Background

Epidemiology of Peripheral Artery Disease (PAD)

Peripheral artery disease (PAD) is the preferred clinical term describing stenosis or occlusion of upper or lower extremity arteries due to atherosclerotic or thromboembolic disease.1 In practice, however, the term PAD generally refers to chronic narrowing or blockage (also referred to as atherosclerotic disease) of the arteries of the lower extremities. Thus the focus of this systematic review is chronic atherosclerotic disease of the lower extremities.

PAD represents a spectrum of disease severity, encompassing both asymptomatic and symptomatic disease. Roughly 20 to 50 percent of patients diagnosed with PAD (diagnosis made by abnormal results of an ankle-brachial index (ABI) test, discussed in the next section) are asymptomatic, though they usually have functional impairment when tested.2 If the disease progresses and blood vessels narrow, arterial flow into the lower extremities worsens and symptoms may manifest either as classic intermittent claudication (IC) or as atypical claudication or leg discomfort. IC is defined as leg muscle discomfort provoked by exertion that is relieved with rest, while atypical claudication (also called atypical leg discomfort) is defined as lower extremity discomfort that is exertional but does not consistently resolve with rest. Roughly 10 to 35 percent of all PAD patients report symptoms of classic IC, and 40 to 50 percent of patients present with the atypical form. If the disease worsens, patients often develop more severe claudication, with reduced walking distance and eventually with pain at rest. In 5 to 10 percent of cases, claudication progresses to a worsened severity of the disease, called critical limb ischemia (CLI)—defined as ischemic rest pain for more than 14 days, ulceration, or tissue loss/gangrene. CLI is the initial presentation in roughly 1 to 2 percent of all patients with PAD, and patients with CLI have 25 percent mortality at 1 year.2

The prevalence of PAD increases with age, such that roughly 20 percent of patients over age 65 have PAD (including symptomatic and asymptomatic disease).3,4 Given the nearly 40 million Americans over age 65, this represents roughly 8 million Americans with the disease. The prevalence of PAD is lower among younger patients, such that estimates of asymptomatic or symptomatic PAD among patients 45 to 64 years of age is roughly 3 percent.5 Given that PAD represents a more systemic atherosclerotic process that is similar to atherosclerotic disease of the coronary vessels, it is not surprising that PAD shares similar risk factors: male gender, age, diabetes, smoking, hypertension, high cholesterol, and renal insufficiency.6 Furthermore, PAD is known to be associated with a reduction in functional capacity; quality of life; and an increased risk for myocardial infarction (MI), stroke, and death. PAD is also a major cause of limb amputation.7-11 Therefore, PAD is prevalent and is associated with significant morbidity and mortality. Although the goals of cardiovascular protection, relief of symptoms, preservation of walking and functional status, and prevention of amputation are general goals of treatment for IC and CLI, the optimal treatment for patients with specific emphasis on the comparative effectiveness of treatment options is not known.12

Diagnostic Tests

Several tests are available to diagnose PAD. The initial test of choice includes the simple ABI measurement. Patients with an ABI of 0.41 to 0.90 are considered to have mild to moderate PAD, and patients with an ABI less than or equal to 0.40 are considered to have severe PAD. Similarly, an ABI greater than 1.30 is associated with noncompressible vessels and is nondiagnostic and requires further testing. Data have shown an inverse relationship between baseline ABI and the risk of ischemic events (MI, stroke, or cardiovascular death), such that as the ABI decreases, the risk of ischemic events increases.13,14 Similarly, mortality increases with an ABI greater than 1.30. If an ABI measurement at rest or at exercise is suggestive of PAD, further noninvasive testing is usually performed to characterize the anatomic location and severity of the disease; such testing includes segmental pressure measurements, pulse-volume recordings, exercise ABI, duplex ultrasonography, computed tomography angiography, and magnetic resonance angiography.

Classification Schemes

While ABI measurements may quantify PAD severity, the ABI represents a numerical value that does not provide clinicians a full picture of the clinical severity of the disease. There are two classification systems, Rutherford and Fontaine,2 generally used by clinicians to grade the severity of the clinical symptoms of patients. While these classification systems are frequently used, a large degree of heterogeneity exists in the spectrum of PAD. Tables 1 and 2 highlight these classification systems and show that patients with a higher stage of the disease have more advanced/severe PAD.

