Long-term management of PAD has been the subject of numerous evidence-based guidelines for secondary prevention of CVD. Application of these therapies to patients with PAD is often not straightforward due to the advanced age and high comorbidity in this patient population. While there is good evidence for the benefit of antiplatelet agents, lipid-lowering drugs, and antihypertensive therapy for patients with PAD, the risk-to-benefit ratio for aggressive application of these therapies to elderly patients with severe PAD has not been well elucidated. Furthermore, the impact of these measures on improvement of symptoms and functional status in PAD patients has not been well studied. High rates of adverse cardiovascular events and mortality in patients with PAD suggest that many patients are not receiving optimal medical therapy.
Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis that is increasingly prevalent in the aging population. PAD can present as intermittent claudication, atypical leg pain on exertion, or ischemic pain at rest. Patients with advanced ischemia may develop skin ulcers or gangrene. The clinical consequences of PAD are felt broadly and severely. Patients with intermittent claudication have higher mortality rates compared to age-matched control subjects, and patients with critical limb ischemia are at very high risk for amputation and death. As such, PAD is an important marker of generalized cardiovascular disease (CVD), and strategies aimed at improving outcomes in PAD patients must take into account the high risk of myocardial infarction and stroke.
Risk Factors and Diagnosis
Indirect recognition of IHD using exercise ECG or stress ECHO may be necessary in some cases. High-risk patients with IIb/III PAD and those with severe intermittent claudication and functionally limiting lifestyle deserve early referral for invasive diagnosis of limb ischemia. They recognize that the diagnosis of PAD is not only useful for establishing the prognosis of vascular disease in general, but it is important in assessing the future prognosis of the patient. They suggest that increased awareness and use of ankle pressure index measurement will lead to increased detection, although it is clear that this may not be suitable for every patient.
Ankle pressure index testing should be performed by suitably trained healthcare professionals of all disciplines using handheld Doppler to help confirm the diagnosis of PAD in people with intermittent claudication. Doppler measurement of ABPI is 95% sensitive and 100% specific for PAD at an ankle brachial pressure index cutoff of 0.90 or less. ABI is cost-effective and accurate, but it should be noted that it may not be reliable in patients with diabetes, chronic renal failure, or end-stage renal failure, as they may have medial calcinosis of the arteries, and it is difficult to obtain a reliable blood pressure measurement. This is a key area in terms of providing an accurate diagnosis, and a more direct route to vascular investigations may improve the detection and diagnosis of disease.
Peripheral artery disease (PAD) is relatively common and is estimated to affect around 10% of the population over the age of 55. The prevalence of PAD increases markedly with age, but the rate of diagnosis and management is considered to be suboptimal. PAD leading to intermittent claudication, more severe ischemia, or critical limb ischemia has a considerable impact on a patient’s mobility, functional ability, and quality of life.
Risk Factors
Peripheral arterial disease shares many risk factors with atherosclerosis and coronary artery disease. The most important risk factor for PAD is smoking. Smokers are at two to four times the risk for PAD than nonsmokers. The risk increases with the number of cigarettes smoked per day. Collaborative data from 18 studies on cigarette smoking and PAD demonstrated a clear dose-response relationship with the risk of PAD. A history of smoking is also an independent risk factor for PAD. Former smokers have a risk of PAD similar to those who have never smoked within 10-15 years of smoking cessation. Hypertension is a significant risk factor for PAD as well. Compared with normotensive individuals, the risk of PAD is approximately doubled among those with hypertension. High blood pressure causes damage to the arterial wall which ultimately leads to the development of atherosclerosis and PAD. Diabetes also significantly increases the risk for PAD. It has been estimated that people with diabetes have a three to four fold higher risk of getting PAD than age-matched non-diabetics. Approximately one in three people over the age of 50 with diabetes will develop PAD. High cholesterol levels and PAD have a direct dose-response relationship. An analysis of plasma lipid levels in the Framingham Heart Study showed that the prevalence of intermittent claudication in people with total cholesterol levels exceeding 260 milligrams was three times that of subjects with cholesterol levels less than 200 milligrams. High cholesterol levels promote atherosclerotic plaque build up in the arteries, which can lead to PAD. Another important risk factor for PAD is obesity. High waist-to-hip ratio has shown to be a better predictor for PAD than either waist circumference or BMI. They also recommended that exercise be measured by an objective test such as a 6-minute walk at a gait speed less than 200 m, or a 4-m walk at less than or equal to 0.4 m/s. More than 6 minutes during the 6-minute walk test or a gait speed greater than 200 m reliably rules out significant functional limitations from claudication. These tests have not been widely adopted or used in clinical research or practice.
