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Society for Vascular Surgery practice guidelines for atherosclerotic occlusive disease of the lower extremities: Management of asymptomatic disease and claudication

Open ArchivePublished:January 28, 2015DOI:https://doi.org/10.1016/j.jvs.2014.12.009
      Peripheral arterial disease (PAD) continues to grow in global prevalence and consumes an increasing amount of resources in the United States health care system. Overall rates of intervention for PAD have been rising steadily in recent years. Changing demographics, evolution of technologies, and an expanding database of outcomes studies are primary forces influencing clinical decision making in PAD. The management of PAD is multidisciplinary, involving primary care physicians and vascular specialists with varying expertise in diagnostic and treatment modalities. PAD represents a broad spectrum of disease from asymptomatic through severe limb ischemia. The Society for Vascular Surgery Lower Extremity Practice Guidelines committee reviewed the evidence supporting clinical care in the treatment of asymptomatic PAD and intermittent claudication (IC). The committee made specific practice recommendations using the GRADE (Grades of Recommendation Assessment, Development and Evaluation) system. There are limited Level I data available for many of the critical questions in the field, demonstrating the urgent need for comparative effectiveness research in PAD. Emphasis is placed on risk factor modification, medical therapies, and broader use of exercise programs to improve cardiovascular health and functional performance. Screening for PAD appears of unproven benefit at present. Revascularization for IC is an appropriate therapy for selected patients with disabling symptoms, after a careful risk-benefit analysis. Treatment should be individualized based on comorbid conditions, degree of functional impairment, and anatomic factors. Invasive treatments for IC should provide predictable functional improvements with reasonable durability. A minimum threshold of a >50% likelihood of sustained efficacy for at least 2 years is suggested as a benchmark. Anatomic patency (freedom from restenosis) is considered a prerequisite for sustained efficacy of revascularization in IC. Endovascular approaches are favored for most candidates with aortoiliac disease and for selected patients with femoropopliteal disease in whom anatomic durability is expected to meet this minimum threshold. Conversely, caution is warranted in the use of interventions for IC in anatomic settings where durability is limited (extensive calcification, small-caliber arteries, diffuse infrainguinal disease, poor runoff). Surgical bypass may be a preferred strategy in good-risk patients with these disease patterns or in those with prior endovascular failures. Common femoral artery disease should be treated surgically, and saphenous vein is the preferred conduit for infrainguinal bypass grafting. Patients who undergo invasive treatments for IC should be monitored regularly in a surveillance program to record subjective improvements, assess risk factors, optimize compliance with cardioprotective medications, and monitor hemodynamic and patency status.

      Development of the guidelines document

      The Society for Vascular Surgery (SVS) Lower Extremity Guidelines Committee began the process by developing a detailed outline of the diagnostic and management choices for peripheral arterial disease (PAD) by stage of disease. Given the broad scope of the field, the committee determined that this document should focus on the evaluation and management of asymptomatic disease and intermittent claudication (IC). Separate practice guidelines for critical limb ischemia (CLI) will be established in a future document. The committee developed sets of key questions and, with the input of a methodologist, condensed these into topics that framed systematic evidence reviews. The quantity and quality of evidence available was also an important factor in determining the rationale for the systematic review topics. De novo evidence reviews were undertaken to examine the rationale for screening in asymptomatic PAD and the comparative effectiveness of current treatments for IC. These systematic reviews are published jointly with this guideline document.
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      • et al.
      A systematic review for the screening for peripheral arterial disease in asymptomatic patients.
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      • et al.
      A systematic review of treatment of intermittent claudication in the lower extremities.
      The committee developed the practice guideline by assigning two or three members to create primary drafts of each section of the document, highlighting specific questions where recommendations were needed and appropriate. Each section was then reviewed and revised by the remainder of the writing group and the two co-chairs. All guideline recommendations were reviewed by the full committee and finalized via an iterative, consensus process. In considering available treatment modalities, we focused on options currently available to patients and physicians in the United States (U.S.).
      The Grades of Recommendation Assessment, Development and Evaluation (GRADE) framework was used for determining the strength of recommendation and the quality of evidence, as previously reported.
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      The quality of evidence is rated as high (A), moderate (B), or low (C). This rating is based on the risk of bias, precision, directness, consistency, and the size of the effect. The strength of recommendation is graded based on the quality of evidence, balance between benefits and harms, patients' values, preferences, and clinical context. Recommendations are graded as strong (1) or weak/conditional (2). The term “we recommend” is used with strong recommendations, and the term “we suggest” is used with conditional recommendations.
      The methodologist assisted the committee in incorporating the evidence into the recommendations and helped in rating the quality of evidence and the strength of recommendations. Finally, this guideline was reviewed by the SVS Documents Oversight Committee that peer reviewed the document and provided content and methodology expertise.

      Conflict of interest

      All members of the committee provided updated disclosures on potential conflicts of interest (COI), in accordance with SVS policies.
      • Elliott B.M.
      Society for Vascular Surgery. Conflict of interest and the Society for Vascular Surgery.
      The final roster of the Lower Extremity Guidelines Committee is in accordance with the current SVS COI policy, which is summarized elsewhere (http://www.vascularweb.org/about/policies/Pages/Conflict-of-Interest-Policy.aspx). COI disclosures for each of the writing group authors are listed at the end of the document in the Appendix.

      1. Epidemiology and risk factors

      Although the worldwide prevalence of lower extremity PAD is uncertain,
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      an estimated 8 to 12 million Americans are affected by PAD.
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      A clear association between the prevalence of PAD and increased age has been established.
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      • Erlinger T.P.
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      • Harris K.A.
      • Fowkes F.G.
      Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).
      In an analysis of 2381 patients participating in the U.S. National Health and Nutrition Examination Survey, the prevalence of PAD was 4.3% overall, with a prevalence of 0.9% in patients aged between 40 and 49 years, 2.5% in patients aged between 50 and 59 years, 4.7% in patients aged between 60 and 69 years, and 14.5% in patients aged >69 years.
      • Selvin E.
      • Erlinger T.P.
      Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999-2000.
      The prevalence of PAD is expected to increase in the United States and worldwide as the population ages, cigarette smoking persists, and the epidemics of diabetes mellitus, hypertension, and obesity grow.
      • Hirsch A.T.
      • Hartman L.
      • Town R.J.
      • Virnig B.A.
      National health care costs of peripheral arterial disease in the Medicare population.
      A recent meta-analysis of 34 studies that examined the prevalence and risk factors of PAD worldwide shattered some preconceived notions related to this disease.
      • Fowkes F.G.
      • Rudan D.
      • Rudan I.
      • Aboyans V.
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      • McDermott M.M.
      • et al.
      Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis.
      With a conservative estimate of >202 million afflicted with this disease globally, this analysis showed a relative increase in PAD prevalence of 23.5% during the first decade of the new millennium. The most striking increases in prevalence were seen in low-income and middle-income countries (28.7%), although significant growth was also evident in high-income countries (13.1%). In high-income countries, PAD prevalence is equal between women and men, whereas in low-income and middle-income countries, PAD prevalence is higher in women, especially at younger ages. Increased longevity (age), smoking, and diabetes are the most strongly associated risk factors across all nations.
      The economic effect of this growing burden of PAD is being experienced acutely in the United States and in many other industrialized nations. In 2001, the U.S. Medicare program spent an estimated >$4.3 billion on PAD-related treatment.
      • Hirsch A.T.
      • Hartman L.
      • Town R.J.
      • Virnig B.A.
      National health care costs of peripheral arterial disease in the Medicare population.
      PAD-related treatment accounted for ∼13% of all Medicare Part A and B expenditures for patients undergoing treatment for PAD and for 2.3% of total Medicare Part A and B expenditures during that year. These Medicare costs have continued to increase markedly. Analysis of data from the Reduction of Atherothrombosis for Continued Health (REACH) Registry estimated total costs of vascular-related hospitalizations was $21 billion in the United States in 2004, with most costs associated with revascularization procedures.
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      • et al.
      Vascular hospitalization rates and costs in patients with peripheral artery disease in the United States.
      Given the ongoing dramatic increases in the use of invasive treatments, these figures are likely underestimates of the current costs for PAD care in the United States.
      Evidence of underlying PAD may be present in the absence of symptoms. For the purpose of this document, this is referred to as asymptomatic disease. Symptomatic PAD may present as IC, or with signs or symptoms consistent with limb-threatening ischemia, often referred to as critical limb ischemia (CLI). In this guidelines document, we will only consider IC within the spectrum of symptomatic PAD.
      IC is defined as a reproducible discomfort in a specific muscle group that is induced by exercise and then relieved with rest. Although the calf muscles are most often affected, any leg muscle group, such as those in the thigh or buttock, may be affected. This condition is caused by arterial obstruction proximal to the affected muscle bed, thereby attenuating exercise-induced augmentation of blood flow leading to transient muscle ischemia. IC is often the first clinical symptom associated with PAD and the most common. It is also well documented that many PAD patients experience “atypical” leg symptoms that may reflect other pathophysiologic mechanisms (eg, myopathy) or the overlay of concomitant conditions, such as neuropathy, arthritis, and lumbar spine disease, that influence lower extremity function. Numerous population-based studies have attempted to ascertain the relative proportion of symptomatic patients amongst all those with PAD; taken in aggregate, these studies indicate that the ratio of symptomatic to asymptomatic PAD is on the order of 1:3.
      • Norgren L.
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      • Fowkes F.G.
      Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).
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      Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population.
      The risk factors associated with PAD are similar to those classically identified in the context of coronary artery disease, although the relative importance of these factors appears different (Fig 1).
      • Selvin E.
      • Erlinger T.P.
      Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999-2000.
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      • et al.
      Peripheral arterial disease detection, awareness, and treatment in primary care.
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      Investigators from the Framingham Heart Study analyzing “factors of risk” for coronary artery disease were the first to identify demographic and comorbid factors independently associated with systemic atherosclerosis.
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      Intermittent claudication. A risk profile from The Framingham Heart Study.
      Numerous reports since have confirmed that advanced age, tobacco use, diabetes, hypertension, and hypercholesterolemia are the primary risk factors associated with PAD. More recent studies have identified non-Hispanic black race,
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      • Erlinger T.P.
      Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999-2000.
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      chronic renal insufficiency,
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      Renal insufficiency and the risk of lower extremity peripheral arterial disease: results from the Heart and Estrogen/Progestin Replacement Study (HERS).
      and elevated homocysteine levels
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      Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project.
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      Homocysteine and atherothrombosis.
      as additional factors associated with the onset of PAD. Elevated markers of inflammation, including high-sensitivity C-reactive protein, interleukin-6, fibrinogen, soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1, asymmetric dimethylarginine, β-2 macroglobulin, and cystatin C are novel risk factors whose clinical utility for predicting PAD onset or progression is not yet clear.
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      Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women.
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      Asymmetric dimethylarginine correlates with measures of disease severity, major adverse cardiovascular events and all-cause mortality in patients with peripheral arterial disease.
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      Beta2-microglobulin as a biomarker in peripheral arterial disease: proteomic profiling and clinical studies.
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      Higher serum levels of soluble intracellular cell adhesion molecule-1 and soluble vascular cell adhesion molecule predict peripheral artery disease in haemodialysis patients.
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      Relation of interleukin-6 and vascular cellular adhesion molecule-1 levels to functional decline in patients with lower extremity peripheral arterial disease.
      Figure thumbnail gr1
      Fig 1The approximate odds ratios (ORs) for risk factors associated with the development of peripheral arterial disease (PAD).
      Adapted from Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).
      • Norgren L.
      • Hiatt W.R.
      • Dormandy J.A.
      • Nehler M.R.
      • Harris K.A.
      • Fowkes F.G.
      Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).
      Figure thumbnail gr2
      Fig 2The natural history of patients with intermittent claudication (IC) treated with non-invasive management. CV, Cardiovascular; MI, myocardial infarction.
      Adapted from American College of Cardiology/Americal Heart Association guidelines.
      • Hirsch A.T.
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      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.

