On January 31, 2013, amendments were made to this protocol. To view the amendments, please see the section titled “Summary of Protocol Amendments.”
Background and Objectives for the Systematic Review
Epidemiology of Peripheral Artery Disease
Peripheral artery disease (PAD) is the preferred clinical term for describing stenosis or occlusion of upper- or lower-extremity arteries due to atherosclerotic or thromboembolic disease.1 However, in practice, the term PAD generally refers to chronic narrowing or blockage (also referred to as atherosclerotic disease) of the lower extremities. Consequently, the focus of this systematic review will be on chronic atherosclerotic disease of the lower extremities.
PAD represents a spectrum of disease severity, encompassing both asymptomatic and symptomatic disease. About 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. As 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. About 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. As the disease progresses, patients may develop more severe claudication, with reduced walking distance and eventually with rest pain. 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 about 1 to 2 percent of all patients with PAD, and patients with CLI have a mortality of 25 percent at 1 year.2
The prevalence of PAD increases with age, such that about 20 percent of patients over age 65 have PAD (including symptomatic and asymptomatic).3,4 Given the nearly 40 million Americans over age 65, this represents about 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 about 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 sex, older 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, stroke, and death. PAD is also a major cause of limb amputation.7-11
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 ≤0.40 are considered to have severe PAD. Similarly, an ABI >1.30 is abnormal and requires further testing. Data have shown an inverse relationship between baseline ABI and the risk of ischemic events (myocardial infarction, stroke, or cardiovascular death), such that as the ABI decreases, the risk of ischemic events increases.12,13 Similarly, mortality increases with an ABI >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.
While ABI measurements may quantify PAD severity, the ABI represents a numerical value that does not give clinicians a full picture of the clinical severity of the disease. There are two classification systems, the Rutherford and the Fontaine,2 used by clinicians to grade the severity of the clinical symptoms of patients. Tables 1 and 2 highlight these classification systems and show that patients with a higher stage of the disease have more advanced/severe PAD.
|Stage I||No symptoms|
|Stage IIa||Intermittent claudication >200 m of walking distance (mild)|
|Stage IIb||Intermittent claudication <200 m of walking distance (moderate to severe)|
|Stage 3||Rest pain|
|Stage 1||Mild claudication|
|Stage 2||Moderate claudication|
|Stage 3||Severe claudication|
|Stage 4||Rest pain|
|Stage 5||Ischemic ulceration not exceeding ulcer of the digits of the foot|
|Stage 6||Severe ischemic ulcers or frank gangrene|
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, intermittent claudication): Fontaine stages IIa and IIb; Rutherford stages 1, 2, and 3
- Critical limb ischemia: Fontaine stages 3 and 4; Rutherford stages 4, 5, and 6
Therapies for PAD
The goals of PAD therapy depend on the severity of the disease. For all patients with symptomatic or asymptomatic PAD, 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 therapeutic goal.
Reducing Cardiovascular Morbidity and Mortality in All Patients With PAD
The goal of medical therapy is to reduce the risk of future cardiovascular morbidity and mortality in patients with high ischemic risk. 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, low-density lipoprotein 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.14-17 Because study data are limited, and because more definitive trial data are needed to permit conclusions about the benefits of ACE inhibitors and statins, we will not include studies of these drugs in our review. The management of risk factors (i.e., tobacco use, diabetes, low-density lipoprotein levels, and hypertension) is considered standard therapy for all patients with PAD regardless of PAD classification and, therefore, will be considered concurrent therapy with the medical and revascularization strategies examined in our review. With respect to antiplatelet therapy, it is not clear what dose of aspirin or which antiplatelet strategy (aspirin vs. clopidogrel, monotherapy vs. dual-antiplatelet therapy) is of most benefit. Further, the role of these agents in patients with asymptomatic PAD is also unclear. Therefore, this study will focus on the comparative effectiveness of aspirin and other antiplatelet agents in reducing the risk of adverse cardiovascular events and in improving functional capacity and quality of life.
A number of trials have addressed the questions of aspirin dose and choice of antiplatelet strategy, but different studies have achieved different results, making firm conclusions difficult. A meta-analysis conducted by the Antithrombotic Trialists’ Collaboration has demonstrated the benefit of at least a 75-mg dose of aspirin among patients with PAD, finding that a 75-mg to 150-mg dose of aspirin was at least as effective as higher doses.18 However, a recent meta-analysis of all trials in which aspirin was used for primary prevention in patients with vascular disease did not find a statistically significant benefit.19 The CAPRIE (clopidogrel versus aspirin in patients at risk of ischaemic events) trial demonstrated that clopidogrel further reduced cardiovascular risk when compared to aspirin in patients with symptomatic PAD.20 Meanwhile, the CHARISMA (clopidogrel for high atherothrombotic risk and ischemic stabilization, management, and avoidance) trial found that although there was no benefit of dual-antiplatelet therapy with clopidogrel plus aspirin versus aspirin monotherapy overall, patients in the symptomatic PAD subgroup derived some benefit from dual-antiplatelet therapy with a reduction in the rate of myocardial infarction and rehospitalization for ischemic attacks.21 The results of the CHARISMA trial were published after the American College of Cardiology and the American Heart Association (ACC/AHA) 2005 practice guidelines,2 so the recommendations for clopidogrel monotherapy as a possible antiplatelet strategy were based on the CAPRIE trial alone.
An updated systematic review that incorporates the results of both the CAPRIE and CHARISMA trials, as well as other published literature, is needed to determine the aspirin dose and optimal choice of antiplatelet strategy for patients with PAD. Furthermore, given the limited available evidence for the 2005 ACC/AHA guidelines, a more contemporary review of the literature is needed to determine the benefit of antiplatelet agents on asymptomatic versus symptomatic patients with PAD.
Improving Functional Status in Patients With Intermittent Claudication
There are three main treatment options for improving functional status in patients with intermittent claudication: exercise training, medical therapy, and revascularization. Questions about comparative effectiveness include whether one approach is better than the other and whether certain combinations of them are most effective.
1. Exercise training
Over the past 30 years, research efforts have focused on the potential benefits of noninvasive therapies, including exercise therapy. Most studies have investigated differences in supervised exercise training when compared with standard home exercise training. More recently, supervised exercise training has also been compared to endovascular revascularization.
Exercise therapy versus usual care. Numerous randomized controlled trials (RCTs) have investigated exercise training in the PAD population. However, there are several challenges in interpreting and comparing the results of these trials. First, there were significant intertrial variations in the control groups, the types and duration of exercise training, and the outcome measures. Further, none of the trials were double-blinded, since it is impossible to blind the patient to an exercise regimen. Exercise regimens were generally supervised and lasted between 3 and 12 months, with outcomes measured between 14 days and 2 years. Exercise regimens varied from strength training to cycling to upper and lower limb exercises. However, outcomes generally included a treadmill walking test, which was alternatively reported as either walking time or walking distance. Also, compliance was highly variable and was reported to be as low as 49 percent in one trial.
The most recent Cochrane review, performed in 2008, compared exercise training to usual care.22 It found statistically significant improvements in walking measures (walking distance or walking time) in patients randomized to exercise training. Since then, two additional RCTs of exercise versus usual therapy in patients with PAD and one additional RCT of home-based exercise versus supervised exercise have been published.23
Exercise therapy versus endovascular therapy. The 2008 Cochrane review by Watson et al.22 identified only two RCTs that compared walking outcomes in endovascular therapy versus exercise training.24,25 These trials showed mixed results, with one trial finding angioplasty superior in increasing walking distance and the other finding exercise superior in improving walking time. A review by Wilson26 identified an additional four RCTs conducted between 1990 and 2008 that compared exercise training to percutaneous transluminal angioplasty with or without a stent. These trials included 56 to 151 randomized patients. None of the trials showed a difference in ABI at 6 months or 1 year after a program of exercise training. Perkins et al.27 and Whyman et al.28 found modest but significant improvements in ABI for patients undergoing percutaneous transluminal angioplasty with or without stenting at 6 months, but this result did not persist at the 1-year followup. While none of the exercise training arms showed any statistical improvement in ABI, all trials did show an increase in maximum walking distance in the exercise arm at 6 months to 2 years.