Table 1. Fontaine classification.

Table 1

Fontaine classification.

Table 2. Rutherford classification.

Table 2

Rutherford classification.

The mapping of these classification schemes to the categories of PAD disease severity is as follows:

  • Asymptomatic: Fontaine stage I, Rutherford stage 0
  • Symptomatic (atypical leg symptoms, IC): Fontaine stages IIa and IIb; Rutherford stages 1, 2, and 3
  • CLI: Fontaine stages 3 and 4; Rutherford stages 4, 5 and 6

Outcome Measures for PAD

This report examines several clinical outcomes of importance in the PAD population, including cardiovascular events, functional capacity, quality of life, pain, repeat revascularization, amputation, and vessel patency.

Cardiovascular Events

Measuring and preventing cardiovascular events such as MI, stroke, cardiovascular and all-cause mortality is important in patients with PAD because they are considered a population with a high risk of ischemia.

Functional Capacity

Functional capacity is often assessed by serial treadmill testing as an objective measure of assessing changes in performance in patients with IC. The most common measures reported in clinical studies to evaluate maximal walking performance are maximal walking distance (MWD), absolute claudication distance (ACD), and peak walking time (PWT). For measuring claudication-free walking time or distance, the measures commonly reported in clinical studies include pain-free walking distance (PFWD), pain-free walking time (PFWT), and claudication onset time (COT).

Quality of Life

Quality of life (QOL) of patients with PAD can be assessed by general and disease-specific measures. General measures include the Medical Outcomes Study Short Form-36 (SF-36®)15 questionnaire and the EuroQOL-5D. The SF-36 evaluates the physical and mental functioning of patients along eight health dimensions—general health, change in health during the past year, physical functioning, social functioning, role limitations due to physical problems, role limitations due to emotional problems, mental health, and bodily pain.16 The EuroQOL-5D17 is a multiple attribute health utility instrument that assesses QOL from a societal perspective and classifies patients into various health states. Disease-specific measures include the Vascular Quality of Life (VascuQOL)18 questionnaire, Walking Impairment Questionnaire (WIQ),19 and Peripheral Artery Questionnaire (PAQ),20 which were developed for PAD patients and are responsive to smaller treatment effects than the general QOL measures. The VascuQOL is a 35-item survey that measures 5 dimensions (activity, symptom, pain, emotion and social functioning). The WIQ measures the ability of PAD patients to walk defined distances and speeds, plus climb stairs, thus evaluating claudication severity and nonclaudication symptoms that limit walking ability. The PAQ is a 20-item questionnaire that quantifies patients' physical limitations, symptoms, social function, treatment satisfaction, and quality of life.

Limb Outcomes

Limb outcomes include repeat revascularization, amputation, and vessel patency. Vessel patency (open blood vessel) can be further characterized into primary patency, primary assisted patency and secondary patency. Primary patency is defined as uninterrupted patency following the revascularization procedure being evaluated. Primary assisted patency occurs when a revision of the revascularization method is performed to prevent progression of stenosis or an impending stenosis. Secondary patency refers to patency of the initially treated vessel following a reintervention to restore patency after occlusion.

Therapies for PAD

The backbone of treatment for PAD is smoking cessation, risk factor modification, dietary modification, and increased physical activity. The goals of therapy for PAD depend on the severity of the disease. For all patients with PAD, both symptomatic and asymptomatic, reducing the risk of cardiovascular morbidity and mortality is a primary concern. For patients with IC, improving functional status is an additional goal. Finally, for patients with CLI, preventing leg amputation, restoring mobility, and reducing mortality are of paramount concern. Depending on the population and the goal, different treatment choices are available. The following sections focus on the different options for achieving each goal.