Diagnosis
Ankle Brachial Pressure Index (ABPI): The ABPI is widely used as a noninvasive investigation for PAD. It is a ratio of the systolic blood pressure at the ankle to the systolic blood pressure in the arm. A reduced ABPI is the most simple and objective measure of atherosclerotic disease in the peripheral circulation and should be measured in all patients with exertional leg symptoms and in those over 65 years of age. An ABPI of less than 0.9 has a sensitivity of 95% and a specificity of 99% for the presence of PAD, and an ABPI of more than 1.40 is usually due to medial artery calcification seen in diabetes and chronic kidney disease. A low ABPI has also been shown to be an independent predictor of cardiovascular morbidity and mortality in a range of patient populations, both with and without a history of cardiovascular disease.
Clinical Presentation: The classic symptom of PAD in the legs is intermittent claudication, which is exertional calf pain that is relieved by rest. However, in more severe cases, this may progress to critical limb ischemia, which manifests as rest pain, ulcers, or gangrene. Patients with PAD have a higher cardiovascular morbidity and mortality than those without PAD, as atheroma in the peripheral circulation is an indicator of systemic atheromatous burden. For this reason, PAD should prompt a search for coronary artery disease and cerebrovascular disease. Although patients with PAD may have a reduced quality of life due to leg symptoms, they also have a high prevalence of other atherosclerotic-related disease, and the leading cause of death is cardiovascular, not death from limb loss.
Background: Estimates of the prevalence of PAD vary between 3% and 10% of the population, depending on the age of the population studied and the diagnostic criteria used. It is more common in men than women, and prevalence increases steeply with age to 15-20% in those over 70 years of age. It is likely that the prevalence of PAD will continue to increase as life expectancy and the prevalence of related risk factors such as diabetes and chronic kidney disease increase.
Treatment Options
Evidence on treatment for PAD is derived principally from studies of patients with intermittent claudication. Few randomized trials have evaluated therapies specifically in patients with more severe or advanced disease. Much of the evidence in these patients, therefore, has been derived from studies that included a mixture of patients with intermittent claudication and those with critical limb ischemia (CLI). Changes in lifestyle, such as quitting smoking and regular physical exercise, are considered the cornerstone of treatment for patients with intermittent claudication. These interventions, however, have not been shown to alter cardiovascular event rates or to improve symptoms in patients with this condition. CLI is an advanced form of PAD that is characterized by chronic ischemic rest pain, ulcers or gangrene in one or both legs attributable to objectively documented PAD. Patients with CLI have a very poor prognosis: up to one third will die and one third will require amputation of a limb within 12 months of first developing these symptoms. Despite this, CLI has been a relatively neglected condition in terms of research into effective treatments for improving patient outcomes. Measures to control risk factors have a strong evidence base for patients at all stages of PAD, particularly in the prevention of cardiovascular events. However, the optimal medical treatment for symptoms of intermittent claudication and the relief of ischemic pain in CLI are still unclear. In recent years, newer medical interventional therapies and surgical techniques, such as angioplasty and stenting, have offered some promise for improving symptoms and quality of life in these patients.