Two additional RCTs have been completed since the Watson et al.22 and Wilson26 reviews and suggested that endovascular revascularization plus exercise training is superior to exercise training alone with regard to maximum walking distance. In the OBACT (Oslo balloon angioplasty versus conservative treatment) trial,29 patients in the combined arm showed an improvement in maximum walking distance with the addition of angioplasty to exercise. The MIMIC (mild to moderate IC) trial30 found that, “PTA against a background of supervised exercise and best medical therapy” was superior to supervised exercise and medical therapy alone with respect to maximum walking distance and ABI at 2 years. Importantly, endovascular intervention in the OBACT and MIMIC trials was primarily confined to the aortoiliac and femoropopliteal areas. In addition, the CLEVER (claudication: exercise versus endoluminal revascularization) trial—a National Institutes of Health–sponsored small, randomized trial studying optimal medical therapy versus supervised exercise therapy versus endovascular revascularization—has recently published 6-month outcome data.31 In this cohort of patients with aortoiliac disease, supervised exercise therapy improved peak walking time and patient-reported quality of life over optimal medical therapy. Notably, while peak walking time showed greater improvement in supervised exercise therapy versus stenting, stenting was superior in improving patient-reported quality of life.
To summarize, because of a longitudinal trend in increased use of endovascular revascularization, it is imperative to compare the efficacy of exercise training and endovascular revascularization on walking measures and quality of life in patients with PAD. An updated systematic review incorporating new RCTs and the results of the CLEVER trial would be useful for understanding the effectiveness of lifestyle modification (exercise) as opposed to endovascular procedures for patients with symptomatic IC.
2. Medical therapy
Selected medical therapies have been shown to improve walking distance. Cilostazol has been shown to significantly improve maximal walking distance32 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 though occasionally patients complain of nausea and diarrhea. However, a previous study comparing cilostazol, pentoxifylline, and placebo found cilostazol to be superior by improving maximal walking distance by 24 weeks while pentoxifylline was not different than placebo.32
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.33 Multiple strategies for revascularization include surgery, angioplasty (cryoplasty, drug-coated, cutting, and standard angioplasty balloons are available for use in peripheral arteries), 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 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 application of 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.34 Large clinical trials have been performed that aim to determine the best revascularization strategy for patients with PAD; 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 (i.e., endovascular vs. 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 and 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.35
Anatomic location may help determine the preferable revascularization strategy (endovascular vs. 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 trials 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 to 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-eluting balloons, and drug-eluting stents) are currently being evaluated in RCTs. An updated systematic review incorporating findings from newer trials will help address questions about the effectiveness of revascularization strategies for IC.
Improving Functional Status and Reducing Leg Amputation in Patients With Critical Limb Ischemia
CLI is the most severe manifestation of PAD and is characterized by lower extremity rest pain, ulceration, and gangrene.2 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 end points have varied significantly.36,37 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.38 Amputation-free survival is generally considered the best limb and patient outcome for revascularization in patients with CLI.37
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.39 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.40 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 vs. surgical) is often made on an individual basis; however, more definitive data are needed to aid clinicians in decisionmaking.
Challenges in Comparing Endovascular With Surgical Revascularization
The challenges of comparing endovascular with surgical revascularization techniques in published trials include:
- Population differences: Inclusion and exclusion criteria have varied among trials, and stratification based on procedural risk is important.
- End point differences: The surgical literature defines success with primary and secondary patency, while the endovascular literature measures success by the lack of need for target lesion or target vessel revascularization.
- Length of followup: Trials have been biased toward shorter duration of followup, thus heavily influencing an important clinical end point: amputation-free survival.
- Evolution of revascularization techniques: Improvement in surgical and endovascular techniques has made direct comparisons between “state-of-the-art” strategies more challenging.
- Crossover between surgical and endovascular therapies: Patients often undergo both surgical and endovascular revascularization in trials as well as in clinical practice, either as part of a hybrid approach to revascularization or because of treatment failure.
The BASIL (bypass versus angioplasty in severe ischaemia of the leg) trial36 was an RCT that compared endovascular and surgical revascularization. In this trial of patients who were enrolled as suitable candidates for either revascularization strategy, patients in both arms of the trial had similar clinical outcomes at 6 months and 2 years when analyzed in an intention-to-treat fashion.36,41 Unfortunately, the trial was limited because the endovascular technology was balloon-only and did not include more recently developed stents. Additionally, the subjects of the trial were a select population because 70 percent of the patients with CLI who were screened were considered ineligible for the trial based on physician belief and preference for a specific revascularization strategy. Further, more recent smaller trials have now demonstrated improved outcomes with revascularization with refined techniques, newer devices, and greater operator experience. Interpretation of the BASIL trial is further complicated by significant crossover between the surgical and angioplasty arms, rendering BASIL a strategy trial rather than a direct comparison of endovascular versus surgical therapy.41 When compared with an intention-to-treat analysis showing no difference in amputation-free survival or mortality at 2 years, the as-treated analysis revealed that amputation-free survival was worse in patients who failed endovascular therapy. Given the limitations of the individual studies available, an updated systematic review incorporating findings from previous and current trials will help address the effectiveness of endovascular interventions when compared with surgical bypass for CLI.
Rationale for Evidence Review and Current Clinical Uncertainty
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 endovascular techniques. The following is a brief summary of the current controversies:
- What is the optimal dose of aspirin to prevent cardiovascular events in patients with PAD? 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?
The Key Questions
The draft key questions (KQs) developed during Topic Refinement were available for public comment from October 7, 2011, to November 3, 2011. Based on comments received in response to this posting, the following changes were made to the KQs:
- Inclusion of symptomatic patients with atypical leg symptoms in KQs 1 and 2
- Expansion of outcome measures for both KQ 2 and KQ 3 to include cardiovascular events, mortality, amputation, functional capacity, and quality of life
The KQs, revised after public comments, are found in the table below. Consideration of public comments also resulted in minor changes to the analytic framework and population of interest.
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):
In adults with symptomatic PAD (atypical leg symptoms or IC):
In adults with CLI due to PAD:
- Adults with PAD:
- KQ 1: Asymptomatic PAD or symptomatic PAD (atypical leg symptoms, IC, or CLI)
- KQ 2: Symptomatic PAD with atypical leg symptoms or IC
- KQ 3: CLI
- KQ 1: Antiplatelet agents (including aspirin)
- KQ 2: Exercise training, medications (cilostazol, pentoxifylline), endovascular intervention (percutaneous transluminal arterial angioplasty, atherectomy, stenting), and surgical revascularization (endarterectomy, bypass surgery)
- KQ 3: Endovascular intervention (percutaneous transluminal arterial angioplasty, atherectomy, stenting) and surgical revascularization (endarterectomy, bypass surgery)
See Appendix 1 for information on the medications and devices under consideration.
- KQ 1: Antiplatelet agents (including aspirin)
- KQ 2: Exercise training, medications (cilostazol, pentoxifylline), endovascular intervention (percutaneous transluminal arterial angioplasty, atherectomy, stenting), and surgical revascularization (endarterectomy, bypass surgery)
- KQ 3: Endovascular intervention (percutaneous transluminal arterial angioplasty, atherectomy, stenting) and surgical revascularization (endarterectomy, bypass surgery)
- KQs 1–3 (if applicable to the intervention/comparator and reported by the publication): Vessel patency, repeat revascularization, wound healing, analog pain scale score, cardiovascular events (e.g., all-cause mortality, myocardial infarction, stroke, cardiovascular death), amputation, functional capacity (e.g., peak walking time, mean or 6-minute walking distance, claudication onset time, mean claudication distance), and quality of life (e.g., Walking Impairment Questionnaire, Peripheral Artery Questionnaire), as well as intervention-related adverse effects (adverse drug reactions, bleeding, contrast nephropathy, radiation, infection, exercise-related harms, periprocedural complications)
- Studies with all durations of followup will be included in the review. The duration of treatment and followup will be considered when evaluating the benefits and risks of IC and CLI therapies: short term (≤30 days), intermediate term (31 days to 1 year), and long term (>1 year).