Reducing Cardiovascular Morbidity and Mortality in All Patients With PAD

The goal of medical therapy in patients with PAD is to reduce the risk of future cardiovascular morbidity and mortality in patients with high ischemic risk, and/or to improve walking distance and functional status in patients with IC. Secondary prevention includes the use of antiplatelet agents and angiotensin-converting enzyme (ACE) inhibitors and the management of other risk factors such as tobacco use, diabetes, LDL levels, and hypertension. Some small studies have suggested that ACE inhibitors and statins may improve functional capacity or reduce the decline in lower extremity performance.21-24 With respect to antiplatelet therapy, there is clinical uncertainty. It is not clear which antiplatelet strategy (aspirin versus clopidogrel, monotherapy versus dual antiplatelet therapy) is of most benefit. Further, the role of these agents in patients with asymptomatic PAD also is unclear. Therefore this review focused on the comparative effectiveness of antiplatelet therapy including aspirin and other antiplatelet agents in reducing the risk of adverse cardiovascular events, functional capacity, and quality of life.

Improving Functional Status in Patients With IC

There are three main treatment options for improving functional status and other clinical outcomes in patients with IC: (1) medical therapy, (2) exercise training, and (3) revascularization. Questions about comparative effectiveness include whether one approach is better than the others and whether certain combinations of them are most effective.

Medical Therapy

Selected medications, such as cilostazol and pentoxifylline, have been shown to improve walking distance in patients with PAD. Cilostazol has been shown to significantly improve MWD25 and is, therefore, considered a Class I therapy in the 2005 ACC/AHA practice guidelines.2 Cilostazol increases blood flow to the limbs both by preventing blood clots and by widening the blood vessels. Common side effects of this medication include headache and diarrhea, though its use is contraindicated in patients with congestive heart failure. An alternative medication to cilostazol is pentoxifylline, which rarely has side effects although occasionally patients complain of nausea and diarrhea. However, a prior study comparing cilostazol, pentoxifylline, and placebo found cilostazol to be superior by improving MWD by 24 weeks while pentoxifylline was not different than placebo.25 The relative effect of medical therapy with regard to exercise therapy and invasive therapies is unknown and central to this review.

Exercise Training

Over the past 30 years, research efforts within PAD have focused on the potential benefits of noninvasive therapies, including exercise therapy. More recent work has refined the mechanism of proposed benefit in exercise therapy to (1) improved endothelial function, (2) reduced systemic inflammation, and (3) improved mitochondrial function and skeletal muscle metabolism.26-35 Most studies have investigated differences in supervised exercise training when compared with home exercise training. More recently, supervised exercise training has also been compared with endovascular revascularization.

Revascularization

Historically, patients with IC have been treated conservatively for their leg symptoms with medical therapy, lifestyle modification, and exercise programs because of the low overall risk of limb-threatening ischemia.36 Strategies for revascularization include surgical or endovascular procedures. Surgical procedures include vessel bypass with venous or prosthetic grafts or endarterectomy. The method of bypass surgery depends on the size and location of the affected artery (e.g., aortobifemoral, femoropopliteal, or femoral-tibial bypass). Endarterectomy is less common and typically performed on the femoral artery. Endovascular procedures include (1) angioplasty (cryoplasty, cutting, and standard angioplasty balloons are available for use in peripheral arteries and drug-coated balloons are being tested in clinical trials), (2) stenting (self-expanding and balloon-expandable stents are available, but drug-eluting stents are not currently approved for treating peripheral arteries in the United States), and (3) atherectomy (laser, directional, orbital, and rotational atherectomy devices are approved for use in the United States). With improvements in endovascular techniques and equipment, the use of balloon angioplasty, stenting, and atherectomy has led to applying endovascular revascularization to a wider range of patients over the past decade, both among those with more severe symptoms and those with less severe symptoms.37 Large clinical studies have been performed that aim to determine the best revascularization strategy; however, many questions remain as newer endovascular therapies are applied to a broader population of patients.

Goals for treating IC with invasive therapies are to improve leg pain, walking distance, and quality of life. Decisions about whether to revascularize and how to revascularize patients with PAD depend on a number of factors, including patient-specific characteristics, anatomic location, severity of symptoms, need for possible repeat revascularization in the future, and patient and physician preferences.2 Clinical guidelines remain vague regarding the absolute indications for and appropriate use of revascularization strategies in patients with PAD.2 Clinical uncertainty exists around whether strategies of optimal medical therapy and exercise training with or without revascularization are better. Once clinicians have decided on a revascularization strategy, further uncertainty exists around the type of revascularization strategy to employ (i.e., endovascular versus surgical).