      2. Diagnosis

      Measurement of the ankle-brachial index (ABI) is the primary method for establishing the diagnosis of PAD. An ABI of ≤0.90 has been demonstrated to have high sensitivity and specificity for the identification of PAD compared with the gold standard of invasive arteriography.
      • Norgren L.
      • Hiatt W.R.
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      • Nehler M.R.
      • Harris K.A.
      • Fowkes F.G.
      Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).
      Additional tests, such as carotid intima-media thickness
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      Carotid intima-media thickness and the prediction of vascular events.
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      Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis.
      and brachial artery flow-mediated dilation,
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      Endothelial function: a barometer for cardiovascular risk?.
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      Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease.
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      Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force.
      have shown promise but have not been broadly applied because they require more specialized equipment and technical expertise. The incremental value of ABI beyond standard risk scores (eg, Framingham) in predicting future death and cardiovascular events has been established by epidemiologic studies.
      • Aboyans V.
      • Criqui M.H.
      • Abraham P.
      • Allison M.A.
      • Creager M.A.
      • Diehm C.
      • et al.
      Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association.
      An ABI <0.9 or >1.4 portends an increased risk of major cardiovascular events.
      The question of whether screening for PAD by ABI would yield public health benefit has been examined by several groups and remains an area of controversy. A recent review by the U.S. Preventive Services Task Force gave ABI screening an indeterminate rating, stating that there was insufficient evidence to assess the balance of benefits and harms.
      • Lin J.S.
      • Olson C.M.
      • Johnson E.S.
      • Whitlock E.P.
      The ankle-brachial index for peripheral artery disease screening and cardiovascular disease prediction among asymptomatic adults: a systematic evidence review for the U.S. Preventive Services Task Force.
      The SVS-commissioned meta-analysis
      • Alahdab F.
      • Wang A.T.
      • Elraiyah T.A.
      • Malgor R.D.
      • Rizvi A.Z.
      • Lane M.A.
      • et al.
      A systematic review for the screening for peripheral arterial disease in asymptomatic patients.
      demonstrates that ABI testing may incrementally improve cardiovascular risk prediction, but existing evidence does not support broad population screening of asymptomatic patients for PAD. However, future studies may identify targeted subgroups of patients, particularly those not yet on cardioprotective treatment regimens (eg, patients with diabetes alone, hypertension alone, or advanced age without clinically evident cardiovascular disease) that may benefit from PAD screening to trigger more aggressive medical management. To date, inadequate data exist to define these specific subgroups, and broad population screening appears unwarranted.
      After a patient is identified with symptoms consistent with IC and an abnormal ABI, it is important to rule out other potential etiologies that can mimic PAD symptoms. The differential diagnosis for IC is extensive and is summarized in Table I. By studying the characteristics associated with each condition listed in Table I, it is clear that most alternative diagnoses can be confirmed or excluded by a thorough history and physical examination. Careful characterization of the specific pattern of symptoms, with special attention to the factors that provoke, exacerbate, and relieve the symptoms, can almost always result in an accurate diagnosis.
      Table IThe differential diagnosis for intermittent claudication (IC)
      (adapted from Inter-Society Consensus for the Management of Peripheral Arterial Disease [TASC II])
      • Norgren L.
      • Hiatt W.R.
      • Dormandy J.A.
      • Nehler M.R.
      • Harris K.A.
      • Fowkes F.G.
      Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).
      ConditionLocationPrevalenceCharacteristicEffect of exerciseEffect of restEffect of positionOther characteristic
      Calf ICCalf muscles3% of adult populationCramping, aching discomfortReproducible onsetQuickly relievedNoneMay have atypical limb symptoms on exercise
      Thigh and buttock ICButtocks, hip, thighRareCramping, aching, discomfortReproducible onsetQuickly relievedNoneImpotence. May have normal pedal pulses with isolated iliac artery disease
      Foot ICFoot archRareSevere pain on exerciseReproducible onsetQuickly relievedNoneAlso may present as numbness
      Chronic compartment syndromeCalf musclesRareTight, bursting painAfter much exercise (jogging)Subsides very slowlyRelief with elevationTypically heavy muscled athletes
      Venous claudicationEntire leg, worse in calfRareTight, bursting painAfter walkingSubsides slowlyRelief speeded by elevationHistory of iliofemoral deep vein thrombosis, signs of venous congestion, edema
      Nerve root compressionRadiates down legCommonSharp lancinating painInduced by sitting, standing, or walkingOften present at restImproved by change in positionHistory of back problems. Worse with sitting. Relief when supine or sitting. Not intermittent
      Symptomatic Baker cystBehind knee, down calfRareSwelling, tendernessWith exercisePresent at restNoneNot intermittent
      Hip arthritisLateral hip, thighCommonAching discomfortAfter variable degree of exerciseNot quickly relievedImproved when not weight bearingSymptoms variable. History of degenerative arthritis
      Spinal stenosisOften bilateral buttocks, posterior legCommonPain and weaknessMay mimic ICVariable relief but can take a long time to recoverRelief by lumbar spine flexionWorse with standing and extending spine
      Foot/ankle arthritisAnkle, foot, archCommonAching painAfter variable degree of exerciseNot quickly relievedMay be relieved by not bearing weightVariable, may relate to activity level and present at rest
      Perhaps worthy of special mention is the differentiation of neurogenic claudication from vasculogenic claudication, because this is the most common clinical diagnostic challenge. In contrast to vasculogenic claudication, neurogenic claudication most often occurs secondary to nerve root compression on exit from the spinal canal. These symptoms may often include lower extremity pain that is radiating in nature, starting at the hips or buttocks and extending down the affected leg. In addition, radicular pain is frequently brought on by simple weight bearing or changes in posture (eg, rising after prolonged sitting) and relieved by a change in position to relieve the load on the spine (eg, lumbar flexion, sitting down). These features are in distinct contrast to vasculogenic claudication, which is induced by leg exercise and quickly relieved by rest (resulting in a decrease in muscular metabolic requirement), without a need to change position.
      As mentioned, the cornerstone of the patient assessment for IC consists of a complete history and physical examination. Qualitative assessment of the extremity for signs of PAD includes the presence of weak or absent distal pulses, the absence of distal hair growth, evidence of dry skin secondary to apocrine gland dysfunction, and in the case of advanced PAD, nonhealing areas of skin breakdown. Quantitative assessment includes noninvasive vascular testing, of which the cornerstone is the measurement of the ABI. If the ABI is ≥1.4 secondary to noncompressibility of the arteries from calcification, a toe-brachial index is a useful alternative because the digital arteries are frequently not calcified. A toe-brachial index value of ≤0.7 is indicative of hemodynamically significant arterial insufficiency.
      • Aboyans V.
      • Criqui M.H.
      • Abraham P.
      • Allison M.A.
      • Creager M.A.
      • Diehm C.
      • et al.
      Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association.
      Although not necessary in all patients, further noninvasive testing with segmental pressures and pulse volume recordings can be helpful in objectively quantifying the magnitude of the deficit in perfusion and aiding in localizing the level of arterial obstruction.
      In the setting of compelling symptoms and normal results on noninvasive vascular testing at rest, obtaining an ABI with exercise can be helpful. A challenge for establishing diagnostic criteria for the exercise ABI is the heterogeneity of the protocols used in vascular laboratories.
      • Sakurai T.
      • Matsushita M.
      • Nishikimi N.
      • Nimura Y.
      Effect of walking distance on the change in ankle-brachial pressure index in patients with intermittent claudication.
      • Hoogeveen E.K.
      • Mackaay A.J.
      • Beks P.J.
      • Kostense P.J.
      • Dekker J.M.
      • Heine R.J.
      • et al.
      Evaluation of the one-minute exercise test to detect peripheral arterial disease.
      • Carter S.A.
      Response of ankle systolic pressure to leg exercise in mild or questionable arterial disease.
      In general, this test is performed using a standardized treadmill protocol that asks patients to walk at a predetermined speed for a maximum of 5 minutes.
      • Aboyans V.
      • Criqui M.H.
      • Abraham P.
      • Allison M.A.
      • Creager M.A.
      • Diehm C.
      • et al.
      Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association.
      During the test, patients are asked to tell the personnel when they start to feel pain in the legs. Patients are encouraged to finish the entire test. Immediately after getting off of the treadmill, the exercise ABI is calculated. A drop in the ABI to a value ≤0.9 is indicative of a hemodynamically significant arterial obstruction.
      • Aboyans V.
      • Criqui M.H.
      • Abraham P.
      • Allison M.A.
      • Creager M.A.
      • Diehm C.
      • et al.
      Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association.
      Other more specific criteria include a drop of 30 mm Hg or 20% of the baseline ABI with exercise, and a delayed (>3 minutes) recovery.
      Additional imaging modalities that can more precisely localize arterial lesions—arterial duplex, computed tomography angiography (CTA), magnetic resonance (MR) angiography (MRA), and contrast arteriography—should be reserved for patients in whom revascularization treatment is being considered. For those patients with asymptomatic PAD or IC who are not appropriate candidates for revascularization, the costs and potential risks associated with anatomic studies are not warranted.

       Recommendations: Diagnosis of peripheral arterial disease (PAD)

      Tabled 1
      GradeLevel of evidence
      2.1.We recommend using the ABI as the first-line noninvasive test to establish a diagnosis of PAD in individuals with symptoms or signs suggestive of disease. When the ABI is borderline or normal (>0.9) and symptoms of claudication are suggestive, we recommend an exercise ABI.1A
      2.2.We suggest against routine screening for lower extremity PAD in the absence of risk factors, history, signs, or symptoms of PAD.2C
      2.3.For asymptomatic individuals who are at elevated risk, such as those aged >70, smokers, diabetic patients, those with an abnormal pulse examination, or other established cardiovascular disease, screening for lower extremity PAD is reasonable if used to improve risk stratification, preventive care, and medical management.2C
      2.4.In symptomatic patients who are being considered for revascularization, we suggest using physiologic noninvasive studies, such as segmental pressures and pulse volume recordings, to aid in the quantification of arterial insufficiency and help localize the level of obstruction.2C
      2.5.In symptomatic patients in whom revascularization treatment is being considered, we recommend anatomic imaging studies, such as arterial duplex ultrasound, CTA, MRA, and contrast arteriography.1B
      ABI, Ankle-brachial index; CTA, computed tomography angiography; MRA, magnetic resonance angiography.

       Summary of evidence: Diagnosis of peripheral arterial disease (PAD)

      Tabled 1
      Clinical questionData sourceFindingQuality of evidence
      Accuracy of ABI in patients suspected to have PADMultiple nonrandomized diagnostic studies with comparison with the gold standardABI <0.9 has a sensitivity ranging from 79% to 95% with a specificity of >95%
      • Hirsch A.T.
      • Haskal Z.J.
      • Hertzer N.R.
      • Bakal C.W.
      • Creager M.A.
      • Halperin J.L.
      • 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.
      A-B
      Accuracy of anatomic imaging studies and physiologic noninvasive studies in patients suspected to have PADNonrandomized diagnostic studies with comparison with the gold standardThe combination of segmental limb pressures and pulse volume recordings had a diagnostic accuracy of 97%.
      • Rutherford R.B.
      • Lowenstein D.H.
      • Klein M.F.
      Combining segmental systolic pressures and plethysmography to diagnose arterial occlusive disease of the legs.
      Duplex ultrasound imaging to detect a stenosis ≥50% in the aortoiliac tract: sensitivity, 86%; specificity, 97%; for the femoropopliteal tract: sensitivity, 80%; specificity, 96%; for the infragenicular arteries: sensitivity, 83%; specificity, 84%.
      • Koelemay M.J.
      • den Hartog D.
      • Prins M.H.
      • Kromhout J.G.
      • Legemate D.A.
      • Jacobs M.J.
      Diagnosis of arterial disease of the lower extremities with duplex ultrasonography.
      Accuracy of CT and MR imaging were >90%
      • Romano M.
      • Mainenti P.P.
      • Imbriaco M.
      • Amato B.
      • Markabaoui K.
      • Tamburrini O.
      • et al.
      Multidetector row CT angiography of the abdominal aorta and lower extremities in patients with peripheral arterial occlusive disease: diagnostic accuracy and interobserver agreement.
      • Menke J.
      • Larsen J.
      Meta-analysis: accuracy of contrast-enhanced magnetic resonance angiography for assessing steno-occlusions in peripheral arterial disease.
      B-C
      Benefits and harms of screening asymptomatic individuals with ABINo dataNo data on benefit or harm in patient-important outcomes
      • Moyer V.A.
      U.S. Preventive Services Task Force
      Screening for peripheral artery disease and cardiovascular disease risk assessment with the ankle-brachial index in adults: U.S. Preventive Services Task Force recommendation statement.
      C
      Incremental value of adding ABI to traditional risk assessment tools (Framingham risk assessment)Meta-analysis of cohort studies. Evidence is considered indirect because risk score is a surrogate outcomeReclassification of risk and change in treatment recommendations in ∼19% of men and 36% of women
      • Fowkes F.G.
      • Murray G.D.
      • Butcher I.
      • Heald C.L.
      • Lee R.J.
      • Chambless L.E.
      • et al.
      Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.
      C
      ABI, Ankle-brachial index; CT, computed tomography; MR, magnetic resonance.

      3. Management of asymptomatic patients with PAD

      The incidence of asymptomatic PAD in the U.S. population is substantial, extends across gender and race divisions, and may be readily confirmed by use of the ABI.
      • Hirsch A.T.
      • Criqui M.H.
      • Treat-Jacobson D.
      • Regensteiner J.G.
      • Creager M.A.
      • Olin J.W.
      • et al.
      Peripheral arterial disease detection, awareness, and treatment in primary care.
      • Criqui M.H.
      • McClelland R.L.
      • McDermott M.M.
      • Allison M.A.
      • Blumenthal R.S.
      • Aboyans V.
      • et al.
      The ankle-brachial index and incident cardiovascular events in the MESA (Multi-Ethnic Study of Atherosclerosis).
      An important question is whether identification and treatment of the asymptomatic PAD population provides incremental health benefits beyond that derived from routine cardiovascular risk factor assessment and treatment. In addition to diagnosing PAD in patients with exertional leg symptoms or nonhealing wounds, the 2011 American College of Cardiology Foundation/American Heart Association PAD Guidelines recommend screening for PAD in all patients aged >65 years and in all patients aged >50 years with a history of diabetes or smoking.
      • Rooke T.W.
      • Hirsch A.T.
      • Misra S.
      • Sidawy A.N.
      • Beckman J.A.
      • Findeiss L.K.
      • et al.
      2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society for Vascular Medicine, and Society for Vascular Surgery.
      As noted above, these recommendations run counter to the findings of the SVS-commissioned systematic review,
      • Alahdab F.
      • Wang A.T.
      • Elraiyah T.A.
      • Malgor R.D.
      • Rizvi A.Z.
      • Lane M.A.
      • et al.
      A systematic review for the screening for peripheral arterial disease in asymptomatic patients.
      which suggests that no clear benefit is derived from screening for PAD in asymptomatic patients.
      The recommendations of the U.S. Preventative Services Task Force in 2005 concluded that the harms of screening asymptomatic adults for PAD would outweigh any benefits.
      • Force U.S.P.S.T.
      U.S. Preventive Services Task Force
      Screening for peripheral arterial disease: recommendation statement.
      The U.S. Preventative Services Task Force again addressed the issue of ABI screening in its 2013 publication
      • Lin J.S.
      • Olson C.M.
      • Johnson E.S.
      • Whitlock E.P.
      The ankle-brachial index for peripheral artery disease screening and cardiovascular disease prediction among asymptomatic adults: a systematic evidence review for the U.S. Preventive Services Task Force.
      and concluded that “there is insufficient evidence to determine the balance of benefits and harms of screening for PAD with the ABI to prevent future cardiovascular disease outcomes.” The conflicting recommendations and ongoing controversy demonstrate that although asymptomatic PAD is a sentinel indicator of cardiovascular morbidity and mortality, specific treatment pathways for this large PAD subpopulation remain poorly defined.
      PAD primarily results from atherosclerotic occlusion of the arteries supplying the lower extremity. Consequently, management of asymptomatic PAD should be directed at accepted risk factor modification for patients with atherosclerosis. Pharmacologic strategies with proven benefit for symptomatic PAD have been empirically applied to the treatment of the asymptomatic PAD population. However, as noted below, certain pharmacologic interventions have failed to show benefit in the asymptomatic population, and others await verification. Nonetheless, accepted preventive strategies for atherosclerosis are appropriate for asymptomatic disease and for IC.

       Smoking cessation

      PAD severity has been shown to correlate to the extent of cigarette smoking.
      • Fowkes F.G.
      • Housley E.
      • Riemersma R.A.
      • Macintyre C.C.
      • Cawood E.H.
      • Prescott R.J.
      • et al.
      Smoking, lipids, glucose intolerance, and blood pressure as risk factors for peripheral atherosclerosis compared with ischemic heart disease in the Edinburgh Artery Study.
      In a broad sample of PAD patients, including ∼27% who were asymptomatic, a community-based intervention (“stop smoking, keep walking”) increased maximal walking distance and frequency of recreational ambulation.
      • Fowler B.
      • Jamrozik K.
      • Norman P.
      • Allen Y.
      • Wilkinson E.
      Improving maximum walking distance in early peripheral arterial disease: randomised controlled trial.

       Antiplatelet therapy

      The Aspirin for Asymptomatic Atherosclerosis Trial
      • Fowkes F.G.
      • Price J.F.
      • Stewart M.C.
      • Butcher I.
      • Leng G.C.
      • Pell A.C.
      • et al.
      Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial.
      randomized 3350 patients with asymptomatic PAD to treatment with enteric-coated aspirin (100 mg) or placebo. During 8 years of follow-up, no difference in vascular event rates was noted. However, this trial used an epidemiologic method of ABI determination in which the lower of the ankle pressures was used to calculate the ABI. Thus, the individuals in this study might not be fully representative of the universe of PAD patients with a greater burden of disease. At present, the benefit of antiplatelet therapy for patients with asymptomatic PAD and no other clinical cardiovascular disease is unknown.

       Statin therapy

      The Heart Protection Study established the protective effects of statin therapy in reducing mortality and cardiovascular events among individuals with PAD.
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      However, asymptomatic PAD patients were not specifically included unless they met other criteria, such as diabetes, hypertension, or other history of clinical cardiovascular or cerebrovascular disease. In addition to reducing cardiovascular event rates, statin use has been associated with improved lower extremity functioning.
      • McDermott M.M.
      • Guralnik J.M.
      • Greenland P.
      • Pearce W.H.
      • Criqui M.H.
      • Liu K.
      • et al.
      Statin use and leg functioning in patients with and without lower-extremity peripheral arterial disease.
      This improvement was not related to improved lipid control or other confounding factors, and the association was noted in patients with and without PAD. At present, the benefit of lipid-lowering therapy in patients with asymptomatic PAD who lack other evidence of clinical cardiovascular disease (coronary, cerebral) or risk factors (diabetes, hypertension) remains unclear. Recently published treatment guidelines for lipid-lowering therapy suggest the use of statins should be considered in all individuals with an estimated 10-year risk of major cardiovascular events >7.5%.
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • Bairey Merz C.N.
      • Blum C.B.
      • Eckel R.H.
      • et al.
      2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      This would seem to include any individual with established PAD.
      • Criqui M.H.
      • Langer R.D.
      • Fronek A.
      • Feigelson H.S.
      • Klauber M.R.
      • McCann T.J.
      • et al.
      Mortality over a period of 10 years in patients with peripheral arterial disease.
      • Criqui M.H.
      • McClelland R.L.
      • McDermott M.M.
      • Allison M.A.
      • Blumenthal R.S.
      • Aboyans V.
      • et al.
      The ankle-brachial index and incident cardiovascular events in the MESA (Multi-Ethnic Study of Atherosclerosis).
      Notably, the recommended risk estimation algorithm does not include evidence of PAD or the ABI value.
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • Bairey Merz C.N.
      • Blum C.B.
      • Eckel R.H.
      • et al.
      2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.