Lifestyle Changes
The first priority in managing PAD is to maximally reduce cardiovascular risk in order to prevent progression of the disease, events such as myocardial infarction or stroke, and to prolong life. This can be achieved through lifestyle changes and medications. The use of surgical and endovascular interventions over recent years has greatly improved symptomatology and the quality of life of patients with PAD; however, it has yet to be proven that these interventions reduce cardiovascular morbidity and mortality. Therefore, a step approach should be taken in managing these patients, reserving the more invasive procedures for those with advanced disease. Lifestyle changes are often underestimated in their benefit. The physician should approach the subject of lifestyle and cardiovascular risk in a positive manner and provide advice and support often over several consultations. In a disease where the risk of cardiovascular events is so high, one might argue that all patients with PAD should be targeted for risk reduction.
Peripheral arterial disease (PAD) is a chronic disorder in which a partial or total arterial obstruction is caused by atherosclerotic stenosis or an occlusive process in the large to medium-sized peripheral arteries. It is known to most as a cause of leg pain, though in its more severe form, it can lead to ulceration and limb loss. It is now known to be part of the spectrum of atherosclerotic disease and is associated with a marked increase in cardiovascular events. The association with coronary artery disease (CAD) is thought to be as high as 70%, and cerebrovascular disease around 50%. Cardiovascular mortality at 10 years is approximately 30%, indicating that this is not a benign disease.
Medications
Antiplatelet agents are the cornerstone of medical therapy for PAD. Aspirin reduces the risk of non-fatal myocardial infarction, non-fatal stroke, and vascular death in patients with PAD. Clopidogrel reduces the same endpoints in patients for whom aspirin is not tolerable or who have diabetes mellitus. There is also evidence to support the use of the combination of aspirin and dipyridamole over aspirin alone. The ESPRIT trial demonstrated a non-significant 10% relative risk reduction of the composite vascular endpoint of non-fatal stroke, non-fatal myocardial infarction, and vascular death. However, pre-specified secondary endpoints including non-fatal stroke and the combination of major vascular events and revascularization both achieved statistical significance in favor of aspirin and dipyridamole. At present, there are no direct comparisons of clopidogrel and aspirin plus dipyridamole. The CHARISMA trial found that the combination of aspirin and clopidogrel did not significantly reduce vascular events compared to aspirin alone but significantly increased the risk of major bleeding. Of note, a recent substudy of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial identified a high-risk subset of patients with prior MI, stroke, or symptomatic PAD who had a 28% relative risk reduction of cardiovascular events with clopidogrel compared to placebo, double the overall reduction of patients randomized to clopidogrel in the main trial. This supports the use of dual antiplatelet therapy for short periods (3-6 months) following percutaneous intervention for PAD. It is recommended that patients with PAD with indications for anticoagulation should receive aspirin plus clopidogrel for short-term therapy after stenting or angioplasty. The addition of cilostazol, an inhibitor of platelet aggregation, can be considered for patients with intermittent claudication, but its expense limits its use in some healthcare settings.
Surgical Interventions
Surgical revascularization improves blood flow to the limb by bypassing the blockage in the artery or by performing angioplasty and stenting to open the artery. The decision to operate should take into consideration the patient’s symptoms, general health, predicted longevity, and the likelihood of improving symptoms and function with the revascularization procedure. Patients with critical leg ischemia and a suitable arterial anatomy should be offered revascularization as the initial treatment. Revascularization is recommended as the best treatment for patients with severe claudication in whom conservative measures have failed. The evidence for increased functional capacity and improved symptoms and quality of life after revascularization in comparison to conservative management for intermittent claudication is not absolute, and resolution of symptoms may not be sustained long term. This, and the risks of revascularization, should be discussed with the patient during the decision-making process. High-risk patients, particularly those with unacceptably high anesthetic or surgical risk, may be managed more appropriately with conservative measures if their life expectancy is not significantly limited by non-ischemic disease.