Patient characteristics such as advanced age, concomitant coronary artery disease or heart failure, and ongoing tobacco use often influence clinical decisionmaking and can make surgical revascularization unfavorable in patients for whom general anesthesia is risky. Endovascular revascularization offers multiple distinct advantages over surgical procedures. These advantages include the use of local anesthesia rather than general anesthesia, short recovery times, and reduced short-term morbidity and mortality. Critics of endovascular intervention cite the shorter duration of improvement and the need for/cost of repeat revascularization procedures as disadvantages. The introduction of hybrid revascularization techniques (endovascular and surgical revascularization performed in the same setting or with a staged approach) presents the potential advantage of combining the durability of surgical revascularization with the lower procedural risk of endovascular therapies.38

Anatomic location may help determine the preferable revascularization strategy (endovascular versus surgical); however, this topic remains controversial. The Trans-Atlantic Inter-Society Consensus Document on Management of Peripheral Arterial Disease6 provides some guidance for the revascularization strategy based on anatomic location and severity. In general, in patients with stenosis of the aortoiliac segments, balloon angioplasty and stenting compare favorably with surgical patency rates while dramatically lowering the periprocedural mortality risk. However, there is still uncertainty about the most effective revascularization strategy in patients with femoropopliteal stenosis. Multiple studies are currently comparing exercise therapy, angioplasty with or without stenting, and surgical revascularization. While improved clinical outcomes have been reported with angioplasty and stenting when compared with medical therapy, the longevity of results in the femoropopliteal segment remains a concern. Tibioperoneal, or below-knee, endovascular interventions are typically reserved for patients with limb-threatening ischemia; however, multiple reports describe the adoption of tibioperoneal intervention for severe claudication.

In an effort to improve the patency rates and longevity seen with angioplasty and stenting, atherectomy devices have gained favor as tools to debulk atherosclerotic plaque. However, randomized comparisons between balloon angioplasty (with or without stenting) and atherectomy are lacking. Additional devices designed to reduce restenosis (cryoplasty balloons, cutting balloons, drug-coated balloons, and drug-eluting stents) are currently being evaluated in RCTs.

Improving Functional Status and Reducing Leg Amputation in Patients With CLI

CLI is the most severe manifestation of PAD, and it includes patients with lower extremity rest pain, ulceration, and gangrene.2 There are currently no approved medical therapies for the treatment of CLI. At 1 year, CLI is associated with a 20-percent mortality rate and a 50-percent risk of major amputation in patients who do not undergo revascularization.2 Medical treatment for CLI is often limited to local wound therapy because there are few available disease-modifying medical treatments. Consequently, revascularization is often attempted to restore blood flow, improve wound healing, and prevent amputation in patients with CLI. The decision to attempt revascularization in patients with CLI is based on a combination of factors, including patient characteristics, severity of symptoms, anatomic considerations, and patient and physician preferences. Few RCTs of revascularization for CLI have been performed, and the clinical endpoints have varied significantly.39,40 Recently, objective performance goals have been established to standardize consensus metrics for clinical outcomes and assist in optimal clinical trial design in investigating peripheral revascularization for patients with CLI.41 Amputation-free survival is defined as the time to first amputation or death from any cause, whichever occurs first, and is generally considered the best limb and patient outcome for revascularization in patients with CLI.40

CLI is a heterogeneous condition that makes the decision to revascularize extremely complex. Patient-specific characteristics such as age, inability to ambulate, and comorbid conditions (especially the presence of diabetes mellitus and coronary heart disease) often influence the decision to perform endovascular or surgical revascularization.42 The presence and severity of tissue loss plays an important role in revascularization decisions and may impact the large degree of variation in amputation rates across geographic regions.43 Finally, the higher prevalence of multilevel disease, involvement of smaller caliber vessels, and longer occlusions often make revascularization in patients with CLI more challenging than in patients with IC. Given these issues, the choice of revascularization strategy (endovascular versus surgical) is often made on an individual basis; however, more definitive data are needed to aid clinicians in decisionmaking. This review attempts to summarize the available comparative data on endovascular versus surgical revascularization strategies.