       Exercise and limb function

      Although asymptomatic PAD patients do not report exertional leg discomfort by definition, careful assessment reveals impaired lower extremity function. An observational study of asymptomatic PAD patients demonstrated slower walking velocity, poorer standing balance, and other negative functional associations, despite correction for age, gender, smoking, and other comorbidities.
      • McDermott M.M.
      • Fried L.
      • Simonsick E.
      • Ling S.
      • Guralnik J.M.
      Asymptomatic peripheral arterial disease is independently associated with impaired lower extremity functioning: the women’s health and aging study.
      Whether targeted physical therapy interventions can reverse decline or improve functional performance and quality of life (QoL) in this population remains unclear.

       Surveillance of asymptomatic patients for disease progression

      In a small study of asymptomatic PAD patients, 35% of legs had developed new lower extremity arterial lesions on duplex scanning, and 26% of patients had developed new IC ≤1 year after diagnosis.
      • Mohler 3rd, E.R.
      • Bundens W.
      • Denenberg J.
      • Medenilla E.
      • Hiatt W.R.
      • Criqui M.H.
      Progression of asymptomatic peripheral artery disease over 1 year.
      It is also important to note that some asymptomatic PAD patients, particularly those with diabetes, may develop CLI without an antecedent history of claudication. The incremental value and frequency of repeat ABI testing in asymptomatic PAD is not established but may be useful in higher-risk patients (eg, diabetic patients) or those with a lower baseline ABI. Regardless of hemodynamic or imaging findings, invasive treatments for PAD are only indicated for those with symptoms, with few exceptions noted below (eg, intervention for failing bypass graft or to support delivery of an indicated cardiovascular implant).

       Recommendations: Management of asymptomatic disease

      Tabled 1
      GradeLevel of evidence
      3.1.We recommend multidisciplinary comprehensive smoking cessation interventions for patients with asymptomatic PAD who use tobacco (repeatedly until tobacco use has stopped).1A
      3.2.We recommend providing education about the signs and symptoms of PAD progression to asymptomatic patients with PAD.1Ungraded
      3.3.We recommend against invasive treatments for PAD in the absence of symptoms, regardless of hemodynamic measures or imaging findings demonstrating PAD.1B
      PAD, Peripheral arterial disease.

       Summary of evidence: Management of asymptomatic disease

      Tabled 1
      Clinical questionData sourceFindingQuality of evidence
      The effect of smoking cessation in patients with asymptomatic PADObservational studies in various settings applicable to patients with asymptomatic PADSmoking cessation reduces overall mortality and morbidity in smokers in generalA
      Benefit for serial ABI testing (surveillance) in patients with asymptomatic PADSparse dataNo data on benefits and harms of surveillanceC
      PAD, Peripheral arterial disease.

      4. Noninterventional management of the patient with IC

      As noted, IC is the most common clinical manifestation of PAD. Patients with IC may exhibit a wide range of symptom severity and associated effect on daily function. Moreover, concomitant conditions, such as cardiopulmonary disease, arthritis, spine disease, and obesity, can markedly limit exercise capacity in a synergistic fashion. Therefore, the treatment of IC must be individualized and based on a careful assessment of risk factors, compliance, and the subjective values of the patient. Of paramount importance at the time of the initial diagnosis is patient education, both regarding the long-term implications of PAD on cardiovascular health and to allay fears of amputation (Fig 2). Multiple studies have established that patients with IC are at increased risk for cardiovascular events, whereas the risk of major amputation is exceedingly low (<1% per year).
      • Criqui M.H.
      • Langer R.D.
      • Fronek A.
      • Feigelson H.S.
      • Klauber M.R.
      • McCann T.J.
      • et al.
      Mortality over a period of 10 years in patients with peripheral arterial disease.
      • Singer A.
      • Rob C.
      The fate of the claudicator.
      Establishing an appropriate therapeutic framework of risk reduction, lifestyle modification, and antiatherosclerotic medical therapies should always precede consideration of invasive procedures for IC.
      Claudication significantly affects QoL, and this effect is often underestimated by treating physicians. IC is associated with severe functional impairment that can be significantly improved by intervention in properly selected patients. Multiple studies by McDermott et al
      • McDermott M.M.
      • Fried L.
      • Simonsick E.
      • Ling S.
      • Guralnik J.M.
      Asymptomatic peripheral arterial disease is independently associated with impaired lower extremity functioning: the women’s health and aging study.
      • McDermott M.M.
      • Greenland P.
      • Liu K.
      • Guralnik J.M.
      • Criqui M.H.
      • Dolan N.C.
      • et al.
      Leg symptoms in peripheral arterial disease: associated clinical characteristics and functional impairment.
      • McDermott M.M.
      • Tian L.
      • Liu K.
      • Guralnik J.M.
      • Ferrucci L.
      • Tan J.
      • et al.
      Prognostic value of functional performance for mortality in patients with peripheral artery disease.
      have objectively documented the adverse effect of PAD and claudication on patients' functional status. Even in patients with mild PAD, results of multiple tests of functional impairment, such as the 6-minute walk test, are significantly worse in PAD patients compared with those without PAD.
      • McDermott M.M.
      • Mehta S.
      • Greenland P.
      Exertional leg symptoms other than intermittent claudication are common in peripheral arterial disease.
      In addition to reduced functioning, severe PAD is associated with reduced survival.
      • McDermott M.M.
      • Tian L.
      • Liu K.
      • Guralnik J.M.
      • Ferrucci L.
      • Tan J.
      • et al.
      Prognostic value of functional performance for mortality in patients with peripheral artery disease.
      Patients in the lowest quartile of an office-administered 6-minute walk performance test exhibited significantly increased mortality (odds ratio [OR], 2.36).

      4A Pharmacotherapy for patients with claudication: Risk reduction

      Patients with IC carry a significant systemic burden of atherosclerosis and are at risk for its associated complications. These patients should have lifelong treatment designed to eliminate or modify known risk factors for atherosclerosis to reduce the risk of cardiovascular complications or death. In addition, treatment of risk factors can reduce the risk of periprocedural complications or death after any invasive treatments undertaken for PAD and may improve the patency of interventions. Many of the recommendations for risk-factor modification in PAD have been extrapolated from the literature on secondary prevention in coronary artery disease. This represents a notable gap in evidence specific to PAD and is particularly relevant in terms of setting defined treatment targets that are population-specific and disease-specific.

       Smoking cessation

      In observational studies, continued smoking is associated with higher rates of amputation, death, and myocardial infarction in patients with PAD compared with those who have quit.
      • Faulkner K.W.
      • House A.K.
      • Castleden W.M.
      The effect of cessation of smoking on the accumulative survival rates of patients with symptomatic peripheral vascular disease.
      Continued smoking has been associated with a twofold to threefold increase in the rate of lower extremity bypass graft failure compared with nonsmokers.
      • Lassila R.
      • Lepantalo M.
      Cigarette smoking and the outcome after lower limb arterial surgery.
      • Willigendael E.M.
      • Teijink J.A.
      • Bartelink M.L.
      • Peters R.J.
      • Buller H.R.
      • Prins M.H.
      Smoking and the patency of lower extremity bypass grafts: a meta-analysis.

       Dyslipidemia

      Treatment of dyslipidemia with statins reduces the likelihood of adverse cardiovascular events in patients with atherosclerosis.
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
      Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.
      • Sacks F.M.
      • Pfeffer M.A.
      • Moye L.A.
      • Rouleau J.L.
      • Rutherford J.D.
      • Cole T.G.
      • et al.
      The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.
      Patients with PAD were designated as high or very high risk for adverse cardiovascular events by the National Cholesterol Educational Program Adult Treatment Panel #3 and are advised to undergo treatment to lower low-density lipoprotein cholesterol to <100 mg/dL or to <70 mg/dL in very high-risk individuals.
      • Grundy S.M.
      • Cleeman J.I.
      • Merz C.N.
      • Brewer Jr., H.B.
      • Clark L.T.
      • Hunninghake D.B.
      • et al.
      Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.
      As noted above, the most recent guidelines on lipid therapy focus on the estimation of 10-year cardiovascular risk rather than specific lipid levels.
      Although PAD per se is not included in the suggested risk estimation algorithm, historical data suggest that all PAD patients would meet the suggested threshold of a 7.5% 10-year risk. It is noteworthy that specific low-density lipoprotein targets have never been validated in the PAD population, who commonly demonstrate a phenotype of dyslipidemia (low high-density lipoprotein, elevated triglycerides), which contrasts with typical patients with isolated coronary artery disease. Statin therapy has also improved pain-free walking time in small studies of patients with IC.
      • Mohler 3rd, E.R.
      • Hiatt W.R.
      • Creager M.A.
      Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease.
      • Mondillo S.
      • Ballo P.
      • Barbati R.
      • Guerrini F.
      • Ammaturo T.
      • Agricola E.
      • et al.
      Effects of simvastatin on walking performance and symptoms of intermittent claudication in hypercholesterolemic patients with peripheral vascular disease.
      The mechanism of this action is unknown. However, in the Claudication: Exercise vs Endoluminal Revascularization (CLEVER) trial,
      • Murphy T.P.
      • Cutlip D.E.
      • Regensteiner J.G.
      • Mohler E.R.
      • Cohen D.J.
      • Reynolds M.R.
      • et al.
      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.
      conventional medical therapy, including statins for atherosclerosis, did not significantly improve walking ability or symptoms in patients with IC compared with supervised exercise or stenting (Section 5C).

       Diabetes mellitus

      The prevalence of PAD in patients with diabetes mellitus is estimated to be 29%.
      • Elhadd T.A.
      • Jung R.T.
      • Newton R.W.
      • Stonebridge P.A.
      • Belch J.J.
      Incidence of asymptomatic peripheral arterial occlusive disease in diabetic patients attending a hospital clinic.
      Although it is unknown whether aggressive treatment to optimize serum glucose levels decreases the likelihood of adverse cardiovascular events in these patients, atherosclerosis tends to be more aggressive, and amputation rates in diabetic patients with atherosclerosis of the lower extremity are five to 10 times higher than in nondiabetic counterparts. Sensory neuropathy and increased susceptibility to infection contribute to the elevated rate of amputation.
      • Norgren L.
      • Hiatt W.R.
      • Dormandy J.A.
      • Nehler M.R.
      • Harris K.A.
      • Fowkes F.G.
      Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).

       Hypertension

      There is a strong association between hypertension and cardiovascular disease, including PAD; however, the relative risk is less for hypertension than for smoking or diabetes. Treatment of hypertension is indicated to reduce cardiovascular events, including congestive heart failure, stroke, and death.
      • Psaty B.M.
      • Smith N.L.
      • Siscovick D.S.
      • Koepsell T.D.
      • Weiss N.S.
      • Heckbert S.R.
      • et al.
      Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis.
      There is no evidence that β-adrenergic blockers worsen the symptoms of IC.
      • Radack K.
      • Deck C.
      Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease. A meta-analysis of randomized controlled trials.
      Angiotensin-converting enzyme inhibitors (ACEIs) reduce the risk of death and nonfatal cardiac events in patients with left ventricular dysfunction.
      • Gustafsson F.
      • Torp-Pedersen C.
      • Kober L.
      • Hildebrandt P.
      Effect of angiotensin converting enzyme inhibition after acute myocardial infarction in patients with arterial hypertension. TRACE Study Group, Trandolapril Cardiac Event.
      • Pfeffer M.A.
      • Braunwald E.
      • Moye L.A.
      • Basta L.
      • Brown Jr., E.J.
      • Cuddy T.E.
      • et al.
      Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators.
      In the Heart Outcomes Prevention Evaluation study, 4051 patients with PAD treated with ramipril had a 25% reduction of cardiac events.
      • Yusuf S.
      • Sleight P.
      • Pogue J.
      • Bosch J.
      • Davies R.
      • Dagenais G.
      Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.
      This is notable, particularly in the context of a recent trial examining the effects of ramipril on walking performance (Section 4B).

       Antiplatelet and antithrombotic agents

      Numerous studies have demonstrated the benefit of antiplatelet therapy, especially aspirin, in doses of 75 to 325 mg/d in reducing rates of myocardial infarction, stroke, and vascular-related deaths in individuals with symptomatic lower extremity atherosclerosis.
      Antithrombotic Trialists' Collaboration
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      The American Heart Association practice guidelines for lower extremity ischemia rated this treatment recommendation class I-A.
      • Hirsch A.T.
      • Haskal Z.J.
      • Hertzer N.R.
      • Bakal C.W.
      • Creager M.A.
      • Halperin J.L.
      • 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.
      In the 6452 patients with PAD in the Clopidogrel vs Aspirin In Patients At Risk of Ischaemic Events trial, clopidogrel reduced the myocardial infarction, stroke, or vascular death rate by 23.8% more than aspirin alone.
      CAPRIE Steering Committee
      A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee.
      Although a single study demonstrated that combination aspirin and clopidogrel therapy was associated with a 20% relative risk reduction for myocardial infarction, cardiovascular death, or stroke,
      • Yusuf S.
      • Zhao F.
      • Mehta S.R.
      • Chrolavicius S.
      • Tognoni G.
      • Fox K.K.
      Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.
      there is no evidence to date that combination therapy is a more effective treatment for PAD than a single agent, and bleeding risks are increased.
      • Berger P.B.
      • Bhatt D.L.
      • Fuster V.
      • Steg P.G.
      • Fox K.A.
      • Shao M.
      • et al.
      Bleeding complications with dual antiplatelet therapy among patients with stable vascular disease or risk factors for vascular disease: results from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial.
      Warfarin has been demonstrated to reduce myocardial infarction or stroke in patients with coronary artery disease, although at the cost of a 4.5-fold increase in major bleeding.
      Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (The Dutch Bypass Oral Anticoagulants or Aspirin Study): a randomised trial.
      • Anand S.S.
      • Yusuf S.
      Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis.
      There is no evidence that warfarin decreases the likelihood of adverse events related to PAD alone. Only one prospective trial exists comparing the effect of warfarin vs aspirin on graft patency. A similar number of graft occlusions occurred in both study cohorts, with a twofold increased risk of major bleeding in the warfarin cohort.
      Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (The Dutch Bypass Oral Anticoagulants or Aspirin Study): a randomised trial.

       Homocysteine-lowering drugs

      Approximately 30% of patients with known PAD have elevated serum levels of homocysteine compared with 1% in the general population.
      • Norgren L.
      • Hiatt W.R.
      • Dormandy J.A.
      • Nehler M.R.
      • Harris K.A.
      • Fowkes F.G.
      Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).
      Folic acid and cobalamin (vitamin B12) have been found to reduce serum homocysteine levels by 25% and 7%, respectively, in clinical trials. However, there are no data demonstrating that reducing homocysteine serum levels decreases the likelihood of adverse cardiovascular events in patients with PAD,
      Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists’ Collaboration.
      although clinical trials are ongoing.
      Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists’ Collaboration.
      VITATOPS Trial Study Group
      The VITATOPS (Vitamins to Prevent Stroke) Trial: rationale and design of an international, large, simple, randomised trial of homocysteine-lowering multivitamin therapy in patients with recent transient ischaemic attack or stroke.

      WENBIT - Western Norway B Vitamin Intervention Trial. Available at: clinicaltrials.gov/show/nct00354081. Accessed June 21, 2014.

      Pending the outcomes of prospective trials, treating hyperhomocysteinemia with folic acid to reduce serum levels to <10 μmol/L is generally safe and well tolerated but is of no proven benefit.