Draft analytic framework for treatment strategies for PAD
Abbreviations: KQ = key question; PAD = peripheral artery disease
In developing this comprehensive review, we will apply the rules of evidence and formulation of strength of evidence recommended by the Agency for Health Care Research and Quality (AHRQ) in its Methods Guide for Effectiveness and Comparative Effectiveness Reviews (hereafter referred to as the Methods Guide).42We will solicit feedback regarding design of the review (such as development of search strategies and identifying outcomes of key importance) from the Task Order Officer and the Technical Expert Panel; however, the Technical Expert Panel will not review or provide feedback on the analysis. We will follow the methodology recommended to the Evidence-based Practice Centers for literature search strategies, inclusion/exclusion of studies in our review, abstract screening, data abstraction and management, assessment of methodological quality of individual studies, data synthesis, and grading of evidence for each KQ. Using prespecified inclusion/exclusion criteria, two reviewers will review titles and abstracts for potential relevance to the KQs. Articles included by either reviewer will undergo full-text screening. At the full-text screening stage, two independent reviewers must agree on a final inclusion/exclusion decision prior to data abstraction. If the paired reviewers arrive at different decisions about whether to include or exclude an article, a third investigator will reconcile the difference.
|Study Characteristic||Inclusion Criteria||Exclusion Criteria|
aFor all included studies, we will indicate the total number of patients enrolled and report followup duration.
Abbreviations: KQ = key question; PAD = peripheral artery disease
|Population||Adult patients (≥18 years of age) with lower extremity PAD (e.g., ankle-brachial index <0.9) who are asymptomatic or symptomatic (atypical leg symptoms, intermittent claudication, or critical limb ischemia)||
|Interventions and comparators||
||No primary or secondary outcomes of interest are reported|
KQs 1–3: Individual characteristics including
|Outcomes (safety)||KQs 1–3: Intervention-related safety and adverse effects including adverse drug reactions, bleeding, contrast nephropathy, radiation, infection, exercise-related harms, and periprocedural complications causing acute limb ischemia||None|
|Timing||All durations of followup will be included; the duration of treatment and followup will be considered when evaluating the benefits and risks of intermittent claudication and critical limb ischemia therapies: short term (≤30 days), intermediate term (31 days to 1 year), and long term (>1 year)||None|
|Setting||Inpatient and outpatient||None|
||Not a clinical study (e.g., editorial, nonsystematic review, letter to the editor, case series)|
||Given the high volume of literature available in English-language publications (including the majority of known important studies), non–English-language articles will be excludedb|
B. Searching for the Evidence: Literature Search Strategies for Identification of Relevant Studies To Answer the Key Questions
Our search strategy will use the National Library of Medicine’s medical subject headings (MeSH®) keyword nomenclature developed for MEDLINE® and adapted for use in other databases. In consultation with our research librarians, we will use PubMed®, EMBASE®, and the Cochrane Database of Systematic Reviews for our literature search. Our proposed search strategy for PubMed is included in Appendix 2; this strategy will be adapted as necessary for use in the other databases. We will date-limit our search to articles published since January 1995, corresponding with the time period when contemporary studies on antiplatelet therapy, exercise training, endovascular interventions, and surgical revascularization were published. The reference list for identified pivotal articles will be manually hand-searched and cross-referenced against our library, and additional manuscripts will be retrieved. All citations will be imported into an electronic database (EndNote® X4 or higher; Thomson Reuters, Philadelphia, PA).
We will also search the gray literature of study registries and conference abstracts for relevant articles from completed studies. Gray literature databases will include ClinicalTrials.gov; metaRegister of Controlled Trials; ClinicalStudyResults.org; the World Health Organization (WHO) International Clinical Trials Registry Platform Search Portal; and ProQuest COS Conference Papers Index. Scientific information packets will be requested from the manufacturers of medications and devices that are listed in Appendix 1 and reviewed for relevant articles from completed studies not previously identified in the literature searches.
C. Data Abstraction and Data Management
The research team will create data abstraction forms and evidence table templates for abstracting data for the KQs. Based on clinical and methodological expertise, a pair of researchers will be assigned to the research questions to abstract data from the eligible articles. One of the pair will abstract the data, and the second researcher will over-read the article and the accompanying abstraction to check for accuracy and completeness. Disagreements will be resolved by consensus or by obtaining a third reviewer’s opinion if consensus cannot be reached between the first two researchers.
To aid in both reproducibility and standardization of data collection, researchers will receive data abstraction instructions directly on each form created specifically for this project with the DistillerSR data synthesis software program (Evidence Partners Inc., Manotick, ON, Canada). We will design the data abstraction forms for this project to collect data required to evaluate the specified eligibility criteria for inclusion in this review (asymptomatic patients, patients with atypical leg pain, IC, or CLI), as well as demographic and other data (patient characteristics, medications, and procedure characteristics) needed for determining outcomes (intermediate outcomes, health outcomes, and safety outcomes). The safety outcomes will be framed to help identify adverse events, including adverse drug reactions, contrast nephropathy, radiation, infection, bleeding, exercise-related harms, and periprocedural complications causing acute limb ischemia.
Data needed to assess quality and applicability as described in the Methods Guide42 will also be abstracted. Before they are used, abstraction form templates will be pilot tested with a sample of included articles to ensure that all relevant data elements are captured and that there is consistency/reproducibility between abstractors. Forms will be revised as necessary before full abstraction of all included articles.
D. Assessment of Methodological Quality of Individual Studies
The included studies will be assessed on the basis of the quality of their reporting of relevant data. We will evaluate the quality of individual studies by using the approach described in the Methods Guide.42 To assess quality, we will employ the strategy to 1) classify the study design, 2) apply predefined criteria for quality and critical appraisal, and 3) arrive at a summary judgment of the study’s quality. To evaluate methodological quality, we will apply criteria for each study type derived from the core elements described in the Methods Guide.42 For RCTs, criteria include adequacy of randomization and allocation concealment; the comparability of groups at baseline; blinding; the completeness of followup and differential loss to followup; whether incomplete data were addressed appropriately; the validity of outcome measures; and conflict of interest. For observational studies, we will assess the following study-specific issues that may affect the internal validity of our systematic review: potential for selection bias (i.e., degree of similarity between intervention and control patients); performance bias (i.e., differences in care provided to intervention and control patients not related to the study intervention); attribution and detection bias (i.e., whether outcomes were differentially detected between intervention and control groups); and magnitude of reported intervention effects (see the section on “Selecting Observational Studies for Comparing Medical Interventions” in AHRQ’s Methods Guide42).
To indicate the summary judgment of the quality of the individual studies, we will use the summary ratings of good, fair, or poor based on their adherence to well-accepted standard methodologies and adequate reporting. For all studies, the overall study quality will be assessed as follows:
- Good (low risk of bias)—These studies had the least bias, and the results were considered valid. These studies adhered to the commonly held concepts of high quality, including the following: a clear description of the population, setting, approaches, and comparison groups; appropriate measurement of outcomes; appropriate statistical and analytic methods and reporting; no reporting errors; a low dropout rate; and clear reporting of dropouts.
- Fair—These studies were susceptible to some bias, but not enough to invalidate the results. They did not meet all the criteria required for a rating of good quality because they had some deficiencies, but no flaw was likely to cause major bias. The study may have been missing information, making it difficult to assess limitations and potential problems.
- Poor (high risk of bias)—These studies had significant flaws that might have invalidated the results. They had serious errors in design, analysis, or reporting; large amounts of missing information; or discrepancies in reporting.
Grading will be outcome-specific; thus, a given study may be graded to be of different quality for two individual outcomes reported within that study. Study design will be considered when grading quality. RCTs will be graded as good, fair, or poor. Observational studies will be graded separately, also as good, fair, or poor. We anticipate that any included retrospective studies would fall into a grading of fair or poor.
