative risk of major coronary events and stroke for each 1% reduction in LDL cholesterol. Stepwise implementation of cholesterol-lowering therapy with the goal of achieving an LDL level less than 100 mg/dl is recommended. High-dose atorvastatin has been used in some patients in an effort to achieve an LDL less than 70 mg/dl.
Patient education with respect to risk factors and healthy lifestyle is an important aspect in the management of PAD, and that is one of the most effective interventions, as has been described above. Perhaps the only other realm where medical therapy has been consistently helpful is in the reduction of cardiovascular events. Certainly, the most cost-effective intervention in patients with PAD and risk factors for CAD and cerebrovascular disease is the use of antiplatelet therapy. In patients with symptomatic PAD, antiplatelet therapy with a daily dose of 75-325 mg of aspirin is indicated. Clopidogrel is an alternative for those patients who are intolerant to aspirin. In these cases, the duration of clopidogrel therapy is based on the patient’s ability to tolerate aspirin.
Medical Procedures for PAD Prevention
Aortoiliac endovascular treatment is primarily done with balloon angioplasty and/or primary stenting. Patency rates of balloon angioplasty alone are poor and generally complicated by elastic recoil and/or dissection, and therefore some form of stent implantation is usually the preferred treatment. Common iliac artery lesions usually have good long-term results with a high primary and secondary patency rate with simple balloon angioplasty. However, lesion complexity with long segment stenoses and occlusions involving the aorta and iliac bifurcation have significantly better results with primary stenting. Lesion location plays a large role in determining success rates, demonstrating that the more proximal lesions towards the aorta have higher primary patency rates. Currently available stents have similar results with long-term patency, but the choice of a specific stent is often made on an individual basis, largely depending on its radial force in calcified lesions and flexibility in tortuous lesions. Randomized trials comparing angioplasty and stenting with aortoiliac surgical bypass are limited, with no significant difference in major adverse cardiac events and in-hospital mortality. Despite a higher 2-year reintervention rate with endovascular treatment, it still tends to be a preferred treatment due to quicker recovery times and therefore less associated morbidity.
Revascularization, through either a surgical or endovascular approach, is recommended for patients with disabling claudication or critical limb ischemia due to aortoiliac disease. Revascularization is useful for the relief of symptoms and results in a maximum benefit when supervised exercise and risk factor management have failed to improve the symptoms. The choice between an endovascular or surgical approach should be based on lesion characteristics, local expertise, and patient factors. By and large, endovascular treatment of aortoiliac stenoses and occlusions has largely replaced surgical bypass because of comparable anatomic and clinical success rates with less morbidity and mortality. Lesion location, length, and complexity are the most important factors in determining whether an endovascular approach is feasible.
Conclusion
However, many patients with PAD are not currently receiving the full benefits of highly effective preventive measures. Successful implementation of preventive therapies to large numbers of PAD patients will require concerted efforts to improve awareness of PAD among the public and various healthcare providers. Many individuals at risk for PAD are not aware of the condition or the extent to which it may impair their health and function. Health literacy with regards to atherosclerotic disease and its risk factors is generally low. This is particularly problematic in the care of patients with asymptomatic PAD, as many will not appreciate the relation between their functional limitations and the presence of PAD. An understanding of the impact of atherosclerotic disease on overall CV risk, combined with specific knowledge of PAD’s manifestations and its equivalence to CAD and cerebrovascular disease, is needed to motivate patients and providers to initiate and adhere to preventive therapies. This increased awareness and disease-specific education must be coupled with systems that facilitate the identification of at-risk patients and ensure that they receive appropriate long-term preventive care. PAD management typically begins with the recognition of lower extremity symptoms.
In conclusion, prevention of PAD is a major public health priority. The prolongation of a healthy, independent life is a goal that implicates the entire global community. The burden of PAD and its consequences are not limited to the individual patient, and strategies aimed at early detection and prevention of PAD are likely to impact the utilization of healthcare resources. The WIF-T trial and related cost analyses underscore the downstream cost benefits associated with preventive therapies applied to asymptomatic PAD. Given the extensive similarities in risk factor profiles, preventive measures aimed at limiting atherosclerotic disease in general are likely to have a substantial impact on the incidence and severity of PAD. Through targeting these general risk factors in addition to those with more specific associations to PAD, it is highly likely that the public health and personal burdens of PAD can be markedly reduced. Practice guidelines have increasingly recognized the high-risk nature of asymptomatic PAD and call for aggressive risk factor modification in these patients. The accumulating body of evidence supports the concept that such measures can alter the natural history of PAD in a manner that reduces symptoms and functional limitations. Primary care, specialty, and subspecialty clinicians all have a role in preventive efforts.