Scope and Key Questions (KQs)

Scope of the Review

This comparative effectiveness review was funded by the Agency for Healthcare Research and Quality (AHRQ). The review was designed to evaluate the effectiveness of available strategies—medications, exercise, revascularization—used to treat patients with PAD.

Although hundreds of RCTs have been published on the management of patients with PAD, notable uncertainties remain about several key components because of conflicting results, differences in outcomes measured, and differences in revascularization techniques. The following briefly summarizes the current controversies:

  • Is aspirin effective for PAD, and if so, what is the optimal dose of aspirin to prevent cardiovascular events in patients with PAD?44 Is there a differential effect of aspirin in patients who are symptomatic versus those who are asymptomatic?
  • When patients with PAD are treated with thienopyridines for additional indications, what is the optimal dose of aspirin to prevent cardiovascular events?
  • Should the decision to treat patients with PAD with aspirin and other antiplatelet agents be based on their comorbid conditions or symptomatic status?
  • With increasing use of endovascular revascularization procedures in patients with IC, is there long-term benefit in functional status and quality of life when compared with medical therapy or exercise training?
  • In patients with IC, what is the comparative effectiveness of balloon angioplasty, stenting, and atherectomy in patients treated with an endovascular approach in improving functional capacity and quality of life?
  • In patients with CLI, what is the comparative effectiveness of endovascular revascularization techniques (balloon angioplasty, stenting, and atherectomy) and surgical revascularization techniques for outcomes such as vessel patency, revascularization, wound healing, pain, cardiovascular events, amputation, and mortality?

KQs

With input from our Technical Expert Panel (TEP), we constructed KQs using the general approach of specifying the population of interest, the interventions, comparators, outcomes, timing of outcomes, and settings (PICOTS; see the section on “Inclusion and Exclusion Criteria” in the Methods section for details). The KQs considered in this comparative effectiveness review were:

  • KQ 1. In adults with peripheral artery disease (PAD), including asymptomatic patients and symptomatic patients with atypical leg symptoms, intermittent claudication (IC), or critical limb ischemia (CLI):
    1. What is the comparative effectiveness of aspirin and other antiplatelet agents in reducing the risk of adverse cardiovascular events (e.g., all-cause mortality, myocardial infarction, stroke, cardiovascular death), functional capacity, and quality of life?
    2. Does the effectiveness of treatments vary according to the patient's PAD classification or by subgroup (age, sex, race, risk factors, or comorbidities)?
    3. What are the significant safety concerns associated with each treatment strategy (e.g., adverse drug reactions, bleeding)? Do the safety concerns vary by subgroup (age, sex, race, risk factors, comorbidities, or PAD classification)?
  • KQ 2. In adults with symptomatic PAD (atypical leg symptoms or IC):
    1. What is the comparative effectiveness of exercise training, medications (cilostazol, pentoxifylline), endovascular intervention (percutaneous transluminal angioplasty, atherectomy, or stents), and/or surgical revascularization (endarterectomy, bypass surgery) on outcomes including cardiovascular events (e.g., all-cause mortality, myocardial infarction, stroke, cardiovascular death), amputation, quality of life , wound healing, analog pain scale score, functional capacity, repeat revascularization, and vessel patency?
    2. Does the effectiveness of treatments vary by use of exercise and medical therapy prior to invasive management or by subgroup (age, sex, race, risk factors, comorbidities, or anatomic location of disease)?
    3. What are the significant safety concerns associated with each treatment strategy (e.g., adverse drug reactions, bleeding, contrast nephropathy, radiation, infection, exercise-related harms, and periprocedural complications causing acute limb ischemia)? Do the safety concerns vary by subgroup (age, sex, race, risk factors, comorbidities, anatomic location of disease)?
  • KQ 3. In adults with CLI due to PAD:
    1. What is the comparative effectiveness of endovascular intervention (percutaneous transluminal angioplasty, atherectomy, or stents) and surgical revascularization (endarterectomy, bypass surgery) for outcomes including cardiovascular events (e.g., all-cause mortality, myocardial infarction, stroke, cardiovascular death), amputation, quality of life, wound healing, analog pain scale score, functional capacity, repeat revascularization, and vessel patency?
    2. Does the effectiveness of treatments vary by subgroup (age, sex, race, risk factors, comorbidities, or anatomic location of disease)?
    3. What are the significant safety concerns associated with each treatment strategy (e.g., adverse drug reactions, bleeding, contrast nephropathy, radiation, infection, and periprocedural complications causing acute limb ischemia)? Do the safety concerns vary by subgroup (age, sex, race, risk factors, comorbidities, or anatomic location of disease)?