E. Data Synthesis
We will summarize the primary literature by abstracting relevant continuous (e.g., age, event rates) and categorical data (e.g., race, presence of coronary disease risk factors). Continuous variable outcomes will be summarized by mean and standard deviation; significance testing will be performed with t-tests (if normally distributed) or nonparametric tests (if non-normally distributed). Categorical variable outcomes will be summarized by proportions; significance testing will be performed by Cochran-Mantel-Haemszel chi-squared analysis. We will then determine the feasibility of completing a quantitative synthesis (i.e., meta-analysis). Feasibility depends on the volume of relevant literature, conceptual homogeneity of the studies (e.g., study design, patient population, intervention, comparator, outcome), and completeness of the results reporting. When a meta-analysis is appropriate, we will use random-effects models to quantitatively synthesize the available evidence. We will test for heterogeneity while recognizing that the ability of statistical methods to detect heterogeneity may be limited. For comparison, we will also perform fixed-effects meta-analysis. We will present summary estimates, standard errors, and confidence intervals.
F. Grading the Evidence for Each Key Question
The strength of evidence for each KQ will be assessed by using the approach described in the Methods Guide.43 The evidence will be evaluated by using the four required domains: risk of bias (low, medium, or high), consistency (consistent, inconsistent, or unknown/not applicable), directness (direct or indirect), and precision (precise or imprecise). Additionally, when appropriate, the studies will be evaluated for dose-response association, the presence of confounders that would diminish an observed effect, strength of association (magnitude of effect), and publication bias. The strength of evidence will also be assigned an overall grade of high, moderate, low, or insufficient according to the following four-level scale:
- High—High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.
- Moderate—Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate.
- Low—Low confidence that the evidence reflects the true effect. Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate.
- Insufficient—Evidence either is unavailable or does not permit estimation of effect.
G. Assessing Applicability
We will use data abstracted on the population studied, the intervention and comparator, the outcomes measured, study settings, and timing of assessments to identify specific issues that may limit the applicability of individual studies or a body of evidence as recommended in the Methods Guide.44 We will use these data to evaluate the applicability to clinical practice, paying special attention to study eligibility criteria, demographic features of the enrolled population (such as age, ethnicity, and sex) in comparison with the target population, version or characteristics of the intervention used in comparison with therapies currently in use (such as specific components of treatments considered to be “optimal medical therapy,” plus advancements in endovascular and surgical revascularization techniques that have changed over time), and clinical relevance and timing of the outcome measures. We will summarize issues of applicability qualitatively.
- Hiatt WR, Goldstone J, Smith SC Jr, et al; American Heart Associaton Writing Group 1. Atherosclerotic Peripheral Vascular Disease Symposium II: nomenclature for vascular diseases. Circulation 2008;118(25):2826-9. PMID: 19106403.
- Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 Practice Guidelines for the Management of Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006;113(11):e463-654. PMID: 16549646.
- Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001;286(11):1317-24. PMID: 11560536.
- Meijer WT, Hoes AW, Rutgers D, et al. Peripheral arterial disease in the elderly: the Rotterdam Study. Arterioscler Thromb Vasc Biol 1998;18(2):185-92. PMID: 9484982.
- Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med 2001;344(21):1608-21. PMID: 11372014.
- Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg 2007;33 Suppl 1:S1-75. PMID: 17140820.
- Criqui MH, Ninomiya JK, Wingard DL, et al. Progression of peripheral arterial disease predicts cardiovascular disease morbidity and mortality. J Am Coll Cardiol 2008;52(21):1736-42. PMID: 19007695.
- Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992;326(6):381-6. PMID: 1729621.
- Remes L, Isoaho R, Vahlberg T, et al. Quality of life among lower extremity peripheral arterial disease patients who have undergone endovascular or surgical revascularization: a case-control study. Eur J Vasc Endovasc Surg 2010;40(5):618-25. PMID: 20418121.
- Nehler MR, McDermott MM, Treat-Jacobson D, et al. Functional outcomes and quality of life in peripheral arterial disease: current status. Vasc Med 2003;8(2):115-26. PMID: 14518614.
- Kannel WB. Risk factors for atherosclerotic cardiovascular outcomes in different arterial territories. J Cardiovasc Risk 1994;1(4):333-9. PMID: 7621317.
- Resnick HE, Lindsay RS, McDermott MM, et al. Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study. Circulation 2004;109(6):733-9. PMID: 14970108.
- Mehler PS, Coll JR, Estacio R, et al. Intensive blood pressure control reduces the risk of cardiovascular events in patients with peripheral arterial disease and type 2 diabetes. Circulation 2003;107(5):753-6. PMID: 12578880.
- Bernardi D, Bartoli P, Ferreri A, et al. Assessment of captopril and nicardipine effects on chronic occlusive arterial disease of the lower extremity using Doppler ultrasound. Angiology 1988;39(11):942-52. PMID: 3052183.
- Roberts DH, Tsao Y, McLoughlin GA, et al. Placebo-controlled comparison of captopril, atenolol, labetalol, and pindolol in hypertension complicated by intermittent claudication. Lancet 1987;2(8560):650-3. PMID: 2887941.
- Van de Ven LL, Van Leeuwen JT, Smit AJ. The influence of chronic treatment with betablockade and angiotensin converting enzyme inhibition on the peripheral blood flow in hypertensive patients with and without concomitant intermittent claudication. A comparative cross-over trial. Vasa 1994;23(4):357-62. PMID: 7817618.
- Giri J, McDermott MM, Greenland P, et al. Statin use and functional decline in patients with and without peripheral arterial disease. J Am Coll Cardiol 2006;47(5):998-1004. PMID: 16516084.
- Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324(7329):71-86. PMID: 11786451. Erratum in: BMJ 2002;324(7330):141.
- Berger JS, Krantz MJ, Kittelson JM, et al. Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials. JAMA 2009;301(18):1909-19. PMID: 19436018.
- CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348(9038):1329-39. PMID: 8918275.
- Cacoub PP, Bhatt DL, Steg PG, et al; CHARISMA Investigators. Patients with peripheral arterial disease in the CHARISMA trial. Eur Heart J 2009;30(2):192-201. PMID: 19136484.
- Watson L, Ellis B, Leng GC. Exercise for intermittent claudication. Cochrane Database Syst Rev 2008 Oct 8;(4):CD000990. PMID: 18843614.
- Gardner AW, Parker DE, Montgomery PS, et al. Efficacy of quantified home-based exercise and supervised exercise in patients with intermittent claudication: a randomized controlled trial. Circulation 2011;123(5):491-8. PMID: 21262997.
- Creasy TS, McMillan PJ, Fletcher EW, et al. Is percutaneous transluminal angioplasty better than exercise for claudication? Preliminary results from a prospective randomised trial. Eur J Vasc Surg 1990;4(2):135-40. PMID: 2140987.
- Hobbs SD, Marshall T, Fegan C, et al. The constitutive procoagulant and hypofibrinolytic state in patients with intermittent claudication due to infrainguinal disease significantly improves with percutaneous transluminal balloon angioplasty. J Vasc Surg 2006;43(1):40-6. PMID: 16414385.
- Wilson SE. Trials of endovascular treatment for superficial femoral artery occlusive lesions: a call for medically managed control patients. Ann Vasc Surg 2010;24(4):498-502. PMID: 20036508.
- Perkins JM, Collin J, Creasy TS, et al. Exercise training versus angioplasty for stable claudication. Long and medium term results of a prospective, randomised trial. Eur J Vasc Endovasc Surg 1996;11(4):409-13. PMID: 8846172.
- Whyman MR, Fowkes FG, Kerracher EM, et al. Is intermittent claudication improved by percutaneous transluminal angioplasty? A randomized controlled trial. J Vasc Surg 1997;26(4):551-7. PMID: 9357454.
- Nylaende M, Abdelnoor M, Stranden E, et al. The Oslo balloon angioplasty versus conservative treatment study (OBACT)—the 2-years results of a single centre, prospective, randomised study in patients with intermittent claudication. Eur J Vasc Endovasc Surg 2007;33(1):3-12. PMID: 17055756.