      4B Pharmacotherapy for patients with IC to improve leg function

      Medical management of IC is aimed at symptom relief (Table II) and slowing the progression of atherosclerotic disease. A number of drugs have been evaluated for use in patients with IC, but in the United States, there are currently only two Food and Drug Administration (FDA)-approved medications—cilostazol and pentoxifylline.
      • Hood S.C.
      • Moher D.
      • Barber G.G.
      Management of intermittent claudication with pentoxifylline: meta-analysis of randomized controlled trials.
      • Porter J.M.
      • Cutler B.S.
      • Lee B.Y.
      • Reich T.
      • Reichle F.A.
      • et al.
      Pentoxifylline efficacy in the treatment of intermittent claudication: multicenter controlled double-blind trial with objective assessment of chronic occlusive arterial disease patients.
      • Robless P.
      • Mikhailidis D.P.
      • Stansby G.P.
      Cilostazol for peripheral arterial disease.
      Of note, a recent review by the Royal College of Physicians in the United Kingdom identifies naftidrofuryl—widely available in Europe but not FDA-approved in the United States—as the drug of choice over both cilostazol and pentoxifylline in the medical management of symptomatic PAD.
      • De Backer T.
      • Vander Stichele R.
      • Lehert P.
      • Van Bortel L.
      Naftidrofuryl for intermittent claudication: meta-analysis based on individual patient data.
      • de Backer T.L.
      • Vander Stichele R.
      • Lehert P.
      • Van Bortel L.
      Naftidrofuryl for intermittent claudication.
      Table IISummary of noninterventional treatments for intermittent claudication (IC)
      References (first author)ModalityTreatment duration, monthsOutcome measures (functional, hemodynamic, QoL)FU duration, months
      Leng
      • Leng G.C.
      • Fowler B.
      • Ernst E.
      Exercise for intermittent claudication.
      Exercise3-15Maximal walking time, pain-free walking distance3-15
      Gardner
      • Gardner A.W.
      • Poehlman E.T.
      Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis.
      1-4Maximal walking time, pain-free walking distance3-15
      Stewart
      • Stewart K.J.
      • Hiatt W.R.
      • Regensteiner J.G.
      • Hirsch A.T.
      Exercise training for claudication.
      1-15Maximal walking time, pain-free walking distance3-15
      Porter,
      • Porter J.M.
      • Cutler B.S.
      • Lee B.Y.
      • Reich T.
      • Reichle F.A.
      • et al.
      Pentoxifylline efficacy in the treatment of intermittent claudication: multicenter controlled double-blind trial with objective assessment of chronic occlusive arterial disease patients.
      Salhiyyah
      • Salhiyyah K.
      • Senanayake E.
      • Abdel-Hadi M.
      • Booth A.
      • Michaels J.A.
      Pentoxifylline for intermittent claudication.
      Pentoxifylline6Pain-free walking distance, maximal walking distance6
      Dawson,
      • Dawson D.L.
      • Cutler B.S.
      • Hiatt W.R.
      • Hobson 2nd, R.W.
      • Martin J.D.
      • Bortey E.B.
      • et al.
      A comparison of cilostazol and pentoxifylline for treating intermittent claudication.
      Regensteiner
      • Regensteiner J.G.
      • Ware Jr., J.E.
      • McCarthy W.J.
      • Zhang P.
      • Forbes W.P.
      • Heckman J.
      • et al.
      Effect of cilostazol on treadmill walking, community-based walking ability, and health-related quality of life in patients with intermittent claudication due to peripheral arterial disease: meta-analysis of six randomized controlled trials.
      Cilostazol6Maximal walking distance, QoL6
      Mondillo
      • Mondillo S.
      • Ballo P.
      • Barbati R.
      • Guerrini F.
      • Ammaturo T.
      • Agricola E.
      • et al.
      Effects of simvastatin on walking performance and symptoms of intermittent claudication in hypercholesterolemic patients with peripheral vascular disease.
      Statins6Pain-free walking time, maximal walking time6
      FU, Follow-up; QoL, quality of life.
      The effect of ramipril on walking performance in patients with IC was originally included but has subsequently been deleted (see Supplementary Material on page 41S.e1, online only).
      Pentoxifylline was the first drug approved by the FDA for IC in 1984. By reducing blood viscosity and retarding platelet aggregation, pentoxifylline use results in improved blood flow and enhanced tissue oxygenation in affected areas. Porter et al
      • Porter J.M.
      • Cutler B.S.
      • Lee B.Y.
      • Reich T.
      • Reichle F.A.
      • et al.
      Pentoxifylline efficacy in the treatment of intermittent claudication: multicenter controlled double-blind trial with objective assessment of chronic occlusive arterial disease patients.
      revealed its effectiveness compared with placebo in a double-blind, placebo-controlled trial conducted at seven centers with use in outpatients. Pentoxifylline increased pain-free and maximal walking distance compared with placebo. Despite its significant findings in the Porter trial, clinical use of the drug has been limited due to the difficulty in identifying the IC patient who will predictably benefit.
      • Salhiyyah K.
      • Senanayake E.
      • Abdel-Hadi M.
      • Booth A.
      • Michaels J.A.
      Pentoxifylline for intermittent claudication.
      Significant positive effects on the ABI at rest or after exercise have not been appreciated in multiple trials.
      • Hood S.C.
      • Moher D.
      • Barber G.G.
      Management of intermittent claudication with pentoxifylline: meta-analysis of randomized controlled trials.
      • Salhiyyah K.
      • Senanayake E.
      • Abdel-Hadi M.
      • Booth A.
      • Michaels J.A.
      Pentoxifylline for intermittent claudication.
      • Dawson D.L.
      • Cutler B.S.
      • Hiatt W.R.
      • Hobson 2nd, R.W.
      • Martin J.D.
      • Bortey E.B.
      • et al.
      A comparison of cilostazol and pentoxifylline for treating intermittent claudication.
      Although it has modest effect, pentoxifylline is well tolerated, safe, and relatively inexpensive. Dosing begins at 400-mg tablets three times per day and can be titrated up to 1800 mg/d. Side effects of nausea, headache, drowsiness, and anorexia have precluded long-term use in some patients. Hypertension can be exacerbated with use.
      Cilostazol is a phosphodiesterase inhibitor that suppresses platelet aggregation and is also a direct vasodilator. Patients can notice improvement in maximal and pain-free walking distance in as short as 4 weeks.
      • Robless P.
      • Mikhailidis D.P.
      • Stansby G.P.
      Cilostazol for peripheral arterial disease.
      Other phosphodiesterase inhibitors have been noted to increase mortality in patients with advanced heart failure; thus, cilostazol is contraindicated in patients with any level of heart failure. In addition to improving blood flow to the limb, there is evidence that cilostazol and pentoxifylline prevent lipid accumulation, oxidation, and coagulation (ie, preventing further progression of atherosclerosis). However, epidemiologic evidence suggests that many patients do not receive meaningful symptom relief with medical therapy alone. This is likely a result of the limited ability of drugs to enhance muscle function or limb blood flow to the levels observed with therapies such as exercise training or invasive revascularization.
      The benefits of cilostazol in the treatment of IC were compared with those of pentoxifylline in a randomized controlled trial (RCT) performed by Dawson et al.
      • Dawson D.L.
      • Cutler B.S.
      • Hiatt W.R.
      • Hobson 2nd, R.W.
      • Martin J.D.
      • Bortey E.B.
      • et al.
      A comparison of cilostazol and pentoxifylline for treating intermittent claudication.
      They found that cilostazol therapy significantly increased maximal walking distance by 107 m (54% increase) compared with a 64-m improvement in the pentoxifylline group (30% increase). There was no difference in maximal walking distance improvement between the pentoxifylline and placebo groups. Regarding the durability of the effect, a recent pooled analysis of seven RCTs demonstrated a significant benefit in maximal walking distance compared with placebo at 6 months.
      • Robless P.
      • Mikhailidis D.P.
      • Stansby G.P.
      Cilostazol for peripheral arterial disease.
      The ACEI ramipril is used in the treatment of hypertension and may also have beneficial effects in patients with PAD and IC. In the Heart Outcomes Protection Evaluation study,
      • Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus
      results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators.
      treatment with ramipril reduced cardiovascular events and mortality even in patients without hypertension. Therefore, ramipril should be considered as a first-line choice for hypertension treatment in PAD patients, although it should be used with caution in the presence of renal artery stenosis. In a recent double-blind, placebo-controlled RCT, ramipril (10 mg/d for 24 weeks) was associated with significant improvements in pain-free and maximal treadmill walking times and in measures of physical function.
      • Ahimastos A.A.
      • Walker P.J.
      • Askew C.
      • Leicht A.
      • Pappas E.
      • Blombery P.
      • et al.
      Effect of ramipril on walking times and quality of life among patients with peripheral artery disease and intermittent claudication: a randomized controlled trial.
      Given the modest size of this trial (212 patients) in three hospitals in Australia, further multicenter studies with longer follow-up are needed to support the routine use of ramipril for IC. This recommendation was stricken post-publication by the guidelines committee based on further review of the evidence and is no longer valid (see Supplementary Material on page 41S.e1, online only).
      The vasoactive drug naftidrofuryl oxalate works by enhancing aerobic glycolysis and oxygen consumption in ischemic tissues, is commonly used in Europe, but is not currently approved in the United States. It has been shown to increase pain-free walking distance.
      • De Backer T.
      • Vander Stichele R.
      • Lehert P.
      • Van Bortel L.
      Naftidrofuryl for intermittent claudication: meta-analysis based on individual patient data.
      • de Backer T.L.
      • Vander Stichele R.
      • Lehert P.
      • Van Bortel L.
      Naftidrofuryl for intermittent claudication.
      Levocarnitine increases energy substrate for skeletal muscle metabolism. In clinical trials, a modest improvement in maximal and pain-free walking distance has been seen compared with placebo; however, no benefit has been noted over exercise alone.
      • Brass E.P.
      • Koster D.
      • Hiatt W.R.
      • Amato A.
      A systematic review and meta-analysis of propionyl-L-carnitine effects on exercise performance in patients with claudication.
      • Delaney C.L.
      • Spark J.I.
      • Thomas J.
      • Wong Y.T.
      • Chan L.T.
      • Miller M.D.
      A systematic review to evaluate the effectiveness of carnitine supplementation in improving walking performance among individuals with intermittent claudication.
      It is available in the United States over-the-counter as a dietary supplement.

       Recommendations: Medical treatment for intermittent claudication (IC)

      Tabled 1
      GradeLevel of evidence
      4.1.We recommend multidisciplinary comprehensive smoking cessation interventions for patients with IC (repeatedly until tobacco use has stopped).1A
      4.2.We recommend statin therapy in patients with symptomatic PAD.1A
      4.3.We recommend optimizing diabetes control (hemoglobin A1c goal of <7.0%) in patients with IC if this goal can be achieved without hypoglycemia.1B
      4.4.We recommend the use of indicated β-blockers (eg, for hypertension, cardiac indications) in patients with IC. There is no evidence supporting concerns about worsening claudication symptoms.1B
      4.5.In patients with IC due to atherosclerosis, we recommend antiplatelet therapy with aspirin (75-325 mg daily).1A
      4.6.We recommend clopidogrel in doses of 75 mg daily as an effective alternative to aspirin for antiplatelet therapy in patients with IC.1B
      4.7.In patients with IC due to atherosclerosis, we suggest against using warfarin for the sole indication of reducing the risk of adverse cardiovascular events or vascular occlusions.1C
      4.8.We suggest against using folic acid and vitamin B12 supplements as a treatment of IC.2C
      4.9.In patients with IC who do not have congestive heart failure, we suggest a 3-month trial of cilostazol (100 mg twice daily) to improve pain-free walking.2A
      4.10.In patients with IC who cannot tolerate or have contraindications for cilostazol, we suggest a trial of pentoxifylline (400 mg thrice daily) to improve pain-free walking.2B
      ACEI, Angiotensin-converting enzyme inhibitor; PAD, peripheral arterial disease.
      A recommendation (4.11) for using ramipril in IC was originally made but subsequently deleted (see Supplementary Material on page 41S.e1, online only).

       Summary of evidence: Medical treatment for intermittent claudication (IC)

      Tabled 1
      Clinical questionData sourceFindingQuality of evidence
      The effect of smoking cessation in patients with ICObservational studies in various settings applicable to patients with ICSmoking cessation reduces overall mortality and morbidity in smokers in generalA
      The effect of lipid lowering therapy on mortality and morbidity of patients with ICMeta-analysis of 18 RCTs of lipid-lowering therapy in patients with PAD of the lower limb. Additional indirect evidence about benefit of statin therapy in secondary cardiovascular disease prevention is also relevantLipid-lowering therapy had no statistically significant effect on mortality (OR, 0.86; 95% CI, 0.49-1.50) or total cardiovascular events (OR, 0.8; 95% CI, 0.59-1.09) but improved total walking distance (152 m; 95% CI, 32.11-271.88 m) and pain-free walking distance (89.76 m; 95% CI, 30.05-149.47 m), with no significant effect on ABI
      • Aung P.P.
      • Maxwell H.G.
      • Jepson R.G.
      • Price J.F.
      • Leng G.C.
      Lipid-lowering for peripheral arterial disease of the lower limb.
      A-B
      The effect of diabetes control on mortality and morbidity of patients with ICNo direct trials in PAD; indirect evidence consideredTight glycemic control in patients with type 2 diabetes reduced amputation (RR, 0.65; 95% CI, 0.45-0.94)
      • Hemmingsen B.
      • Lund S.S.
      • Gluud C.
      • Vaag A.
      • Almdal T.P.
      • Hemmingsen C.
      • et al.
      Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus.
      B
      The effect of antiplatelet therapy on mortality and morbidity of patients with ICMeta-analysis
      • Wong P.F.
      • Chong L.Y.
      • Mikhailidis D.P.
      • Robless P.
      • Stansby G.
      Antiplatelet agents for intermittent claudication.
      of 12 trials in patients with IC
      Antiplatelet agents reduced all cause (RR, 0.76; 95% CI, 0.60-0.98), cardiovascular mortality (RR, 0.54; 95% CI, 0.32-0.93), and the risk of needing revascularization (RR, 0.65; 95% CI, 0.43-0.97). Major bleeding estimate was imprecise (RR, 1.73; 95% CI, 0.51-5.83). In one trial, clopidogrel had a modest advantage over aspirinA
      The effect of cilostazol and pentoxifylline on walking performance in patients with ICMeta-analysis
      • Stevens J.W.
      • Simpson E.
      • Harnan S.
      • Squires H.
      • Meng Y.
      • Thomas S.
      • et al.
      Systematic review of the efficacy of cilostazol, naftidrofuryl oxalate and pentoxifylline for the treatment of intermittent claudication.
      of 26 trials in patients with IC
      Compared with placebo, maximal walking distance for cilostazol and pentoxifylline increased by 25% (11 to 40 m) and 11% (–1 to 24 m), respectively. Pain-free walking distance increased by 13% and 9%, respectivelyA for cilostazol and B for pentoxifylline (imprecision)
      ABI, Ankle-brachial index; CI, confidence interval; OR, odds ratio; PAD, peripheral arterial disease; RCT, randomized controlled trial; RR, risk ratio.
      The effect of ramipril on walking performance in patients with IC was originally included but has subsequently been deleted (see Supplementary Material on page 41S.e1, online only).

      4C Exercise therapy for claudication

      Exercise therapy has been a cornerstone in the management of IC for >40 years and has been the subject of case series, randomized trials, and meta-analyses (Table II). Exercise programs for patients with IC have been found to increase the distance to onset of claudication and increase the distance to maximum claudication pain. A meta-analysis of 1200 patients determined exercise therapy, compared with placebo or usual care, provides an overall improvement in walking ability of 50% to 200%, with improvements maintained for up to 2 years.
      • Watson L.
      • Ellis B.
      • Leng G.C.
      Exercise for intermittent claudication.
      The American Heart Association for many years has considered the quality of the evidence supporting exercise therapy in the treatment of IC to be sufficiently robust to merit a Level I recommendation.
      • Hirsch A.T.
      • Haskal Z.J.
      • Hertzer N.R.
      • Bakal C.W.
      • Creager M.A.
      • Halperin J.L.
      • 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.