Long-Term Management and Follow-Up Care
Typical follow up for the majority of patients should be 6-month intervals for up to two years, then annually thereafter. Patients with diabetes mellitus, or those with end-stage renal disease on dialysis, have a much higher incidence of developing progressive disease and would benefit from closer surveillance. It is equally important to try to prevent the disease from progressing and worsening of symptoms through modification of atherosclerotic risk factors. If there is evidence of deterioration during this period, then the follow-up frequency should be increased. Randomized trials have shown that lipid-reducing therapy with statins can reduce the risk of amputation, and possibly improve claudication distance. These patients require close monitoring of lipid profiles to assess therapeutic response. Smoking cessation should be encouraged and assessed at every visit. Blood pressure control, tight glucose control for diabetic patients, and ACE inhibitor therapy have all been shown to retard progression of disease for both claudication and critical limb ischemia. Modification of these risk factors should improve long-term cardiovascular outcome for PAD patients. The effectiveness of risk factor management can be monitored by the ankle brachial pressure index. Type and intensity of treatment for claudication symptoms can often be monitored by changes in quality of life questionnaires and provide evidence for cost-effectiveness.
Monitoring Progression
Having checked the pulse, auscultates the bruit using the bell of the stethoscope in the same four sites to check for a change in the intensity or the development of a bruit in a previously non-noisy site. Assesses the change in the ankle systolic pressure at each visit as a means of objective progress. An ankle pressure that is consistent with mild PAD (i.e., 50-70 mmHg) may not be re-measured as any change will not influence the management of the symptoms. Any patient with more severe PAD should have their ankle pressure measured discontinuously until the symptoms become stable. At this stage, the ankle pressures do not need to be monitored further unless there is a possibility of surgery or change in symptoms. Repeating a full leg aorto-iliac-femoro-tibial run-off is not indicated, and selective angiography should only be used if the clinical condition suggests a change in the arterial lesion. This should be avoided whenever possible because of the risk of complications associated with the procedure. Monitoring arterial lesions through exercise testing on the affected limb using a treadmill and pulse volume recordings may be useful in some patients. Finally, assessment of the response to treatment of risk factors by comparing cholesterol levels and blood pressure to baseline values can be a good indication of whether the symptoms are likely to deteriorate in the future.
Preventing Complications
Management with dual antiplatelet therapy for 4 weeks following diagnosis and antiplatelet therapy throughout is important. The CAPRIE trial compared clopidogrel and aspirin, and despite there being no statistical difference in cardiovascular event reduction, clopidogrel, being a more costly option, was not deemed a cost-effective use of resources in the UK at the time, highlighting preference for clopidogrel where cost is not an issue. Patients should be counseled on how to recognize and manage any cuts or abrasions to reduce the risk of future adverse clinical presentations and be informed of proper footwear to prevent trauma to the foot. One key to preventing complications associated with PAD progression is reduction of it. This can be achieved with tight control of blood pressure and diabetes; however, the most effective method is considered to be smoking cessation. The UKPDS trial demonstrated in diabetic patients that tight control of blood pressure and glucose reduced cardiovascular-related events, microvascular, and macrovascular complications. Hypertension and diabetes management was heavily associated with patient compliance, and with regards to complications and PAD progression, it is suggested that due to patient compliance typically being poor, these complications are often due to poor disease management. Regular follow-up is therefore imperative.
Regular Check-ups
Regular follow-up appointments are necessary for patients with peripheral arterial disease. The assessment of risk factors and functional status are important parts of these visits. Through surveillance and management of comorbidities, one can aim to prevent the progression of PAD and limit its associated cardiovascular morbidity and mortality. When aggressive medical therapy or revascularization is successful in achieving relief of symptoms, it is not uncommon for patients to be lost to follow-up and return only after symptoms have recurred. These patients should be encouraged to continue regular follow-up to maximize the durability of their symptom relief. The specific recommendations for follow-up are as follows: in patients with claudication who are managing their risk factors and have no decline in functional status, a history and physical every 6-12 months may be sufficient. Those with more severe or worsening symptoms will require closer follow-up, as will patients who have undergone revascularization. An exercise program is an effective treatment for claudication, and in addition to close medical management, can lead to improvement in functional status. Serial treadmill testing may be considered in these patients to monitor the response to exercise and walking ability. This test can also be an effective motivator for patients.