- Greenhalgh RM, Belch JJ, Brown LC, et al; MIMIC Trial Participants. The adjuvant benefit of angioplasty in patients with mild to moderate intermittent claudication (MIMIC) managed by supervised exercise, smoking cessation advice and best medical therapy: results from two randomised trials for stenotic femoropopliteal and aortoiliac arterial disease. Eur J Vasc Endovasc Surg 2008;36(6):680-8. PMID: 19022184.
- Murphy TP, Cutlip DE, Regensteiner JG, et al; CLEVER Study Investigators. Supervised exercise versus primary stenting for claudication resulting from aortoiliac peripheral artery disease: six-month outcomes from the Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) Study. Circulation 2012;125(1):130-9. PMID: 22090168.
- Dawson DL, Cutler BS, Hiatt WR, et al. A comparison of cilostazol and pentoxifylline for treating intermittent claudication. Am J Med 2000;109(7):523-30. PMID: 11063952.
- Schmieder FA, Comerota AJ. Intermittent claudication: magnitude of the problem, patient evaluation, and therapeutic strategies. Am J Cardiol 2001;87(12A):3D-13D. PMID: 11434894.
- Jaff MR, Cahill KE, Yu AP, et al. Clinical outcomes and medical care costs among medicare beneficiaries receiving therapy for peripheral arterial disease. Ann Vasc Surg 2010;24(5):577-87. PMID: 20579582.
- Dosluoglu HH, Lall P, Cherr GS, et al. Role of simple and complex hybrid revascularization procedures for symptomatic lower extremity occlusive disease. J Vasc Surg 2010;51(6):1425-35.e1. PMID: 20488323.
- Adam DJ, Beard JD, Cleveland T, et al; BASIL Trial Investigators. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet 2005;366(9501):1925-34. PMID: 16325694.
- Conte MS, Bandyk DF, Clowes AW, et al; PREVENT III Investigators. Results of PREVENT III: a multicenter, randomized trial of edifoligide for the prevention of vein graft failure in lower extremity bypass surgery. J Vasc Surg 2006;43(4):742-51; discussion 751. PMID: 16616230.
- Goodney PP, Schanzer A, Demartino RR, et al; Vascular Study Group of New England. Validation of the Society for Vascular Surgery's objective performance goals for critical limb ischemia in everyday vascular surgery practice. J Vasc Surg 2011;54(1):100-8.e4. PMID: 21334173.
- Abou-Zamzam AM Jr, Gomez NR, Molkara A, et al. A prospective analysis of critical limb ischemia: factors leading to major primary amputation versus revascularization. Ann Vasc Surg 2007;21(4):458-63. PMID: 17499967.
- Feinglass J, Sohn MW, Rodriguez H, et al. Perioperative outcomes and amputation-free survival after lower extremity bypass surgery in California hospitals, 1996-1999, with follow-up through 2004. J Vasc Surg 2009;50(4):776-83.e1. PMID: 19595538
- Bradbury AW; BASIL Trial Investigators and Participants. Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial in perspective. J Vasc Surg 2010;51(5 Suppl):1S-4S. PMID: 20435257.
- Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality; August 2011. AHRQ Publication No. 10(11)-EHC063-EF. Chapters available at: www.effectivehealthcare.ahrq.gov. 43. Owens DK, Lohr KN, Atkins D, et al. AHRQ series paper 5: grading the strength of a body of evidence when comparing medical interventions—Agency for Healthcare Research and Quality and the Effective Health-Care Program. J Clin Epidemiol 2010;63(5):513-23. PMID: 19595577.
- Atkins D, Chang SM, Gartlehner G, et al. Assessing applicability when comparing medical interventions: AHRQ and the Effective Health Care Program. J Clin Epidemiol 2011;64(11):1198-207. PMID: 21463926.
Definition of Terms
ABI ankle-brachial index
ACC American College of Cardiology
ACE angiotensin-converting enzyme
AHA American Heart Association
CLI critical limb ischemia
IC intermittent claudication
KQ key question
PAD peripheral artery disease
RCT randomized controlled trial
Summary of Protocol Amendments
Protocol Amendment Code
Review of Key Questions
For all EPC reviews, key questions were reviewed and refined as needed by the EPC with input from Key Informants and the Technical Expert Panel (TEP) to assure that the questions are specific and explicit about what information is being reviewed. In addition, for Comparative Effectiveness reviews, the key questions were posted for public comment and finalized by the EPC after review of the comments.
Key Informants are the end-users of research, including patients and caregivers, practicing clinicians, relevant professional and consumer organizations, purchasers of health care, and others with experience in making health care decisions. Within the EPC program, the Key Informant role is to provide input into identifying the Key Questions for research that will inform health care decisions. The EPC solicits input from Key Informants when developing questions for systematic review or when identifying high-priority research gaps and needed new research. Key Informants are not involved in analyzing the evidence or writing the report and have not reviewed the report, except as given the opportunity to do so through the peer or public review mechanism.
Key Informants must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their role as end-users, individuals are invited to serve as Key Informants and those who present with potential conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential conflicts of interest identified.
Technical Experts comprise a multidisciplinary group of clinical, content, and methodological experts who provide input in defining populations, interventions, comparisons, or outcomes as well as identifying particular studies or databases to search. They are selected to provide broad expertise and perspectives specific to the topic under development. Divergent and conflicted opinions are common and perceived as healthy scientific discourse that results in a thoughtful, relevant systematic review. Therefore study questions, design, and/or methodological approaches do not necessarily represent the views of individual technical and content experts. Technical Experts provide information to the EPC to identify literature search strategies and recommend approaches to specific issues as requested by the EPC. Technical Experts do not do analysis of any kind nor contribute to the writing of the report and have not reviewed the report, except as given the opportunity to do so through the public review mechanism.
Technical Experts must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their unique clinical or content expertise, individuals are invited to serve as Technical Experts and those who present with potential conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential conflicts of interest identified.
Peer reviewers are invited to provide written comments on the draft report based on their clinical, content, or methodological expertise. Peer review comments on the preliminary draft of the report are considered by the EPC in preparation of the final draft of the report. Peer reviewers do not participate in writing or editing of the final report or other products. The synthesis of the scientific literature presented in the final report does not necessarily represent the views of individual reviewers. The dispositions of the peer review comments are documented and will, for CERs and Technical briefs, be published 3 months after the publication of the Evidence report.
Potential Reviewers must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Invited Peer Reviewers may not have any financial conflict of interest greater than $10,000. Peer reviewers who disclose potential business or professional conflicts of interest may submit comments on draft reports through the public comment mechanism.
EPC Team Disclosures
Two EPC team investigators participate in the DECIDE consortium on PAD sponsored by AHRQ. No other team members have disclosures to report.