       Mechanism of benefit of exercise therapy

      Exercise therapy is in essence athletic training, albeit on a much more limited scale than that generally associated with competitive athletes. Exercise therapy alone has been associated with improvement in walking biomechanics but not an improvement in resting ABI.
      • Gardner A.W.
      • Forrester L.
      • Smith G.V.
      Altered gait profile in subjects with peripheral arterial disease.
      An underlying biochemical mechanism of benefit is therefore highly likely, but the precise mechanisms are unknown. Among the potential biomechanical or biochemical mechanisms of benefit of exercise therapy include are enlargement of existing collateral vessels, exercise induced angiogenesis, enhanced nitric oxide (NO) endothelium-dependent vasodilatation of the microcirculation, improved bioenergetics of skeletal muscle, and improved hemorrheology.

       Requirements for exercise therapy

      Participation in an exercise program for IC first requires an objective diagnosis, with vascular laboratory testing confirming the presence of PAD. Such testing may include measurement of the ABI, exercise treadmill testing or peripheral arterial duplex scanning, or both. Initiation of risk factor modification for atherosclerotic risk factors is a component of any exercise program. At a minimum, therapy with aspirin and statin medications should also be considered as pharmacologic adjuncts to any exercise program for IC (see above). Patients must be screened for sufficient cardiopulmonary reserve to tolerate an exercise program.
      American College of Sports Medicine Position Stand and American Heart Association
      Recommendations for cardiovascular screening, staffing, and emergency policies at health/fitness facilities.

       Barriers to exercise therapy

      There are both patient-specific and system-specific barriers to participation in exercise programs for IC. The exact magnitude of effect of these barriers is unknown, but in patients screened for participation in exercise research studies, far less than one-half are ever enrolled in the study. Perhaps the most important patient-specific limitations are compliance with an exercise program and that many patients with IC have medical comorbidities (angina, congestive heart failure, chronic obstructive pulmonary disease, or arthritis) that may preclude them from participating. Patients should therefore be evaluated to ensure their medical comorbidities are sufficiently well controlled to allow safe participation in such a program. Many of the same factors that may render a patient a poor candidate for exercise therapy should be considered as relative contraindications to invasive treatments for IC because they negatively affect the risk-to-benefit analysis. Thus, an initial attempt at exercise therapy is an appropriate consideration for most patients with IC before revascularization. Although patients with severe hemodynamic compromise may improve with an exercise program, there are clearly patients with such advanced disease and disability that meaningful participation in an exercise program is not realistic. In addition, although supervised exercise programs are the most effective and well-studied form of exercise therapy, many U.S. insurance carriers do not currently provide benefits for participation in such programs. At present, this represents a major obstacle to the use of exercise therapy for IC in clinical practice.

       Components of an exercise program for IC

      Exercise programs for IC potentially consist of various forms of lower extremity exercise alone or in combination (walking, running, cycling, etc) or upper extremity exercise, or both, and vary with respect to intervals of training, duration of training, intensity of training, and claudication end points. Programs may be self-directed, supervised, of varying intensity, institution based or home based, and may be combined with medical or interventional therapies, or both. A classic meta-analysis of the potential components of an exercise program for IC determined the greatest effects were achieved with a >6 month walking program that had at least three sessions per week of durations >30 minutes per session that used nearly maximal claudication pain as the claudication pain end point. Claudication pain end point, mode of exercise (walking), and duration of the exercise program were all independent predictors of increased walking distance with an exercise program.
      • Gardner A.W.
      • Poehlman E.T.
      Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis.

       Type, duration, and intensity of exercise

      The superiority of walking over other forms of lower extremity exercise, including cycling, stair climbing, tiptoe raises, dancing, and static and dynamic leg exercises, has been demonstrated.
      • Carter S.A.
      • Hamel E.R.
      • Paterson J.M.
      • Snow C.J.
      • Mymin D.
      Walking ability and ankle systolic pressures: observations in patients with intermittent claudication in a short-term walking exercise program.
      Moreover, neither lower extremity strength training nor upper extremity aerobic exercise appear to augment responses to a walking exercise program.
      • Hiatt W.R.
      • Wolfel E.E.
      • Meier R.H.
      • Regensteiner J.G.
      Superiority of treadmill walking exercise versus strength training for patients with peripheral arterial disease. Implications for the mechanism of the training response.
      Low-intensity exercise appears as equally effective as high-intensity exercise in improving claudication parameters, provided the duration of exercise is extended in the low-intensity group to achieve similar levels of exercise exposure.
      • Gardner A.W.
      • Montgomery P.S.
      • Flinn W.R.
      • Katzel L.I.
      The effect of exercise intensity on the response to exercise rehabilitation in patients with intermittent claudication.
      However, use claudication end points of nearly maximal pain vs onset of pain does appear to produce greater changes in distance to onset and maximal pain.
      • Gardner A.W.
      • Poehlman E.T.
      Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis.
      Data supporting nearly maximal pain during exercise are derived from time to maximal claudication pain achieved with treadmill testing and may actually underestimate benefits under the submaximal conditions more characteristic of everyday community walking.
      • Carter S.A.
      • Hamel E.R.
      • Paterson J.M.
      • Snow C.J.
      • Mymin D.
      Walking ability and ankle systolic pressures: observations in patients with intermittent claudication in a short-term walking exercise program.
      The time length of exercise training sessions as well as its frequency and duration are important in achieving maximal benefit with training sessions: >30 minutes per session provides greater benefit than sessions for <30 minutes, scheduling more than three sessions per week is more effective than <3 sessions per week, and program lengths of >26 weeks are more effective than programs <26 weeks.
      • Gardner A.W.
      • Poehlman E.T.
      Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis.
      Exercise programs can vary from completely unstructured programs based on patient instruction done on their own accord to programs that are supervised and institutionally based. All exercise programs depend on patient compliance, so it is not surprising that structured, supervised exercise programs demonstrate superior outcomes to unsupervised programs (home exercise programs) and are therefore the preferred strategy for exercise therapy when possible.
      As previously stated, reimbursement for structured exercise programs in the United States is currently lacking, making self-directed home programs an important alternative for many patients. Home exercise programs may be able to be modified or supplemented to improve their effectiveness. Patterson et al
      • Patterson R.B.
      • Pinto B.
      • Marcus B.
      • Colucci A.
      • Braun T.
      • Roberts M.
      Value of a supervised exercise program for the therapy of arterial claudication.
      determined a 12-week home-based exercise program supplemented with a lecture program and weekly exercise instruction resulted in improvement at 6 months in initial claudication time and in maximal walking time. The improvements were statistically significant compared with baseline values, although not as great as those achieved with supervised exercise. Mouser et al
      • Mouser M.J.
      • Zlabek J.A.
      • Ford C.L.
      • Mathiason M.A.
      Community trial of home-based exercise therapy for intermittent claudication.
      found that patients completing a home-based exercise program demonstrated improvement in the initial claudication distance and absolute claudication distances, although less than what would be expected in a supervised program. Unfortunately, 47% of those not completing the program dropped out by not returning for their follow-up appointment.
      Providing patients with regular feedback on their progress and results may improve compliance with home-based programs. In one study, providing patients engaged in a home-based 12-week exercise program of intermittent walking to nearly maximal claudication pain with a step monitor to quantify their progress and results achieved the same level of patient adherence and increased claudication time and peak walking time to a similar degree as a supervised exercise program.
      • Gardner A.W.
      • Parker D.E.
      • Montgomery P.S.
      • Scott K.J.
      • Blevins S.M.
      Efficacy of quantified home-based exercise and supervised exercise in patients with intermittent claudication: a randomized controlled trial.

       Supplements to an exercise program

      All exercise programs for treatment of IC, as noted above, should include atherosclerotic risk factor modification and best medical management. Interventional therapies, percutaneous or open, can also be viewed as a supplement to an exercise program. Conversely, exercise therapy can be used as a supplement to interventional procedures.
      Angioplasty and stenting has been studied as an alternative to exercise therapy for IC and as a supplement to exercise therapy for IC. A systematic review examined the efficacy of catheter-based techniques as an alternative or as an adjunct to exercise therapy for treatment of IC.
      • Ahimastos A.A.
      • Pappas E.P.
      • Buttner P.G.
      • Walker P.J.
      • Kingwell B.A.
      • Golledge J.
      A meta-analysis of the outcome of endovascular and noninvasive therapies in the treatment of intermittent claudication.
      The end points evaluated in the trials reviewed were mostly walking distances and QoL parameters. The authors concluded that the effectiveness of percutaneous transluminal angioplasty (PTA) and supervised exercise training were generally equivalent; however, despite similar end points in the trials, pooling of data was impossible due to marked heterogeneity of the data and only one of the nine randomized trials was of high quality.
      The 6-month results of the CLEVER trial were reported in 2012.
      • Murphy T.P.
      • Cutlip D.E.
      • Regensteiner J.G.
      • Mohler E.R.
      • Cohen D.J.
      • Reynolds M.R.
      • et al.
      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.
      The CLEVER trial randomized 111 patients with IC due to aortoiliac occlusive disease (AIOD) to one of three treatments: optimal medical care, optimal medical care plus supervised exercise, or optimal medical care plus stent revascularization. The primary end point was peak walking time on a graded treadmill test at 6 months. Secondary end points included assessment of QoL and free-living step activity.
      At 6 months, changes in peak walking time were greatest with supervised exercise therapy combined with optimal medical care compared with both optimal medical care alone and stenting therapy combined with optimal medical care. Stenting provided greater improvement in peak walking time than optimal medical care alone. Measures of improvement in QoL were both greater for supervised exercise and stenting therapy compared with optimal medical care alone, but improvement in QoL parameters was greater for stent revascularization than supervised exercise. A conceptually similar trial, Supervised Exercise Therapy or Immediate PTA for Intermittent Claudication in patients with an Iliac Artery Obstruction (SUPER Study), is planned for 15 Dutch centers with enrollment of 400 patients (ClinicalTrials.gov NCT01385774). Primary end points at 1 year are maximal walking distance and measures of health-related QoL.
      • Frans F.A.
      • Bipat S.
      • Reekers J.A.
      • Legemate D.A.
      • Koelemay M.J.
      SUPERvised exercise therapy or immediate PTA for intermittent claudication in patients with an iliac artery obstruction—a multicentre randomised controlled trial; SUPER study design and rationale.
      The costs of interventional treatment appear to be higher than those for supervised exercise therapy.
      • Spronk S.
      • Bosch J.L.
      • den Hoed P.T.
      • Veen H.F.
      • Pattynama P.M.
      • Hunink M.G.
      Intermittent claudication: clinical effectiveness of endovascular revascularization versus supervised hospital-based exercise training—randomized controlled trial.
      Overall, at this point, there are no compelling data to favor endovascular interventions over supervised exercise for treatment of IC in patients who are candidates for both forms of therapy.
      Given its efficacy as primary therapy, it is not surprising that a number of small trials have suggested the benefit of exercise as an adjunct to percutaneous or open interventions performed for treatment of IC. A randomized trial of 70 patients treated with a percutaneous intervention primarily but not exclusively for AIOD demonstrated the addition of supervised exercise therapy to a percutaneous intervention improved absolute claudication distance at 6 months compared with percutaneous intervention alone.
      • Kruidenier L.M.
      • Nicolai S.P.
      • Rouwet E.V.
      • Peters R.J.
      • Prins M.H.
      • Teijink J.A.
      Additional supervised exercise therapy after a percutaneous vascular intervention for peripheral arterial disease: a randomized clinical trial.
      Exercise therapy may also be beneficial after bypass surgery. In a small randomized study of 14 patients with IC comparing infrainguinal lower extremity bypass alone vs bypass with the addition of supervised exercise, the investigators found a significant increase in maximal walking distance with the addition of exercise to bypass.
      • Badger S.A.
      • Soong C.V.
      • O'Donnell M.E.
      • Boreham C.A.
      • McGuigan K.E.
      Benefits of a supervised exercise program after lower limb bypass surgery.
      In an older study, 75 patients with IC were randomly allocated treatment to surgical reconstruction alone, surgical reconstruction with the addition of supervised training, and supervised exercise alone. The surgical reconstructions were relatively evenly split between aortoiliac reconstructions and infrainguinal reconstructions, with three multilevel reconstructions and 23 bilateral reconstructions. Symptom-free and maximal walking distance were improved in all three groups, with the greatest improvement in the patients treated with the combination of open surgical reconstruction and supervised exercise therapy.
      • Lundgren F.
      • Dahllof A.G.
      • Lundholm K.
      • Schersten T.
      • Volkmann R.
      Intermittent claudication—surgical reconstruction or physical training? A prospective randomized trial of treatment efficiency.

       Recommendations: Exercise therapy

      Tabled 1
      GradeLevel of evidence
      4.12.We recommend as first-line therapy a supervised exercise program consisting of walking a minimum of three times per week (30-60 min/session) for at least 12 weeks to all suitable patients with IC.1A
      4.13.We recommend home-based exercise, with a goal of at least 30 minutes of walking three to five times per week when a supervised exercise program is unavailable or for long-term benefit after a supervised exercise program is completed.1B
      4.14.In patients who have undergone revascularization therapy for IC, we recommend exercise (either supervised or home based) for adjunctive functional benefits.1B
      4.15.We recommend that patients with IC be followed up annually to assess compliance with lifestyle measures (smoking cessation, exercise) and medical therapies as well as to determine if there is evidence of progression in symptoms or signs of PAD. Yearly ABI testing may be of value to provide objective evidence of disease progression.1C
      ABI, Ankle-brachial index; IC, intermittent claudication; PAD, peripheral arterial disease.

       Summary of evidence: Exercise therapy

      Tabled 1
      Clinical questionData sourceFindingQuality of evidence
      The effect of exercise on walking performance and morbidity in patients with ICMeta-analysis of 22 RCTs at low risk of bias
      • Watson L.
      • Ellis B.
      • Leng G.C.
      Exercise for intermittent claudication.
      Compared with usual care or placebo, exercise significantly improved maximal walking time: 5.12 minutes (95% CI, 4.51-5.72 minutes), walking ability (50% to 200%), pain-free walking distance and maximal walking distance, but not the ABI, mortality, or amputationA
      The effect of supervised vs nonsupervised exercise on walking performance and morbidity in patients with ICMeta-analysis of 14 RCTs
      • Fokkenrood H.J.
      • Bendermacher B.L.
      • Lauret G.J.
      • Willigendael E.M.
      • Prins M.H.
      • Teijink J.A.
      Supervised exercise therapy versus non-supervised exercise therapy for intermittent claudication.
      Supervised exercise therapy showed statistically significant improvement in maximal treadmill walking distance compared with nonsupervised exercise therapy regimens (an increase in walking distance of ∼180 m)A
      ABI, Ankle-brachial index; CI, confidence interval; IC, intermittent claudication; RCT, randomized controlled trial.

