Peripheral Arterial Disease: Promising Strategies for Limb Preservation

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PAD is responsible for an annual cost of approximately $21 billion in the United States. This includes the costs of hospitalizations, office-based care, amputation, and loss of work. With the predicted increase in the prevalence of PAD, this cost is likely to increase significantly. This data serves to illustrate the magnitude of the problem and its implications for the United States in the 21st century.

The most common initial symptom of lower extremity arterial disease is an aching pain or cramping in the muscle of the leg brought on by exercise and relieved with rest. This is known as intermittent claudication. Patients with chronic critical limb ischemia (CLI) can develop pain at rest or non-healing wounds, most frequently on the feet or toes, due to inadequate blood flow. Roughly 1 million people in the United States are currently living with CLI, with an average amputation rate of 25% and a 50% mortality rate in 5 years. With the increasing elderly population and prevalence of diabetes, the United States can expect to see a growing number of patients with CLI and thus an increasing number of amputations. It is estimated that the number of amputations performed annually in the United States is between 160,000 and 180,000.

It is estimated that over 10 million people in the United States have lower extremity peripheral arterial disease (PAD). The prevalence of PAD increases with age and it affects 15-20% of people over the age of 75 years. Based on the National Health and Nutrition Examination Survey (NHANES) data, approximately one in every 20 Americans over the age of 50 has PAD, and the rate increases to one in every five for those over 70. PAD is one of the most significant causes of chronic disease morbidity in the United States, affecting 5% of all Americans in the 40 years or older age group and 19% of Americans over the age of 80.

Diagnosis and Assessment

Additional diagnostic studies may be used to quantify the degree of functional impairment of the patient’s limbs and to locate the anatomical site and severity of the arterial obstruction. An exercise treadmill is useful for quantifying functional impairment. Measurement of the time of onset of pain with a standard treadmill protocol provides an objective means of stratifying patients with intermittent claudication, while the ankle brachial index is typically used to assess the approximate level of arterial obstruction.

Presents in a variety of forms, and thus the first step in its diagnosis is awareness, both on the part of the patient who must recognize the symptoms and seek medical care, and on the part of the medical care giver who must consider the diagnosis in patients at risk. The patient with claudication may attribute his leg symptoms to aging and inactivity and not seek medical attention until the disease is quite advanced. Diagnosing intermittent claudication usually entails taking a good history. The physician should inquire about the nature, location, and duration of the patient’s leg symptoms. The classic description of cramping or fatigue occurring at a consistent distance walked is easily diagnosed as claudication due to an arterial flow limiting process. If the patient reports hip or buttock pain on ambulation, one must consider the possibility of aortoiliac disease.

Treatment Approaches

The first line in minimally invasive therapy for PAD is angioplasty and stenting. Although thought to be promising, there are many lesions and anatomical areas where this procedure is not effective. For instance, studies have shown a primary patency rate of less than 50% in long femoral lesions. Other anatomical limitations include calcified lesions, and lesions near the origin of an artery where the risks of acute closure are high. Even when angioplasty is effective at opening a lesion, there have been high restenosis rates which has led to the development of covered stents for the peripheral vasculature. While the data is limited, the above types of lesions may be better treated with alternative techniques such as atherectomy, gene therapy, or laser therapy.

While the demographics regarding vascular diseases and interventions are changing, the three mainstays of traditional treatment of PAD have been amputation, bypass surgery, and more recently, angioplasty and stenting. Of these modalities, the decision tree of which one to pick depends on many factors including the patient’s medical history, the anatomy and location of the lesion, and the local surgical expertise. Although this decision algorithm covered a large percentage of patients in the past, as the general health of the population increases, there are more patients for which these treatments are inappropriate. This has led to an increased interest in the development of newer, more advanced, and minimally invasive techniques to treat peripheral artery disease.

Future Directions

An additional area for future work is in identifying and reversing the risk factors that lead to the development of CLI. We have a good understanding of the risk factors for the development of the atherosclerotic disease process, and in many western countries, there has been success in lowering the incidence of coronary artery disease and stroke. Conversely, the incidence of lower limb amputation is on the increase, and while it is multifactorial, this suggests a failure of secondary prevention and treatment of PVD. Epidemiological studies have identified associations between the development of CLI and diabetes, the metabolic syndrome, chronic kidney disease, and hypercoagulable states. Future work should aim to improve the general health of patients with peripheral arterial disease, particularly those with identified risk factors.

Despite the increasing technology, our understanding of the factors governing the development of critical limb preservation ischaemia and the natural history of peripheral arterial disease is still poor. Our development of cell culture models of ischaemia and animal models of advanced limb ischaemia have greatly aided our understanding and provide potential for future translational research in this area. This may ultimately allow us to identify patients at risk and prevent the development of advanced limb ischaemia.