Role of the Funder
This project was funded under Contract No. 290-2007-10066-I from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. The Task Order Officer reviewed contract deliverables for adherence to contract requirements, including the objectivity and independence of the research process and the methodological quality of the report. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Appendix 1. Devices and Medications
|Registered or Trademark Name||Type||Manufacturer||Comments|
|Fox Plus||Standard||Abbott Vascular||FDA approved|
|FoxCross||Standard||Abbott Vascular||FDA approved|
|Fox Sv||Standard||Abbott Vascular||FDA approved|
|Viatrac||Standard||Abbott Vascular||FDA approved|
|Agiltrac||Standard||Abbott Vascular||FDA approved|
|Profiler||Standard||Angiodynamics Inc||FDA approved|
|WorkHorse||Standard||Angiodynamics Inc||FDA approved|
|Angiosculpt||Cutting||Angioscore Inc||FDA approved|
|Vaccess||Standard||Bard Peripheral Vascular||FDA approved|
|Opti-Plast||Standard||Bard Peripheral Vascular||FDA approved|
|Dorado||Standard||Bard Peripheral Vascular||FDA approved|
|Opti-Plast XL||Standard||Bard Peripheral Vascular||FDA approved|
|Ultraverse||Standard||Bard Peripheral Vascular||FDA approved|
|Biopore||Standard||Biopore, Inc.||FDA approved|
|Rider||Standard||Bolton Medical, Inc.||FDA approved|
|PE-MT5||Standard||Boston Scientific Corporation||FDA approved|
|Flextome||Cutting||Boston Scientific Corporation||FDA approved|
|Coyote ES||Standard||Boston Scientific Corporation||FDA approved|
|Sterling||Standard||Boston Scientific Corporation||FDA approved|
|Mustang||Standard||Boston Scientific Corporation||FDA approved|
|Symmetry||Standard||Boston Scientific Corporation||FDA approved|
|Diamond||Standard||Boston Scientific Corporation||FDA approved|
|Blue Max 20||Standard||Boston Scientific Corporation||FDA approved|
|Accent||Standard||Cook, Inc.||FDA approved|
|Savvy||Standard||Cook, Inc.||FDA approved|
|Powerflex||Standard||Cordis Corporation/Johnson and Johnson||FDA approved|
|Powercross||Standard||ev3, Inc.||FDA approved|
|Evercross||Standard||ev3, Inc.||FDA approved|
|GPS Cath||Standard||Hotspur Technologies||FDA approved|
|IQ Cath||Standard||Hotspur Technologies||FDA approved|
|Arriva||Standard||Insitu Technologies, Inc.||FDA approved|
|Hercules||Standard||Insitu Technologies, Inc.||FDA approved|
|Perseus||Standard||Insitu Technologies, Inc.||FDA approved|
|Pacific Xtreme||Standard||Invatec GmbH||FDA approved|
|Marauder||Standard||Numed, Inc.||FDA approved|
|Tyshak||Standard||Numed, Inc.||FDA approved|
|Z-MED||Standard||Numed, Inc.||FDA approved|
|Ghost||Standard||Numed, Inc.||FDA approved|
|Impact||Standard||Numed, Inc.||FDA approved|
|PolarCath||Cryoballoon||Boston Scientific Corporation||FDA approved|
|Omnilink||Open-cell stent||Abbott Vascular||FDA approved|
|Herculink||Open-cell stent||Abbott Vascular||FDA approved|
|Dynalink||Open-cell stent||Abbott Vascular||FDA approved|
|Xpert||Open-cell stent||Abbott Vascular||FDA approved|
|Xceed||Open-cell stent||Abbott Vascular||FDA approved|
|Absolute||Open-cell stent||Abbott Vascular||FDA approved|
|JoStent Graftmaster||Closed-cell stent||Abbott Vascular||FDA approved|
|Vistaflex||Open-cell stent||AngioDynamics||FDA approved|
|Express||Open-cell stent||Boston Scientific Corporation||FDA approved|
|Symphony||Open-cell stent||Boston Scientific Corporation||FDA approved|
|IntrsStent LD||Open-cell stent||Boston Scientific Corporation||FDA approved|
|WallStent||Closed-cell stent||Boston Scientific Corporation||FDA approved|
|Sentinol||Open-cell stent||Boston Scientific Corporation||FDA approved|
|WallGraft||Closed-cell stent||Boston Scientific Corporation||FDA approved|
|Formula 418||Open-cell stent||Cook Medical||FDA approved|
|Zilver 635||Open-cell stent||Cook Medical||FDA approved|
|Zilver PTX||Open-cell stent||Cook Medical||FDA approved|
|Zilver PTX Drug-eluting stent||Drug-eluting stent||Cook Medical||FDA approved|
|LifeStent||Open-cell stent||Bard Peripheral Vascular||FDA approved|
|LifeStent FlexStar||Open-cell stent||Bard Peripheral Vascular||FDA approved|
|Luminexx||Open-cell stent||Bard Peripheral Vascular||FDA approved|
|Conformexx||Open-cell stent||Bard Peripheral Vascular||FDA approved|
|Fluency||Open-cell stent||Bard Peripheral Vascular||FDA approved|
|Racer||Open-cell stent||Medtronic||FDA approved|
|Bridge Assurant||Open-cell stent||Medtronic||FDA approved|
|Aurora||Open-cell stent||Medtronic||FDA approved|
|SMART||Open-cell stent||Cordis Corporation, Johnson & Johnson||FDA approved|
|Palmaz Blue||Open-cell stent||Cordis Corporation, Johnson & Johnson||FDA approved|
|Cobalt Blue||Open-cell stent||Cordis Corporation, Johnson & Johnson||FDA approved|
|Genesis||Open-cell stent||Cordis Corporation, Johnson & Johnson||FDA approved|
|Precise||Open-cell stent||Cordis Corporation, Johnson & Johnson||FDA approved|
|Protégé||Open-cell stent||ev3 Inc.||FDA approved|
|Visi-Pro||Open-cell stent||ev3 Inc.||FDA approved|
|Paramount GPS||Open-cell stent||ev3 Inc.||FDA approved|
|Supera||Open-cell stent||IDEV Technologies, Inc.||FDA approved|
|Complete||Open-cell stent||Edwards Lifesciences Technology||FDA approved|
|iCAST||Closed-cell stent||Atrium Medical Corporation||FDA approved|
|Viabahn||Closed-cell stent||W.L. Gore & Associates||FDA approved|
|aSpire||Open-cell stent||Vascular Architects, Inc.||FDA approved|
|Driver||Bare-metal stent||Medtronic||FDA approved|
|Integrity||Bare-metal stent||Medtronic||FDA approved|
|Vision||Bare-metal stent||Abbott Vascular||FDA approved|
|Veriflex||Bare-metal stent||Boston Scientific Corporation||FDA approved|
|JoStent Graftmaster||Closed-cell stent||Abbott Vascular||FDA approved|
|Express||Open-cell stent||Boston Scientific Corporation||FDA approved|
|ACS Multi-Link||Bare-metal stent||Abbott Vascular||FDA approved|
|Omega||Bare-metal stent||Boston Scientific Corporation||FDA approved|
|Cypher||Drug-eluting stent||Cordis Corporation/Johnson and Johnson||FDA approved|
|Endeavor||Drug-eluting stent||Medtronic||FDA approved|
|Taxus/Ion||Drug-eluting stent||Boston Scientific Corporation||FDA approved|
|Xience/Promus||Drug-eluting stent||Abbott Vascular||FDA approved|
|SilverHawk atherectomy||Directional atherectomy||ev3 Inc.||FDA approved|
|X-Sizer||Thrombectomy||ev3 Inc.||FDA approved|
|TurboHawk||Directional atherectomy||ev3 Inc.||FDA approved|
|Amplatz Thrombectomy||Thrombectomy||ev3 Inc.||FDA approved|
|Jetstream G2 and G3||Rotational atherectomy||Pathway Medical Technologies, Inc.||FDA approved|
|Diamondback 360 atherectomy||Orbital atherectomy||Cardiovascular Systems Inc.||FDA approved|