      5. The role of revascularization for IC

       Patient selection for intervention

      The natural history of IC is usually one of a slowly progressive decline in the ability to walk a distance before the onset of pain. With intensive medical management, <5% of patients will develop symptoms of advanced ischemia, such as ischemic rest pain and tissue loss, or will ultimately require amputation.
      • Norgren L.
      • Hiatt W.R.
      • Dormandy J.A.
      • Nehler M.R.
      • Harris K.A.
      • Fowkes F.G.
      Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).
      • Kannel W.B.
      • Skinner Jr., J.J.
      • Schwartz M.J.
      • Shurtleff D.
      Intermittent claudication. Incidence in the Framingham Study.
      The relatively benign natural history of claudication must be weighed against the effect of the loss of ambulatory function on activities of daily living, occupation, and QoL. Consequently, the decision to intervene should be individualized, taking into consideration these factors as well as the clinical response to noninterventional therapies, and weighing the potential risks against the expected functional benefits for the patient. This initial consideration of candidacy is largely independent of technical factors, such as the anatomy of the occlusive lesions or the type of procedure, either endovascular or surgical, that would be required. Although most patients with IC who adhere to risk factor modification and conservative management decline slowly or generally maintain their current level of function, a significant minority (20%-30%) will develop increased disability over time that warrants intervention. Interventions for claudication are done to improve function in the setting of significant ongoing disability in an active person. In this context, it is important to recognize that some patients seek treatment based solely on the fear that IC will inexorably lead to amputation. Reassurance about the expected natural history of claudication to alleviate their anxiety may be all that is required in such patients and should always predate a discussion of invasive treatment. Performing prophylactic interventions in patients with IC that is minimally symptomatic or well tolerated has no benefit, may cause harm, and is never indicated.
      It is also important to recognize that the degree of disability in claudication correlates relatively poorly with both physiologic testing and anatomic findings. It has been well established that the resting ABI, for example, is a modest predictor of the degree of walking impairment by self-reported symptoms or objective testing.
      • Feinglass J.
      • McCarthy W.J.
      • Slavensky R.
      • Manheim L.M.
      • Martin G.J.
      Effect of lower extremity blood pressure on physical functioning in patients who have intermittent claudication. The Chicago Claudication Outcomes Research Group.
      • Myers S.A.
      • Johanning J.M.
      • Stergiou N.
      • Lynch T.G.
      • Longo G.M.
      • Pipinos II,
      Claudication distances and the Walking Impairment Questionnaire best describe the ambulatory limitations in patients with symptomatic peripheral arterial disease.
      Similarly the burden of disease by anatomic imaging correlates poorly with function in everyday life. This may relate to nonvascular causes of walking impairment, the adaptation of each individual to the disability, and the variable contributions of collaterals. Justification for interventions for IC is not based primarily on physiologic (eg, ABI) measures or on anatomic findings but rather on the severity of functional impairment specific to arterial insufficiency and its perceived effect on QoL, supported by objective evidence of significant disease. Promoting intervention in an individual with mild disability based on physiologic or imaging studies is strongly discouraged.
      Determining the degree of functional impairment from IC is not straightforward and varies from patient to patient.
      • Mays R.J.
      • Casserly I.P.
      • Kohrt W.M.
      • Ho P.M.
      • Hiatt W.R.
      • Nehler M.R.
      • et al.
      Assessment of functional status and quality of life in claudication.
      This should be assessed from the patient's perspective and not based on the biases or value judgments of the physician. A patient's perception of the degree of impairment may vary according to his or her baseline level of physical activity; that is, moderate claudication may be perceived as severely disabling in a very active patient, whereas more severe claudication may be well tolerated in a more sedentary individual. IC causing loss of the ability to perform an occupation or that impairs basic activities of daily living and/or mobility often justifies invasive treatment. Equally important are QoL issues such as the need to provide care to a spouse or family member or loss of the ability to engage in recreational or social activities.
      On the other hand, loss of ambulatory function may be multifactorial when arthritis of weight-bearing joints or the lumbar spine is also present. Treatment of PAD alone may not result in improved ambulatory function in patients so afflicted. Similarly, the treatment of IC may provide no benefit to patients with significant ischemic or structural heart disease, chronic obstructive pulmonary disease, morbid obesity, stroke, etc. In addition, such patients present a greater risk of complications or death, potentially outweighing the benefit of treatment, especially when surgery is required.
      Numerous studies have demonstrated the efficacy of both endovascular and surgical therapy for the relief of symptoms of claudication by reducing pain and improving walking distance as well as gains in QoL and ambulatory function. Both forms of revascularization appear superior to medical therapy for limb-related outcomes, although not necessarily to supervised exercise training.
      • Murphy T.P.
      • Cutlip D.E.
      • Regensteiner J.G.
      • Mohler E.R.
      • Cohen D.J.
      • Reynolds M.R.
      • et al.
      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.
      • Gardner A.W.
      • Poehlman E.T.
      Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis.
      • Leng G.C.
      • Fowler B.
      • Ernst E.
      Exercise for intermittent claudication.
      Pharmacologic treatment with cilostazol is a modestly effective and less expensive alternative to invasive treatment
      • Regensteiner J.G.
      • Ware Jr., J.E.
      • McCarthy W.J.
      • Zhang P.
      • Forbes W.P.
      • Heckman J.
      • et al.
      Effect of cilostazol on treadmill walking, community-based walking ability, and health-related quality of life in patients with intermittent claudication due to peripheral arterial disease: meta-analysis of six randomized controlled trials.
      and may be appropriate in some patients. In most claudicant patients being evaluated initially, a 6-month trial of smoking cessation, risk factor modification, exercise, or cilostazol, or a combination, should be initiated before any invasive therapy.
      Surgical and endovascular therapy (EVT) are likely to be similar in efficacy overall, although the quality of supporting evidence comparing the two is poor and the likelihood of durable clinical success different, especially for extensive disease, more distal disease, and disease involving the common or deep femoral arteries where surgery is usually preferred. Specific factors predicting treatment success should be carefully considered in each individual before determining the optimal strategy.
      Anatomic patency and hemodynamic improvement are considered necessary (although not sufficient) for clinical success of revascularization in IC. In the setting of IC, where the limb is not threatened and the natural history is generally benign, durable benefit at low risk is required to justify invasive vascular treatment. The anatomic spectrum of disease in IC is broad, and has a major impact on both technical success and durability of vascular interventions. In selecting a revascularization strategy for patients with IC, the expected durability in the circumstance at hand should be carefully considered. We suggest that a minimal effectiveness threshold for invasive therapy in IC be a >50% likelihood of sustained clinical improvement for at least 2 years. Freedom from hemodynamically significant restenosis in the treated limb is considered a prerequisite for this goal.
      Because anatomic durability is generally inferior for infrainguinal vs aortoiliac procedures and for bilateral vs unilateral infrainguinal interventions, most experienced clinicians have a higher treatment threshold for IC in these settings. In bilateral disease, treating physicians should consider the probability of overall efficacy as the product of expected outcomes in each limb, because functional gains are unlikely if success is achieved and maintained in one limb only. Similarly, as new data are published demonstrating the expected patency outcomes of evolving technologies in various anatomic and clinical settings, this suggested benchmark should be carefully considered before applying such strategies to everyday practice in claudicant patients. Patient-centered outcomes data are sorely needed to better define functional gains, symptom relief, and patient perceptions on the relative trade-offs (eg, durability of improvement vs need for repeat interventions) to better enable shared decision making in the invasive treatment of IC. The concept of a minimal clinically important difference has been developed for other chronic diseases to increase the relevance of study end points to patients and is needed in this field.
      • McGlothlin A.E.
      • Lewis R.J.
      Minimal clinically important difference: defining what really matters to patients.

       Anatomic selection factors: Imaging

      Once the decision has been made to consider invasive treatment, patients should undergo imaging studies to determine the arterial anatomy, the extent of disease, and whether they are best treated with EVT or open surgical therapy. This enables a more comprehensive discussion about risks, benefits, and durability trade-offs for various treatment options. Currently used imaging modalities include CTA,
      • Adriaensen M.E.
      • Kock M.C.
      • Stijnen T.
      • van Sambeek M.R.
      • van Urk H.
      • Pattynama P.M.
      • et al.
      Peripheral arterial disease: therapeutic confidence of CT versus digital subtraction angiography and effects on additional imaging recommendations.
      • Catalano C.
      • Fraioli F.
      • Laghi A.
      • Napoli A.
      • Bezzi M.
      • Pediconi F.
      • et al.
      Infrarenal aortic and lower-extremity arterial disease: diagnostic performance of multi-detector row CT angiography.
      MRA,
      • Holland G.A.
      • Dougherty L.
      • Carpenter J.P.
      • Golden M.A.
      • Gilfeather M.
      • Slossman F.
      • et al.
      Breath-hold ultrafast three-dimensional gadolinium-enhanced MR angiography of the aorta and the renal and other visceral abdominal arteries.
      duplex ultrasound imaging,
      • Rosfors S.
      • Eriksson M.
      • Hoglund N.
      • Johansson G.
      Duplex ultrasound in patients with suspected aorto-iliac occlusive disease.
      and catheter angiography. Although all modalities may provide excellent imaging of the arterial circulation, each has its own unique set of advantages and disadvantages and may vary in quality and availability from institution to institution. Consequently, the modality of choice varies widely depending on clinical practice. There is insufficient evidence at present to define the most efficient, cost-effective strategy for arterial imaging in this population.
      Catheter arteriography represents the gold standard due to superior image resolution and the unique ability of being able to perform a diagnostic study and EVT at the same time. However, catheter arteriography is invasive and may be complicated by contrast nephropathy, allergic reactions, and access-site events.
      Modern, multislice spiral CT scans are noninvasive and provide image resolution of nearly the same quality as conventional arteriography. Moreover, the imaging data set can be reconfigured into different formats, including axial, coronal, sagittal, and three-dimensional images. However, CTA requires a large dose of intravenous contrast and is subject to artifact degradation due to calcification.
      MRA has poorer resolution than angiography or CTA, but its images are not degraded by calcium, and like CTA, is noninvasive. Image quality is enhanced by the use of gadolinium; however, its use is contraindicated in patients with significant renal impairment due to the potential risk of causing nephrogenic systemic fibrosis. In addition, MRA cannot be used in patients with pacemakers and a variety of other implanted medical devices.
      Duplex ultrasound arterial examination is most commonly used as a screening modality to confirm the diagnosis and to determine the severity of disease both before and after treatment. It is occasionally used as a primary imaging modality during EVT, principally in the setting of isolated focal disease in the superficial femoral artery (SFA).
      • Ascher E.
      • Marks N.A.
      • Hingorani A.P.
      • Schutzer R.W.
      • Mutyala M.
      Duplex-guided endovascular treatment for occlusive and stenotic lesions of the femoral-popliteal arterial segment: a comparative study in the first 253 cases.
      For patients with severe infrainguinal disease, assessment of available vein conduit is another important element in the decision process, given the superiority of good-quality saphenous vein for femoropopliteal (FP) bypass. Ultrasound vein mapping is therefore recommended as part of the preoperative evaluation of patients who are being considered as potential open bypass candidates (see below).

       Recommendations: General considerations on invasive treatment for intermittent claudication (IC)

      Tabled 1
      GradeLevel of evidence
      5.1.We recommend EVT or surgical treatment of IC for patients with significant functional or lifestyle-limiting disability when there is a reasonable likelihood of symptomatic improvement with treatment, when pharmacologic or exercise therapy, or both, have failed, and when the benefits of treatment outweigh the potential risks.1B
      5.2.We recommend an individualized approach to select an invasive treatment for IC. The modality offered should provide a reasonable likelihood of sustained benefit to the patient (>50% likelihood of clinical efficacy for at least 2 years). For revascularization, anatomic patency (freedom from hemodynamically significant restenosis) is considered a prerequisite for sustained efficacy.1C
      EVT, Endovascular therapy.

       Aortoiliac occlusive disease

      AIOD, or inflow disease, most commonly leads to buttock and thigh claudication. In men, bilateral iliac artery involvement or occlusion of the internal iliac arteries may be a cause of vasculogenic erectile dysfunction. With continued walking, it is not uncommon for patients with AIOD to also develop claudication in the calf muscles. With bilateral disease, symptoms can be quite severe and disabling due to the large number of muscle groups being affected.
      Invasive treatments for AIOD are performed to provide symptom relief and functional improvements. The one scenario where treatment of asymptomatic AIOD may be justified is to provide vascular access for another indicated cardiovascular implant (eg, thoracic endovascular aortic repair, endovascular aneurysm repair, transcatheter aortic valve replacement, mechanical circulatory support).
      Surgical options for AIOD include direct aortic reconstructions (aortofemoral bypass [AFB], aortoiliac bypass, aortoiliac endarterectomy), which have proven to be most durable but also have significant morbidity and mortality. In patients with suitable anatomy or those deemed to be at high risk for aortic surgery, or both, extra-anatomic bypasses (axillary-femoral [AxFB], iliac-femoral [IFB], femoral-femoral bypass [FFB]) are less morbid alternatives but are also less durable.
      A tremendous paradigm shift has occurred in the last two decades in the treatment of AIOD.
      • Upchurch G.R.
      • Dimick J.B.
      • Wainess R.M.
      • Eliason J.L.
      • Henke P.K.
      • Cowan J.A.
      • et al.
      Diffusion of new technology in health care: the case of aorto-iliac occlusive disease.
      Although intersocietal guidelines previously recommended endovascular procedures as primary treatment for more focal disease and traditional surgery for more diffuse disease,
      • Norgren L.
      • Hiatt W.R.
      • Dormandy J.A.
      • Nehler M.R.
      • Harris K.A.
      • Fowkes F.G.
      Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).
      • Galaria II,
      • Davies M.G.
      Percutaneous transluminal revascularization for iliac occlusive disease: long-term outcomes in TransAtlantic Inter-Society Consensus A and B lesions.
      improvements in technology and endovascular techniques have resulted in EVT replacing open surgical bypass as a primary treatment for both focal and advanced AIOD in many cases. For iliac angioplasty using stents, long-term results compare favorably with open surgery.
      • Galaria II,
      • Davies M.G.
      Percutaneous transluminal revascularization for iliac occlusive disease: long-term outcomes in TransAtlantic Inter-Society Consensus A and B lesions.
      • Schurmann K.
      • Mahnken A.
      • Meyer J.
      • Haage P.
      • Chalabi K.
      • Peters I.
      • et al.
      Long-term results 10 years after iliac arterial stent placement.
      • Bosch J.L.
      • Hunink M.G.
      Meta-analysis of the results of percutaneous transluminal angioplasty and stent placement for aortoiliac occlusive disease.
      • Ye W.
      • Liu C.W.
      • Ricco J.B.
      • Mani K.
      • Zeng R.
      • Jiang J.
      Early and late outcomes of percutaneous treatment of TransAtlantic Inter-Society Consensus class C and D aorto-iliac lesions.
      • Indes J.E.
      • Pfaff M.J.
      • Farrokhyar F.
      • Brown H.
      • Hashim P.
      • Cheung K.
      • et al.
      Clinical outcomes of 5358 patients undergoing direct open bypass or endovascular treatment for aortoiliac occlusive disease: a systematic review and meta-analysis.
      Other techniques, including devices for crossing long-segment total occlusions,
      • Carnevale F.C.
      • De Blas M.
      • Merino S.
      • Egana J.M.
      • Caldas J.G.
      Percutaneous endovascular treatment of chronic iliac artery occlusion.
      stent grafts,
      • Mwipatayi B.P.
      • Thomas S.
      • Wong J.
      • Temple S.E.
      • Vijayan V.
      • Jackson M.
      • et al.
      A comparison of covered vs bare expandable stents for the treatment of aortoiliac occlusive disease.
      • Rzucidlo E.M.
      • Powell R.J.
      • Zwolak R.M.
      • Fillinger M.F.
      • Walsh D.B.
      • Schermerhorn M.L.
      • et al.
      Early results of stent-grafting to treat diffuse aortoiliac occlusive disease.
      and hybrid procedures
      • Huded C.P.
      • Goodney P.P.
      • Powell R.J.
      • Nolan B.W.
      • Rzucidlo E.M.
      • Simone S.T.
      • et al.
      The impact of adjunctive iliac stenting on femoral-femoral bypass in contemporary practice.
      • Chang R.W.
      • Goodney P.P.
      • Baek J.H.
      • Nolan B.W.
      • Rzucidlo E.M.
      • et al.
      Long-term results of combined common femoral endarterectomy and iliac stenting/stent grafting for occlusive disease.
      combining iliac stenting with femoral endarterectomy or with FFB are alternatives to aortofemoral surgical reconstructions in appropriate patients with suitable anatomy. Open surgery is generally now reserved for patients with such extensive disease that EVT is impossible or ill advised, in patients with severe disease and associated aortic aneurysms, and in those with failed endovascular interventions (Table III).
      Table IIIOutcomes of revascularization for aortoiliac occlusive disease (AIOD) in patients with intermittent claudication (IC)
      References (first author)ModalityFU duration, yearsPatency (PAP), %
      Yilmaz,
      • Yilmaz S.
      • Sindel T.
      • Golbasi I.
      • Turkay C.
      • Mete A.
      • Luleci E.
      Aortoiliac kissing stents: long-term results and analysis of risk factors affecting patency.
      Soga,
      • Soga Y.
      • Iida O.
      • Kawasaki D.
      • Yamauchi Y.
      • Suzuki K.
      • Hirano K.
      • et al.
      Contemporary outcomes after endovascular treatment for aorto-iliac artery disease.
      Ichihashi,
      • Ichihashi S.
      • Higashiura W.
      • Itoh H.
      • Sakaguchi S.
      • Kichikawa K.
      Iliac artery stent placement relieves claudication in patients with iliac and superficial femoral artery lesions.
      Indes
      • Indes J.E.
      • Pfaff M.J.
      • Farrokhyar F.
      • Brown H.
      • Hashim P.
      • Cheung K.
      • et al.
      Clinical outcomes of 5358 patients undergoing direct open bypass or endovascular treatment for aortoiliac occlusive disease: a systematic review and meta-analysis.
      PTA + stent563-79
      deVries,
      • de Vries S.O.
      • Hunink M.G.
      Results of aortic bifurcation grafts for aortoiliac occlusive disease: a meta-analysis.
      Rutherford,
      • Rutherford R.B.
      Aortobifemoral bypass, the gold standard: technical considerations.
      Reed,
      • Reed A.B.
      • Conte M.S.
      • Donaldson M.C.
      • Mannick J.A.
      • Whittemore A.D.
      • Belkin M.
      The impact of patient age and aortic size on the results of aortobifemoral bypass grafting.
      Brewster,
      • Brewster D.C.
      • Darling R.C.
      Optimal methods of aortoiliac reconstruction.
      Chiu
      • Chiu K.W.
      • Davies R.S.
      • Nightingale P.G.
      • Bradbury A.W.
      • Adam D.J.
      Review of direct anatomical open surgical management of atherosclerotic aorto-iliac occlusive disease.
      AFB581-93
      Cham,
      • Cham C.
      • Myers K.A.
      • Scott D.F.
      • Devine T.J.
      • Denton M.J.
      Extraperitoneal unilateral iliac artery bypass for chronic lower limb ischaemia.
      Melliere,
      • Melliere D.
      • Desgranges P.
      • de Wailly G.W.
      • Roudot-Thoraval F.
      • Allaire E.
      • Becquemin J.P.
      Extensive unilateral iliofemoral occlusions: durability of four techniques of arterial reconstructions.
      Van der Vliet,
      • van der Vliet J.A.
      • Scharn D.M.
      • de Waard J.W.
      • Roumen R.M.
      • van Roye S.F.
      • Buskens F.G.
      Unilateral vascular reconstruction for iliac obstructive disease.
      Chiu,
      • Chiu K.W.
      • Davies R.S.
      • Nightingale P.G.
      • Bradbury A.W.
      • Adam D.J.
      Review of direct anatomical open surgical management of atherosclerotic aorto-iliac occlusive disease.
      Ricco
      • Ricco J.B.
      • Probst H.
      French University Surgeons Association
      Long-term results of a multicenter randomized study on direct versus crossover bypass for unilateral iliac artery occlusive disease.
      IFB573-88
      Criado,
      • Criado E.
      • Burnham S.J.
      • Tinsley Jr., E.A.
      • Johnson Jr., G.
      • Keagy B.A.
      Femorofemoral bypass graft: analysis of patency and factors influencing long-term outcome.
      Ricco,
      • Ricco J.B.
      • Probst H.
      French University Surgeons Association
      Long-term results of a multicenter randomized study on direct versus crossover bypass for unilateral iliac artery occlusive disease.
      Mii
      • Mii S.
      • Eguchi D.
      • Takenaka T.
      • Maehara S.
      • Tomisaki S.
      • Sakata H.
      Role of femorofemoral crossover bypass grafting for unilateral iliac atherosclerotic disease: a comparative evaluation with anatomic bypass.
      FFB560-83
      AFB, Aortofemoral bypass; FFB, femorofemoral bypass; FU, follow-up; IFB, iliofemoral bypass; PAP, primary assistant patency; PTA, percutaneous transluminal angioplasty.