Analytic Framework

Figure 1 shows the analytic framework for this comparative effectiveness review.

Figure 1 depicts the key questions (KQs) within the context of the PICO (population, interventions, comparators, and outcomes) described elsewhere in this document. In general, the figure shows that the population of interest is adults with peripheral artery disease, including asymptomatic patients and patients with intermittent claudication or critical limb ischemia. Key Question 1 considers the comparative effectiveness of aspirin and other antiplatelet agents in reducing the risk of adverse cardiovascular events (e.g., myocardial infarction, stroke, cardiovascular death) and whether the effectiveness of treatments varies according to the patient's symptomatic status or by subgroup (age, sex, race, comorbidities). For patients with intermittent claudication due to peripheral artery disease, Key Question 2 considers the comparative effectiveness of exercise training, medications (cilostazol, pentoxifylline), endovascular intervention (percutaneous transluminal angioplasty, atherectomy, or stents), and/or surgical revascularization (endarterectomy, bypass surgery) on improving functional capacity and quality of life as well as whether the effectiveness of treatments varies by subgroup (age, sex, race, comorbidities, anatomic location of disease). For patients with critical limb ischemia, Key Question 3 considers the comparative effectiveness of endovascular intervention and surgical revascularization for outcomes including vessel patency, revascularization, wound healing, analog pain scale, cardiovascular events, amputation, and mortality (including amputation‐free survival) and whether the effectiveness of treatments varies by subgroup (age, sex, race, comorbidities, anatomic location of disease). All three Key Questions consider the significant safety concerns associated with each treatment strategy (e.g., adverse drug reactions, contrast nephropathy, radiation, infection, bleeding, exercise-related harms, and periprocedural complications causing acute limb ischemia) as well as whether the risks vary by subgroup (age, sex, race, comorbidities, anatomic location of disease).

Figure 1

Analytic framework. Abbreviations: KQ=Key Question; PAD=peripheral artery disease.

The analytic framework depicts the KQs within the context of the PICOTS described above. In general, the figure shows that the population of interest is adults with PAD, including asymptomatic patients and patients with IC or CLI. KQ 1 considers the comparative effectiveness of aspirin and other antiplatelet agents in reducing the risk of adverse cardiovascular events (e.g., MI, stroke, cardiovascular death) and whether the effectiveness of treatments varies according to the patient's symptomatic status or by subgroup (age, sex, race, comorbidities).

For patients with IC due to PAD, KQ 2 considers the comparative effectiveness of exercise training, medications (cilostazol, pentoxifylline), endovascular intervention (percutaneous transluminal angioplasty, atherectomy, or stents), and/or surgical revascularization (endarterectomy, bypass surgery) on improving functional capacity and quality of life as well as whether the effectiveness of treatments varies by subgroup (age, sex, race, comorbidities, anatomic location of disease).

For patients with CLI, KQ 3 considers the comparative effectiveness of endovascular intervention and surgical revascularization for outcomes including vessel patency, revascularization, wound healing, analog pain scale, cardiovascular events, amputation, and mortality (including amputation‐free survival) and whether the effectiveness of treatments varies by subgroup (age, sex, race, comorbidities, anatomic location of disease). All three KQs consider the significant safety concerns associated with each treatment strategy (e.g., adverse drug reactions, contrast nephropathy, radiation, infection, bleeding, exercise-related harms, and periprocedural complications causing acute limb ischemia) as well as whether the risks vary by subgroup (age, sex, race, comorbidities, anatomic location of disease).