|Excimer laser atherectomy||Laser ablative atherectomy||Spectranetics Corp||FDA approved|
|CLiRpath||Laser ablative atherectomy||Spectranetics Corp||FDA approved|
|ThromCat Thrombectomy||Thrombectomy||Spectranetics Corp||FDA approved|
|Percutaneous Thrombolytic Device||Thrombolysis catheter||Arrow International, Inc.||FDA approved|
|Phoenix Atherectomy||Directional atherectomy||Atheromed||FDA approved|
|Rotablator||Rotational atherectomy||Boston Scientific Corporation||FDA approved|
|Fogarty Graft Thrombectomy||Thrombectomy||Edwards Lifesciences Technology||FDA approved|
|AngioJet||Thrombectomy||MedRad, Inc.||FDA approved|
|Cleaner Rotational Thrombectomy||Thrombectomy||Rex Medical LP||FDA approved|
|Bypass graft devices|
|CryoVein||Cryo-preserved Vascular graft||CryoLife||FDA approved|
|Ultramax||Vascular graft||Atrium Medical Corporation||FDA approved|
|Flixene||Vascular graft||Atrium Medical Corporation||FDA approved|
|Advanta||Stent graft||Atrium Medical Corporation||FDA approved|
|Dynaflo||Vascular graft||Bard Peripheral Vascular||FDA approved|
|Distaflo||Vascular graft||Bard Peripheral Vascular||FDA approved|
|Venaflo||Vascular graft||Bard Peripheral Vascular||FDA approved|
|Carboflow||Vascular graft||Bard Peripheral Vascular||FDA approved|
|Impra||Vascular graft||Bard Peripheral Vascular||FDA approved|
|DeBakey||Vascular graft||Bard Peripheral Vascular||FDA approved|
|EPTFE||Vascular graft||LeMaitre Vascular Inc.||FDA approved|
|Lifespan||Vascular graft||LeMaitre Vascular Inc.||FDA approved|
|Albograft||Vascular graft||LeMaitre Vascular Inc.||FDA approved|
|Hemashield||Vascular graft||Maquet Cardiovascular LLC||FDA approved|
|Exxcel||Vascular graft||Maquet Cardiovascular LLC||FDA approved|
|Vectra||Vascular graft||Thoratec Corp||FDA approved|
|VP1200K||Vascular graft||Vascutek LTD||FDA approved|
|Gelsoft||Vascular graft||Vascutek LTD||FDA approved|
|Gelweave||Vascular graft||Vascutek LTD||FDA approved|
|Gelseal||Vascular graft||Vascutek LTD||FDA approved|
|Twillweave||Vascular graft||Vascutek LTD||FDA approved|
|SealPTFE||Vascular graft||Vascutek LTD||FDA approved|
|Maxiflo||Vascular graft||Vascutek LTD||FDA approved|
|Gore Propaten||Vascular graft||W.L. Gore & Associates, Inc.||FDA approved|
|Gore-Tex||Vascular graft||W.L. Gore & Associates, Inc.||FDA approved|
|EPTFE||Vascular graft||W.L. Gore & Associates, Inc.||FDA approved|
|Diastat||Vascular graft||W.L. Gore & Associates, Inc.||FDA approved|
|Aor-Tex||Vascular graft||W.L. Gore & Associates, Inc.||FDA approved|
|PeriPatch||Bovine Pericardial Patch||Neovasc||FDA approved|
|Chronic total occlusion (CTO) recanalization devices|
|Outback||Re-entry Device||Cordis Corporation/Johnson & Johnson||FDA approved|
|Stingray||Re-entry Device||Bridgepoint Medical||FDA approved|
|Pioneer||Re-entry Device||Medtronic /
|FDA approved; Joint venture between Medtronic and Volcano Corporations|
|Frontrunner||Recanalization catheter||Cordis Corporation/Johnson & Johnson||FDA approved|
|Crosser CTO||Recanalization catheter||Bard Peripheral Vascular||FDA approved|
|Abbreviations: CTO = chronic total occlusion; FDA = Food and Drug Administration|
|Registered or Trademark Name||Generic Name||Manufacturer||Dosage||Frequency||Method of Administration||FDA Status||Indications/ Warnings|
|Plavix||Clopidogrel||Bristol Myers Squibb Sanofi Pharmaceuticals partnership||75 mg||Daily||Oral||Approved||Indicated for reduction of atherothrombotic events in ACS and patients with recent MI, recent stroke, or established PAD|
|Effient||Prasugrel||Eli Lilly and Co||10 mg, 5 mg||Daily||Oral||Approved for use during PCI for ACS||Indicated for acute coronary syndromes|
|Brilinta||Ticagrelor||AstraZeneca LP||90 mg||Twice daily||Oral||Not yet commercially available in the US but has been FDA approved||Indicated for reduction of cardiovascular death and MI in patients with ACS|
|Angiomax||Bivalirudin||The Medicines Company||1.0 mg/kg/hr loading, then 4 hr of 2.5 mg/kg/hr, ± 0.2 mg/kg/hr for an additional 18 hr||One time, at the time of procedure||Intravenous||Approved||FDA approved for patients with unstable angina undergoing PTCA|
|Pletal||Cilostazol||Otsuka Pharmaceutical Company, Ltd.||50 mg, 100 mg||Twice daily||Oral||Approved|
|Trental||Pentoxifylline||Sanofi-Aventis||400 mg||Three times daily with meals||Oral||Approved|
|Bayer||Aspirin||Bayer Healthcare LLC||75 mg, 81 mg, 162 mg, 324 mg, 325 mg||Daily||Oral|
|Abbreviations: ACS = acute coronary syndrome; FDA = Food and Drug Administration; hr = hour; kg = kilogram; mg = milligram; MI = myocardial infarction; PAD = peripheral artery disease; PCI = percutaneous coronary intervention; PTCA = percutaneous transluminal coronary angioplasty|
Appendix 2. Literature Search Strategy (10/12/11)
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||"Peripheral Arterial Disease"[Mesh] OR "Peripheral Vascular Diseases"[Mesh] OR PAD[tiab] OR "peripheral arterial disease"[tiab] OR "peripheral vascular disease"[tiab] OR "arterial occlusive disease"[tiab] OR "intermittent claudication"[MeSH Terms] OR claudication[tiab] OR "rest pain"[tiab] OR (critical[tiab] AND ("extremities"[MeSH Terms] OR "extremities"[tiab] OR "limb"[tiab]) AND ("ischaemia"[tiab] OR "ischemia"[MeSH Terms] OR "ischemia"[tiab])) OR (("ischaemia"[tiab] OR "ischemia"[MeSH Terms] OR "ischemia"[tiab]) AND ("lower extremity"[MeSH Terms] OR ("lower"[tiab] AND "extremity"[tiab]) OR "lower extremity"[tiab])) OR (("extremities"[MeSH Terms] OR "extremities"[tiab] OR "limb"[tiab]) AND ("ischaemia"[tiab] OR "ischemia"[MeSH Terms] OR "ischemia"[tiab])) OR “vascular ulcer”[tiab] OR (vascular[tiab] AND ulcer[tiab]) OR “vascular ulcers”[tiab] OR (vascular[tiab] AND ulcers[tiab]) OR “varicose ulcer”[MeSH] OR “varicose ulcer”[tiab] OR (varicose[tiab] AND ulcer[tiab]) OR “varicose ulcers”[tiab] OR (varicose[tiab] AND ulcers[tiab]) OR “leg ulcer”[MeSH] OR “leg ulcer”[tiab] OR (leg[tiab] AND ulcer[tiab]) OR “leg ulcers”[tiab] OR (leg[tiab] AND ulcers[tiab]) OR gangrene[MeSH] OR gangrene[tiab]||107767|
|2||"aspirin"[MeSH Terms] OR "aspirin"[tw] OR ("clopidogrel"[Supplementary Concept] OR "clopidogrel"[tw] OR "plavix"[tw]) OR "prasugrel"[Supplementary Concept] OR "prasugrel"[tw] OR Effient[tw] OR "Ticagrelor"[Supplementary Concept] OR "Ticagrelor"[tw] OR brilinta[tw]||51202|