      5A Aortoiliac revascularization: Catheter-based interventions

       Aortic disease

      Although open surgical reconstruction for aortic occlusive disease is considered the gold standard,
      • Brewster D.C.
      Clinical and anatomical considerations for surgery in aortoiliac disease and results of surgical treatment.
      • Rutherford R.B.
      Aortobifemoral bypass, the gold standard: technical considerations.
      there is no question the incidence of aortic and iliac interventions is increasing, and interventional therapies have become more commonly used in treating this condition.
      • Upchurch G.R.
      • Dimick J.B.
      • Wainess R.M.
      • Eliason J.L.
      • Henke P.K.
      • Cowan J.A.
      • et al.
      Diffusion of new technology in health care: the case of aorto-iliac occlusive disease.
      There are limited data providing information regarding the use of interventional therapy for treatment of aortic occlusive disease. Although initial information reported the use of angioplasty as a method of dealing with aortic occlusive disease,
      • Hallisey M.J.
      • Meranze S.G.
      • Parker B.C.
      • Rholl K.S.
      • Miller W.J.
      • Katzen B.T.
      • et al.
      Percutaneous transluminal angioplasty of the abdominal aorta.
      stenting is the most commonly used approach in this vascular bed. Primary technical success rates for intervention vary from 90% to 100%, with 1-year primary patency rates from 75% to 100% and 4-year primary patency rates of 60% to 80%. Secondary patency can usually be maintained with repeat percutaneous interventional therapy, with 1-year and 5-year secondary patency noted to be 90% to 100% and 60% to 100%, respectively.
      • Feugier P.
      • Toursarkissian B.
      • Chevalier J.M.
      • Favre J.P.
      Endovascular treatment of isolated atherosclerotic stenosis of the infrarenal abdominal aorta: long-term outcome.
      • Kim T.H.
      • Ko Y.G.
      • Kim U.
      • Kim J.S.
      • Choi D.
      • Hong M.K.
      • et al.
      Outcomes of endovascular treatment of chronic total occlusion of the infrarenal aorta.
      • Moise M.A.
      • Alvarez-Tostado J.A.
      • Clair D.G.
      • Greenberg R.K.
      • Lyden S.P.
      • Srivastava S.D.
      • et al.
      Endovascular management of chronic infrarenal aortic occlusion.
      Percutaneous approaches can be achieved through a femoral or brachial approach or combinations of the two approaches. Stent types used include balloon-expandable and self-expanding stents,
      • Lastovickova J.
      • Peregrin J.H.
      Primary self-expandable nitinol stent placement in focal lesions of infrarenal abdominal aorta: long term results.
      with or without covering. The choice of stent used relates to the type of disease and size of stent available. More calcific disease will usually require greater resistance to crush, which is achieved with balloon-expandable stents, whereas self-expanding stents are more readily available in slightly larger diameters. Few comparative data are available for assessing outcomes of these varied stent types. Covered stent placement in the aorta has few data on which to base any specific recommendations regarding use.
      • Bruijnen R.C.
      • Grimme F.A.
      • Horsch A.D.
      • Van Oostayen J.A.
      • Zeebregts C.J.
      • Reijnen M.M.
      Primary balloon expandable polytetrafluoroethylene-covered stenting of focal infrarenal aortic occlusive disease.
      Stents should be sized appropriately to the native aorta, with consideration given for the tissue displaced (especially calcific disease). This may necessitate undersizing the stent relative to the diameter of the native normal-caliber aorta to reduce the risk of rupture, which has been reported with this approach.
      In general, care should be taken not to preclude possible AFB grafting in the future in surgical candidates, such as by extending stents into the perirenal aorta. Stents should not be placed across the orifice of the renal arteries, and disease abutting the renal ostia poses increased risk for obstruction or embolization of the renal arteries. The aortic bifurcation is best currently treated with “kissing stents” at the origin of the iliac arteries or with a combination of aortic stent placement down to the bifurcation and then kissing stents placed at the iliac vessel origins.
      • Sharafuddin M.J.
      • Hoballah J.J.
      • Kresowik T.F.
      • Sharp W.J.
      Kissing stent reconstruction of the aortoiliac bifurcation.
      • Yilmaz S.
      • Sindel T.
      • Golbasi I.
      • Turkay C.
      • Mete A.
      • Luleci E.
      Aortoiliac kissing stents: long-term results and analysis of risk factors affecting patency.
      The use of aortic stent grafts for occlusive disease
      • Rzucidlo E.M.
      • Powell R.J.
      • Zwolak R.M.
      • Fillinger M.F.
      • Walsh D.B.
      • Schermerhorn M.L.
      • et al.
      Early results of stent-grafting to treat diffuse aortoiliac occlusive disease.
      has been described in only limited situations, and the routine use of this approach awaits further data acquisition.
      Caution should be exercised in the treatment of AIOD where concomitant aneurysm disease is also present. If an aneurysm is of sufficient size to meet treatment guidelines, therapy should be primarily guided by appropriate aneurysm exclusion with concomitant restoration of unimpeded blood flow to the lower extremities. In the case of small aneurysms, any treatment considered for symptomatic AIOD should achieve simultaneous aneurysm exclusion or not impede any future open or endovascular aneurysm repair options.
      Mortality for endovascular interventions in the aorta can range from 1% to 3%, and morbidity ranges from 5% to 20%, with aortic rupture a possibility.
      • Feugier P.
      • Toursarkissian B.
      • Chevalier J.M.
      • Favre J.P.
      Endovascular treatment of isolated atherosclerotic stenosis of the infrarenal abdominal aorta: long-term outcome.
      • Kim T.H.
      • Ko Y.G.
      • Kim U.
      • Kim J.S.
      • Choi D.
      • Hong M.K.
      • et al.
      Outcomes of endovascular treatment of chronic total occlusion of the infrarenal aorta.
      • Moise M.A.
      • Alvarez-Tostado J.A.
      • Clair D.G.
      • Greenberg R.K.
      • Lyden S.P.
      • Srivastava S.D.
      • et al.
      Endovascular management of chronic infrarenal aortic occlusion.
      Importantly, one should be prepared for potential aortic rupture when embarking on treatment for an aortic lesion with interventional therapy. Renal dysfunction has been reported in 2% to 10% of patients. Intensive care unit stay, blood transfusion requirements, and infection rates are generally lower with EVT than with open aortic reconstructions.
      • Burke C.R.
      • Henke P.K.
      • Hernandez R.
      • Rectenwald J.E.
      • Krishnamurthy V.
      • Englesbe M.J.
      • et al.
      A contemporary comparison of aortofemoral bypass and aortoiliac stenting in the treatment of aortoiliac occlusive disease.
      • Kashyap V.S.
      • Pavkov M.L.
      • Bena J.F.
      • Sarac T.P.
      • O'Hara P.J.
      • Lyden S.P.
      • et al.
      The management of severe aortoiliac occlusive disease: endovascular therapy rivals open reconstruction.
      • de Vries S.O.
      • Hunink M.G.
      Results of aortic bifurcation grafts for aortoiliac occlusive disease: a meta-analysis.

       Iliac interventions

      Angioplasty remains a therapy for treatment of iliac artery disease but has largely been supplanted by a primary stenting approach for this disease. In general, the more extensive and complex the occlusive disease, the more likely a primary stent approach will improve patency. For this reason, except for very focal disease, primary stenting of iliac occlusive disease offers the best approach for long-term patency.
      • Bosch J.L.
      • Hunink M.G.
      Meta-analysis of the results of percutaneous transluminal angioplasty and stent placement for aortoiliac occlusive disease.
      The use of balloon-expandable vs self-expanding stents has been inadequately studied to claim an advantage of one device over another; however, certain characteristics and locations may favor one stent design over another. As in other beds, lesions with more calcium or especially ostial lesions favor the use of balloon-expandable stents, which have greater radial strength and resistance to crush. This allows for improved expansion and retention of vessel diameter after stent placement.
      The percutaneous approach to iliac disease can vary from ipsilateral to contralateral groin to brachial, but one should be certain that devices with an appropriate length are available before initiating a procedure. If there is an expectation of the brachial approach being used, longer delivery systems should be available. When treating from the ipsilateral femoral approach, one should be certain that placement of the most distal stent will not be so close to the sheath access to prohibit accurate delivery. Here a contralateral or brachial approach is favored to allow placement of stents to the end of the diseased segment, which may be to the inguinal ligament.
      Treatment of bilateral iliac occlusive disease is indicated in individuals with appropriate bilateral lesions and symptoms. Outcomes with bilateral interventions appear to be similar to those noted in individuals where a single side is treated; however, it is likely that patency is modestly reduced compared with unilateral interventions. Treatment in the common and external iliac arteries appears also to have similar outcomes. Use of uncovered stents across the orifice of the internal iliac artery will maintain adequate hypogastric artery perfusion in most instances, and it remains more important to treat the full extent of the disease than to limit coverage because of concern regarding stenting across the internal iliac artery origin. In situations where there is concern for flow preservation through a hypogastric artery, a kissing stent technique can be used at this bifurcation to maintain patency of both vessels; however, this is rarely necessary.
      A key consideration in the treatment of iliac occlusive disease is the extension of the disease into the femoral artery. Use of stents in the common femoral artery (CFA) is not recommended because they are more likely to fracture or fail due to flexion of the artery that occurs with hip flexion. If disease extends into the CFA, the use of a hybrid approach combining femoral endarterectomy with iliac stenting is a better alternative in most patients.
      Covered stents have been used in the treatment of iliac occlusive disease. Covered balloon-expandable stents had better primary patency rates when used in more complex lesions in the iliac artery.
      • Mwipatayi B.P.
      • Thomas S.
      • Wong J.
      • Temple S.E.
      • Vijayan V.
      • Jackson M.
      • et al.
      A comparison of covered vs bare expandable stents for the treatment of aortoiliac occlusive disease.
      In the prospective, randomized Covered vs Balloon Expandable Stent Trial,
      • Mwipatayi B.P.
      • Thomas S.
      • Wong J.
      • Temple S.E.
      • Vijayan V.
      • Jackson M.
      • et al.
      A comparison of covered vs bare expandable stents for the treatment of aortoiliac occlusive disease.
      covered balloon-expandable stents demonstrated better primary patency rates than bare-metal stents (BMSs) in AIOD, particularly in the more advanced lesions. However, in a more recent single-center, retrospective study, BMSs had superior patency to covered stents at 1 year.
      • Humphries M.D.
      • Armstrong E.
      • Laird J.
      • Paz J.
      • Pevec W.
      Outcomes of covered versus bare-metal balloon-expandable stents for aortoiliac occlusive disease.
      Regardless of any potential patency advantages, covered stents may provide a safety margin in the treatment of calcified common iliac lesions or ectatic vessels where rupture is a distinct possibility. For the external iliac artery, flexible, self-expanding stents are recommended because of the motion these vessels undergo and the potential for kinking and crimping of balloon-expandable stents placed in this location. Similarly, covered versions of these stents have also been used in the external iliac artery, although specific indications favoring one vs the other are not clear.
      Initial technical success for iliac stenting varies from 90% to 100% and depends on the extent of the disease, with more complex lesions having lower initial technical success rates. Long-segment occlusion of the external iliac artery, particularly in women or patients with smaller vessels or circumferential calcification, or both, remains an important limitation for durable patency.
      • Galaria II,
      • Davies M.G.
      Percutaneous transluminal revascularization for iliac occlusive disease: long-term outcomes in TransAtlantic Inter-Society Consensus A and B lesions.
      The 1-year primary and secondary patency rates range from 70% to 100% and 90% to 100%, respectively.
      • Ruggiero 2nd, N.J.
      • Jaff M.R.
      The current management of aortic, common iliac, and external iliac artery disease: basic data underlying clinical decision making.
      The 5-year primary and secondary patency rates are noted to be 60% to 85% and 80% to 95%, respectively.
      • Indes J.E.
      • Pfaff M.J.
      • Farrokhyar F.
      • Brown H.
      • Hashim P.
      • Cheung K.
      • et al.
      Clinical outcomes of 5358 patients undergoing direct open bypass or endovascular treatment for aortoiliac occlusive disease: a systematic review and meta-analysis.
      • Ruggiero 2nd, N.J.
      • Jaff M.R.
      The current management of aortic, common iliac, and external iliac artery disease: basic data underlying clinical decision making.
      • Ichihashi S.
      • Higashiura W.
      • Itoh H.
      • Sakaguchi S.
      • Kichikawa K.
      Iliac artery stent placement relieves claudication in patients with iliac and superficial femoral artery lesions.
      • Soga Y.
      • Iida O.
      • Kawasaki D.
      • Yamauchi Y.
      • Suzuki K.
      • Hirano K.
      • et al.
      Contemporary outcomes after endovascular treatment for aorto-iliac artery disease.
      Perioperative mortality can be expected to be approximately ≤1%,
      • Indes J.E.
      • Pfaff M.J.
      • Farrokhyar F.
      • Brown H.
      • Hashim P.
      • Cheung K.
      • et al.
      Clinical outcomes of 5358 patients undergoing direct open bypass or endovascular treatment for aortoiliac occlusive disease: a systematic review and meta-analysis.
      • Soga Y.
      • Iida O.
      • Kawasaki D.
      • Yamauchi Y.
      • Suzuki K.
      • Hirano K.
      • et al.
      Contemporary outcomes after endovascular treatment for aorto-iliac artery disease.
      and morbidity can range from 5% to 20%.
      • Indes J.E.
      • Pfaff M.J.
      • Farrokhyar F.
      • Brown H.
      • Hashim P.
      • Cheung K.
      • et al.
      Clinical outcomes of 5358 patients undergoing direct open bypass or endovascular treatment for aortoiliac occlusive disease: a systematic review and meta-analysis.
      • Ruggiero 2nd, N.J.
      • Jaff M.R.
      The current management of aortic, common iliac, and external iliac artery disease: basic data underlying clinical decision making.
      Long-term outcomes may be inferior in younger (<50 years) patients, particularly women.
      • Bechter-Hugl B.
      • Falkensammer J.
      • Gorny O.
      • Greiner A.
      • Chemelli A.
      • Fraedrich G.
      The influence of gender on patency rates after iliac artery stenting.

       CFA interventions

      Limited data are available to support the use of interventional therapy in occlusive disease of the CFAs, but several single-center experiences have been published,
      • Bonvini R.F.
      • Rastan A.
      • Sixt S.
      • Beschorner U.
      • Noory E.
      • Schwarz T.
      • et al.
      Angioplasty and provisional stent treatment of common femoral artery lesions.
      • Baumann F.
      • Ruch M.
      • Willenberg T.
      • Dick F.
      • Do D.D.
      • Keo H.H.
      • et al.
      Endovascular treatment of common femoral artery obstructions.
      • Paris C.L.
      • White C.J.
      • Collins T.J.
      • Jenkins J.S.
      • Reilly J.P.
      • Grise M.A.
      • et al.
      Catheter-based therapy of common femoral artery atherosclerotic disease.
      presenting a technical success rate of nearly 90% and 1-year primary patency rate of 75%. Information on longer-term patency is limited, and no information is available regarding stent stability in this area over even this short period of time. Given the limited morbidity and risk entailed with femoral endarterectomy, the use of interventions in this vessel for the present time should be limited to those with a prohibitive risk for open surgical therapy related to local or systemic risk factors.

       Hybrid interventions

      The use of interventional therapies for iliac disease allows treatment of occlusive disease in patients with limited morbidity; however, when the disease extends into the CFAs, an approach using open surgical techniques to treat the CFA and stents to treat the iliac or inflow vessels offers an alternative to traditional aortofemoral grafting.
      • Rzucidlo E.M.
      • Powell R.J.
      • Zwolak R.M.
      • Fillinger M.F.
      • Walsh D.B.
      • Schermerhorn M.L.
      • et al.
      Early results of stent-grafting to treat diffuse aortoiliac occlusive disease.
      • Chang R.W.
      • Goodney P.P.
      • Baek J.H.
      • Nolan B.W.
      • Rzucidlo E.M.
      • et al.
      Long-term results of combined common femoral endarterectomy and iliac stenting/stent grafting for occlusive disease.
      • Kashyap V.S.
      • Pavkov M.L.
      • Bena J.F.
      • Sarac T.P.
      • O'Hara P.J.
      • Lyden S.P.
      • et al.
      The management of severe aortoiliac occlusive disease: endovascular therapy rivals open reconstruction.
      In these instances, the endarterectomy is extended proximally into the external iliac artery, and stenting is done into the upper area of the endarterectomy to limit progression of disease in an intervening segment. Surgical angioplasty of the femoral artery can be performed with an eversion or standard patch technique. Stenting of the iliac artery can usually be done from an ipsilateral approach, with the sheath entry site well below the upper extent of the endarterectomy to allow stents to be placed through the full length of the diseased segment.
      Initial technical success with this approach is reported at 99% to 100% with 3-year to 5-year primary patency rates reported at 90% and secondary patency rates of 98% to 100%.
      • Chang R.W.
      • Goodney P.P.
      • Baek J.H.
      • Nolan B.W.
      • Rzucidlo E.M.
      • et al.
      Long-term results of combined common femoral endarterectomy and iliac stenting/stent grafting for occlusive disease.
      When compared with open aortofemoral reconstruction,
      • Chiu K.W.
      • Davies R.S.
      • Nightingale P.G.
      • Bradbury A.W.
      • Adam D.J.
      Review of direct anatomical open surgical management of atherosclerotic aorto-iliac occlusive disease.
      this approach appears to have similar low mortality, with associated reductions in systemic morbidity, infection risks, and a number of postsurgical complications while providing similar patency rates, especially when comparing secondary patency rates.

      5B Aortoiliac revascularization: Surgery

       General considerations

      Although endovascular intervention has become dominant in this vascular territory, surgery continues to have an important role in the current treatment of patients with disabling claudication secondary to AIOD. Relative indications for surgical vs endovascular approaches will be discussed below but primarily relate to disease distribution, prior interventions performed, and overall patient risk. A range of surgical options is available, depending on these and other technical considerations.
      There are a number of key anatomic considerations that directly influence the choice of an optimal surgical strategy in AIOD. The nature and extent of aortic disease is pre-eminent. Axial imaging studies, typically CTA, are important in the revascularization planning. The location and severity of the occlusive lesions, as well as the presence of any aneurysmal changes, have direct implications. Noncontrast scans are particularly helpful in preoperative planning to assess calcification, which can severely complicate clamping and suturing. Total occlusions, most commonly up to the subrenal aorta, are best approached by direct reconstruction with thromboendarterectomy of the aortic cuff and an end-to-end bypass graft in suitable candidates. Combined occlusive and aneurysmal disease should be treated by complete exclusion of the aneurysmal segment rather than simple bypass. When choosing between end-to-end and end-to-side aortic graft configuration, the extent of disease in the subrenal aorta and the status of the pelvic circulation are major issues.
      • Jaquinandi V.
      • Picquet J.
      • Saumet J.L.
      • Benharash P.
      • Leftheriotis G.
      • Abraham P.
      Functional assessment at the buttock level of the effect of aortobifemoral bypass surgery.
      • Juleff R.S.
      • Brown O.W.
      • McKain M.M.
      • Glover J.L.
      • Bendick P.J.
      The influence of competitive flow on graft patency.
      There are no clear differences in long-term outcomes for end-to-end vs end-to-side aortofemoral grafts
      • Pierce G.E.
      • Turrentine M.
      • Stringfield S.
      • Iliopoulos J.
      • Hardin C.A.
      • Hermreck A.S.
      • et al.
      Evaluation of end-to-side v end-to-end proximal anastomosis in aortobifemoral bypass.
      • Brewster D.C.
      Current controversies in the management of aortoiliac occlusive disease.
      ; however, the end-to-end technique requires less disease-free aorta and the graft is somewhat easier to cover with retroperitoneal tissue. In general, proximal anastomoses should be performed to the immediate subrenal segment (ie, the zone between the renal and inferior mesenteric arteries) because progression of atherosclerosis is highly likely in the more distal abdominal aorta and may limit durability.
      The pattern of iliac disease encountered may be highly variable. Unilateral disease, with complete occlusion of both common and external iliac arteries, or occlusion of the external iliac artery alone, may be approached surgically with either in-line (unilateral AFB or IFB) or extra-anatomic (FFB or AxFB) strategies. The choice between these depends on patient risk, status of the contralateral iliofemoral system and contralateral groin, and suitability of the proximal common iliac or aorta for inflow anastomosis. The presence of pre-existing stents or stent grafts in any of these segments will also influence the choice and conduct of the procedure.
      As noted above, the presence and severity of CFA disease is a critical point that often dictates whether a purely endovascular vs an open surgical or hybrid approach is undertaken. Long-term outcomes and limb status after reconstructions for AIOD are highly dependent on continued patency of the CFAs and deep femoral arteries (DFAs).
      • Malone J.M.
      • Moore W.S.
      • Goldstone J.
      Life expectancy following aortofemoral arterial grafting.
      • Morris Jr., G.C.
      • Edwards E.
      • Cooley D.A.
      • Crawford E.S.
      • De Bakey M.E.
      Surgical importance of profunda femoris artery. Analysis of 102 cases with combined aortoiliac and femoropopliteal occlusive disease treated by revascularization of deep femoral artery.
      The presence of FP and distal occlusive disease is also common, particularly in smokers. For patients with disabling claudication and rest pain (Rutherford 2-4), inflow reconstruction of significant AIOD is frequently all that is required to improve symptoms. A staged approach is therefore recommended in such patients with multilevel disease, with re-evaluation of symptom status after inflow correction.

       Direct (in-line) aortofemoral and iliofemoral reconstruction

      Direct surgical revascularization for AIOD is often considered the gold standard for durable vascular interventions, with patency rates >80% at 10 years for AFB or aortoiliac endarterectomy.
      • Brewster D.C.
      Clinical and anatomical considerations for surgery in aortoiliac disease and results of surgical treatment.
      • Inahara T.
      Evaluation of endarterectomy for aortoiliac and aortoiliofemoral occlusive disease.
      • Stoney R.R.
      • Reilly L.M.
      Current therapy in vascular therapy.
      Patency rates for unilateral IFB are also typically in the range of 90% at 3 to 5 years.
      • Chiu K.W.
      • Davies R.S.
      • Nightingale P.G.
      • Bradbury A.W.
      • Adam D.J.
      Review of direct anatomical open surgical management of atherosclerotic aorto-iliac occlusive disease.
      • Ricco J.B.
      • Probst H.
      French University Surgeons Association
      Long-term results of a multicenter randomized study on direct versus crossover bypass for unilateral iliac artery occlusive disease.
      • Cham C.
      • Myers K.A.
      • Scott D.F.
      • Devine T.J.
      • Denton M.J.
      Extraperitoneal unilateral iliac artery bypass for chronic lower limb ischaemia.
      • Melliere D.
      • Desgranges P.
      • de Wailly G.W.
      • Roudot-Thoraval F.
      • Allaire E.
      • Becquemin J.P.
      Extensive unilateral iliofemoral occlusions: durability of four techniques of arterial reconstructions.
      • van der Vliet J.A.
      • Scharn D.M.
      • de Waard J.W.
      • Roumen R.M.
      • van Roye S.F.
      • Buskens F.G.
      Unilateral vascular reconstruction for iliac obstructive disease.
      The disease pattern most amenable to endarterectomy (ie, localized lesions in the terminal aorta and common iliacs) is readily treated by endovascular means; hence, this operation has become extremely uncommon in current practice.
      Transperitoneal or retroperitoneal approaches may be used without significant differences in outcomes. Unilateral operations are readily performed via retroperitoneal approaches. In addition to considerations regarding the nature of the proximal anastomosis discussed above, a critical point is treatment of the CFAs and DFAs at the distal anastomosis. Ensuring an adequate caliber profunda outflow is essential and mandates careful preoperative and intraoperative evaluation. In circumstances of truly isolated AIOD and no or minimal disease in the common femoral/bifurcation, the anastomosis may be performed to the mid-CFA level. In all other circumstances, the arteriotomy in the CFA should allow direct interrogation of the DFA and SFA orifices, with use of adjunctive endarterectomy and patch angioplasty as needed based on burden and location of disease. Failure to address this critical point may significantly limit the durability of the bypass graft, because the presence or progression of outflow disease, or both, is the most common reason for midterm and late-term graft occlusions. Very rarely, disease spares the external iliac arteries and the femoral arteries, and in these circumstances, an aortoiliac bypass may be performed to the distal external iliac arteries via a transabdominal approach.
      • York J.W.
      • Johnson B.L.
      • Cicchillo M.
      • Taylor S.M.
      • Cull D.L.
      • Kalbaugh C.
      Aortobiiliac bypass to the distal external iliac artery versus aortobifemoral bypass: a matched cohort study.
      One must be cautious to ensure the absence of any significant femoral disease by imaging studies in such cases.
      Prosthetic grafts (Dacron, expanded polytetrafluoroethylene [ePTFE]) are typically used for AFB and IFB and have excellent durability. Small graft sizes (eg, 12 × 6 mm) have been associated with decreased patency and should be avoided.
      • Reed A.B.
      • Conte M.S.
      • Donaldson M.C.
      • Mannick J.A.
      • Whittemore A.D.
      • Belkin M.
      The impact of patient age and aortic size on the results of aortobifemoral bypass grafting.
      In the special circumstance of infected or contaminated fields, or removal of a previous infected graft, autogenous and cryopreserved conduits (artery or vein) have been used with good success.
      Perioperative mortality for these procedures is generally <3%,
      • Dimick J.B.
      • JA Jr., Cowan
      • Henke P.K.
      • Wainess R.M.
      • Posner S.
      • Stanley J.C.
      • et al.
      Hospital volume-related differences in aorto-bifemoral bypass operative mortality in the United States.
      although morbidity may include cardiac, pulmonary, infectious, wound, and gastrointestinal complications in 10% to 15%. Patency rates for AFB, aortoiliac endarterectomy, and IFB, as noted, have ranged from 80% to 90% at 5-year and 10-year intervals.
      • Burke C.R.
      • Henke P.K.
      • Hernandez R.
      • Rectenwald J.E.
      • Krishnamurthy V.
      • Englesbe M.J.
      • et al.
      A contemporary comparison of aortofemoral bypass and aortoiliac stenting in the treatment of aortoiliac occlusive disease.
      • de Vries S.O.
      • Hunink M.G.
      Results of aortic bifurcation grafts for aortoiliac occlusive disease: a meta-analysis.
      • Chiu K.W.
      • Davies R.S.
      • Nightingale P.G.
      • Bradbury A.W.
      • Adam D.J.
      Review of direct anatomical open surgical management of atherosclerotic aorto-iliac occlusive disease.
      • Inahara T.
      Evaluation of endarterectomy for aortoiliac and aortoiliofemoral occlusive disease.
      • Stoney R.R.
      • Reilly L.M.
      Current therapy in vascular therapy.
      • Reed A.B.
      • Conte M.S.
      • Donaldson M.C.
      • Mannick J.A.
      • Whittemore A.D.
      • Belkin M.
      The impact of patient age and aortic size on the results of aortobifemoral bypass grafting.
      • Brewster D.C.
      • Darling R.C.
      Optimal methods of aortoiliac reconstruction.
      Functional outcomes for claudicant patients, although less frequently reported, are generally quite good but depend on the presence of infrainguinal disease and modification of lifestyle and risk factors. Long-term complications include limb occlusions, pseudoaneurysm, graft infection, and graft-enteric fistula. Although the overall results are excellent, caution is warranted in certain subgroups of patients who have demonstrated inferior outcomes, particularly younger patients (age <50 years), hypercoagulable patients, and those with very small-caliber outflow vessels.
      • Reed A.B.
      • Conte M.S.
      • Donaldson M.C.
      • Mannick J.A.
      • Whittemore A.D.
      • Belkin M.
      The impact of patient age and aortic size on the results of aortobifemoral bypass grafting.