|3||"evaluation studies"[Publication Type] OR "evaluation studies as topic"[MeSH Terms] OR "evaluation study"[tw] OR evaluation studies[tw] OR "intervention studies"[MeSH Terms] OR "intervention study"[tw] OR "intervention studies"[tw] OR "case-control studies"[MeSH Terms] OR "case-control"[tw] OR "cohort studies"[MeSH Terms] OR cohort[tw] OR "longitudinal studies"[MeSH Terms] OR "longitudinal"[tw] OR longitudinally[tw] OR "prospective"[tw] OR prospectively[tw] OR "retrospective studies"[MeSH Terms] OR "retrospective"[tw] OR "follow up"[tw] OR "comparative study"[Publication Type] OR "comparative study"[tw] OR systematic[subset] OR "meta-analysis"[Publication Type] OR "meta-analysis as topic"[MeSH Terms] OR "meta-analysis"[tw] OR "meta-analyses"[tw] OR randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR randomised[tiab] OR randomization[tiab] OR randomisation[tiab] OR placebo[tiab] OR "drug therapy"[Subheading] OR randomly[tiab] OR trial[tiab] OR groups[tiab] OR Clinical trial[pt] OR "clinical trial"[tw] OR "clinical trials"[tw] NOT (Editorial[ptyp] OR Letter[ptyp] OR Case Reports[ptyp] OR Comment[ptyp])NOT (Editorial[ptyp] OR Letter[ptyp] OR Case Reports[ptyp] OR Comment[ptyp])||5103944|
|4||(#1 AND #2 AND #3 ) not (ANIMALS[MH] not HUMANS[MH])||901|
|5||#5 Limits: English, Publication Date from 1995 to 2011||535|
KQ 2: In adults with symptomatic PAD with atypical leg symptoms or IC:
|1||"intermittent claudication"[MeSH Terms] OR claudication[tiab]||9852|
|2||("angioplasty"[MeSH Terms] OR "angioplasty"[tiab] OR ("percutaneous"[tiab] AND "transluminal"[tiab] AND "angioplasty"[tiab]) OR "percutaneous transluminal angioplasty"[tiab]) OR PTA[tiab] OR ("stents"[MeSH Terms] OR "stents"[tiab] OR "stent"[tiab]) OR (percutaneous[tiab] AND revascularization[tiab]) OR ("endovascular procedures"[MeSH Terms] OR ("endovascular"[tiab] AND "procedures"[tiab]) OR "endovascular procedures"[tiab]) OR endovascular[tiab] OR ("exercise therapy"[MeSH Terms] OR ("exercise"[tiab] AND "therapy"[tiab]) OR "exercise therapy"[tiab]) OR (("exercise"[MeSH Terms] OR "exercise"[tiab]) AND (program[tiab] OR class[tiab] OR training[tiab] OR prescribed[tiab] OR structure[tiab] OR structured[tiab] OR supervised[tiab]) OR ("cilostazol"[Supplementary Concept] OR "cilostazol"[tiab]) OR ("pentoxifylline"[MeSH Terms] OR "pentoxifylline"[tiab])||240361|
|3||"Femoral Artery/surgery"[Mesh] OR "Popliteal Artery/surgery"[Mesh] OR "tibial arteries/surgery"[Mesh Terms] OR "arteries/surgery"[Mesh Terms] OR "transplants"[MeSH Terms] OR transplants[tiab] OR graft[tiab] OR grafts[tiab] OR grafting[tiab] OR bypass[tiab] OR conduit[tiab] OR femoropopliteal[tiab] OR femorotibial[tiab] OR aortobifemoral[tiab] OR ballon[tiab] OR "atherectomy"[MeSH Terms] OR atherectomy[tiab]||327256|
|4||"evaluation studies"[Publication Type] OR "evaluation studies as topic"[MeSH Terms] OR "evaluation study"[tw] OR evaluation studies[tw] OR "intervention studies"[MeSH Terms] OR "intervention study"[tw] OR "intervention studies"[tw] OR "case-control studies"[MeSH Terms] OR "case-control"[tw] OR "cohort studies"[MeSH Terms] OR cohort[tw] OR "longitudinal studies"[MeSH Terms] OR "longitudinal"[tw] OR longitudinally[tw] OR "prospective"[tw] OR prospectively[tw] OR "retrospective studies"[MeSH Terms] OR "retrospective"[tw] OR "follow up"[tw] OR "comparative study"[Publication Type] OR "comparative study"[tw] OR systematic[subset] OR "meta-analysis"[Publication Type] OR "meta-analysis as topic"[MeSH Terms] OR "meta-analysis"[tw] OR "meta-analyses"[tw] OR randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR randomised[tiab] OR randomization[tiab] OR randomisation[tiab] OR placebo[tiab] OR "drug therapy"[Subheading] OR randomly[tiab] OR trial[tiab] OR groups[tiab] OR Clinical trial[pt] OR "clinical trial"[tw] OR "clinical trials"[tw] NOT (Editorial[ptyp] OR Letter[ptyp] OR Case Reports[ptyp] OR Comment[ptyp])NOT (Editorial[ptyp] OR Letter[ptyp] OR Case Reports[ptyp] OR Comment[ptyp])||5103944|
|5||#1 AND (#2 OR #3) AND #4 NOT (animals[mh] NOT humans[mh])||2407|
|6||#5 Limits: English, Publication Date from 1995 to 2011||1414|
KQ 3: In adults with CLI due to PAD:
|1||"rest pain"[tiab] OR (critical[tiab] AND ("extremities"[MeSH Terms] OR "extremities"[tiab] OR "limb"[tiab]) AND ("ischaemia"[tiab] OR "ischemia"[MeSH Terms] OR "ischemia"[tiab])) OR (("ischaemia"[tiab] OR "ischemia"[MeSH Terms] OR "ischemia"[tiab]) AND ("lower extremity"[MeSH Terms] OR ("lower"[tiab] AND "extremity"[tiab]) OR "lower extremity"[tiab])) OR (("extremities"[MeSH Terms] OR "extremities"[tiab] OR "limb"[tiab]) AND ("ischaemia"[tiab] OR "ischemia"[MeSH Terms] OR "ischemia"[tiab]))||18495|
|2||"angioplasty"[MeSH Terms] OR "angioplasty"[tiab] OR ("percutaneous"[tiab] AND "transluminal"[tiab] AND "angioplasty"[tiab]) OR "percutaneous transluminal angioplasty"[tiab] OR PTA[tiab] OR "stents"[MeSH Terms] OR "stents"[tiab] OR "stent"[tiab] OR (percutaneous[tiab] AND revascularization[tiab]) OR "endovascular procedures"[MeSH Terms] OR endovascular[tiab]||125370|
|3||"Femoral Artery/surgery"[Mesh] OR "Popliteal Artery/surgery"[Mesh] OR "tibial arteries/surgery"[Mesh Terms] OR "arteries/surgery"[Mesh Terms] OR "transplants"[MeSH Terms] OR transplants[tiab] OR graft[tiab] OR grafts[tiab] OR grafting[tiab] OR bypass[tiab] OR conduit[tiab] OR femoropopliteal[tiab] OR femorotibial[tiab] OR aortobifemoral[tiab] OR ballon[tiab] OR "atherectomy"[MeSH Terms] OR atherectomy[tiab]||327418|
|4||"evaluation studies"[Publication Type] OR "evaluation studies as topic"[MeSH Terms] OR "evaluation study"[tw] OR evaluation studies[tw] OR "intervention studies"[MeSH Terms] OR "intervention study"[tw] OR "intervention studies"[tw] OR "case-control studies"[MeSH Terms] OR "case-control"[tw] OR "cohort studies"[MeSH Terms] OR cohort[tw] OR "longitudinal studies"[MeSH Terms] OR "longitudinal"[tw] OR longitudinally[tw] OR "prospective"[tw] OR prospectively[tw] OR "retrospective studies"[MeSH Terms] OR "retrospective"[tw] OR "follow up"[tw] OR "comparative study"[Publication Type] OR "comparative study"[tw] OR systematic[subset] OR "meta-analysis"[Publication Type] OR "meta-analysis as topic"[MeSH Terms] OR "meta-analysis"[tw] OR "meta-analyses"[tw] OR randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR randomised[tiab] OR randomization[tiab] OR randomisation[tiab] OR placebo[tiab] OR "drug therapy"[Subheading] OR randomly[tiab] OR trial[tiab] OR groups[tiab] OR Clinical trial[pt] OR "clinical trial"[tw] OR "clinical trials"[tw] NOT (Editorial[ptyp] OR Letter[ptyp] OR Case Reports[ptyp] OR Comment[ptyp])NOT (Editorial[ptyp] OR Letter[ptyp] OR Case Reports[ptyp] OR Comment[ptyp])||5106763|
|5||#1 AND (#2 OR #3) AND #4 NOT (animals[mh] NOT humans[mh])||3664|
|6||#5 Limits: Publication Date from 1995 to 2011||2180|
|KQ 1 OR KQ 2 OR KQ 3||3443|