Revascularization for Claudication: Aortoiliac and Femoropopliteal Disease (Excluding Common Femoral Artery Disease)

* 4.

Multiple RCTs have compared endovascular procedures with various combinations of medical treatment with or without supervised or unsupervised exercise programs for patients with aortoiliac and/or femoropopliteal disease and claudication.7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 Although these trials have used different endpoints and enrolled patients with anatomic disease distribution at different levels, overall, these studies have shown the effectiveness of revascularization to improve walking performance and QOL in patients with claudication.8,10,23,30 Combining revascularization with either supervised exercise or pharmacotherapy results in greater improvements in these endpoints than exercise or medical therapy alone.9,10,23,24,56 In a network meta-analysis of 37 trials (15 of which included endovascular therapy) that randomized 2,983 patients over a mean weighted follow-up of 12 months to best medical therapy, SET, endovascular therapy (12 trials), or endovascular therapy plus SET (8 trials), the combination of endovascular therapy plus SET outperformed other treatment modalities with respect to walking performance and QOL.57 Symptom improvement after endovascular treatment for claudication is related to vessel patency, and long-term patency is greater in the aortoiliac than in the femoropopliteal segment.58

3: No Benefit| B-R|

* 5.In patients with chronic symptomatic PAD, chelation therapy is not recommended for treatment of claudication.13
Synopsis
In patients with chronic symptomatic PAD and claudication, medical therapy with cilostazol has been shown to reduce symptoms of claudication and improve walking distance.1, 2, 3, 4 In limited studies, cilostazol has also been shown to reduce restenosis after endovascular therapy for femoropopliteal stenosis and may therefore be useful in patients undergoing such therapy.5, 6, 7 Cilostazol is a phosphodiesterase III inhibitor; previous evaluation of oral milrinone—also a phosphodiesterase inhibitor—was shown to increase the mortality rate in patients with severe chronic heart failure. As a result, cilostazol is labeled as contraindicated in patients with congestive heart failure.8, 9, 10 Other medical therapies, including pentoxifylline and chelation therapy, have not been shown to provide benefit in terms of leg symptoms for individuals with symptomatic stable PAD and are therefore not recommended.11, 12, 13
Recommendation-Specific Supportive Text

* 1.

In a Cochrane review of 15 double-blind RCTs with 3,718 participants, cilostazol was associated with improvement in claudication symptoms but no changes in cardiovascular deaths or QOL compared with placebo.1 In a longitudinal prospective registry, cilostazol significantly improved Peripheral Artery Questionnaire (PAQ) outcomes and physical limitation score.2

Symptom improvement after endovascular treatment for claudication is related to vessel patency, and long-term patency is greater in the aortoiliac than in the femoropopliteal segment.58 Furthermore, factors associated with lower vessel patency include longer lesion length, occlusion rather than stenosis, the presence of multiple and diffuse lesions, poor-quality runoff, diabetes, CKD, renal failure, and smoking.59, 60, 61, 62

* The CLEVER (Claudication: Exercise Versus Endoluminal Revascularization) trial, which enrolled patients with aortoiliac disease and compared endovascular therapy with SET and with medications alone, showed that endovascular therapy and supervised exercise had improved walking time compared with medication alone at 6 months.11,12 Other RCTs that included patients with aortoiliac disease have shown improvement in QOL, as assessed by questionnaires and time to onset of claudication, may be superior with endovascular treatment in combination with a medical and exercise treatment plan, compared with medical treatment alone.7,8,15 The ERASE (Endovascular Revascularization And Supervised Exercise) trial randomized patients with claudication and aortoiliac and femoropopliteal disease to endovascular revascularization plus supervised exercise or supervised exercise alone.9 After 1 year, patients in both groups had significant improvements in walking distances and health-related QOL, with greater improvements in the combined-therapy group.9 The long-term comparative effectiveness of 1) endovascular revascularization versus SET and 2) medical therapy versus SET and medical therapy without revascularization for aortoiliac disease is unknown.

More than 70% of patients prefer to have an active role in determining their treatment plan for claudication.46, 47, 48 Such discussions should be undertaken when considering whether to undergo a revascularization procedure, its timing, and approach for revascularization (ie, endovascular or surgical), and should take into account the patient’s goals, treatment preferences, and perception of risk. Patient engagement is also essential to facilitate smoking cessation, medication adherence, and participation in structured exercise.
Endovascular therapy typically involves the displacement or removal of stenotic or occlusive atherosclerotic disease using catheter-based techniques. Endovascular techniques for claudication include PTA (sometimes referred to as “plain-old balloon angioplasty”); drug-coated balloon angioplasty; bare-metal, drug-eluting, and covered stents; lithotripsy; and atherectomy. Endovascular tools are selected based upon lesion characteristics (eg, anatomic location, lesion length, degree of calcification), operator experience, and the range of available technologies. The appropriateness of particular endovascular therapies for the treatment of claudication is beyond the scope of this document but has been addressed in other multisocietal statements.49, 50, 51
Surgical revascularization for claudication most commonly involves the removal of plaque from diseased arteries (endarterectomy) or bypass around narrowed or occluded segments, sometimes performed in combination with endovascular treatments (“hybrid approaches”). Assessment of options for bypass conduit is performed as part of evaluation for surgical revascularization.

The Society for Vascular Surgery appropriate use criteria (AUC) for the management of intermittent claudication were created using the RAND appropriateness method, a validated and standardized method that combines the best available evidence from medical literature with expert opinion, using a modified Delphi process. These criteria serve as a framework on which individualized patient and clinician shared decision-making can grow. These criteria are not absolute. AUC should not be interpreted as a requirement to administer treatments rated as appropriate (benefit outweighs risk). Nor should AUC be interpreted as a prohibition of treatments rated as inappropriate (risk outweighs benefit). Clinical situations will occur in which moderating factors, not included in these AUC, will shift the appropriateness level of a treatment for an individual patient. Proper implementation of AUC requires a description of those moderating patient factors. For scenarios with an indeterminate rating, clinician judgement combined with the best available evidence should determine the treatment strategy. These scenarios require mechanisms to track the treatment decisions and outcomes. AUC should be revisited periodically to ensure that they remain relevant. The panelists rated 2280 unique scenarios for the treatment of intermittent claudication (IC) in the aortoiliac, common femoral, and femoropopliteal segments in the round 2 rating. Of these, only nine (0.4%) showed a disagreement using the interpercentile range adjusted for symmetry formula, indicating an exceptionally high degree of consensus among the panelists. Post hoc, the term "inappropriate" was replaced with the phrase "risk outweighs benefit." The term "appropriate" was also replaced with "benefit outweighs risk." The key principles for the management of IC reflected within these AUC are as follows. First, exercise therapy is the preferred initial management strategy for all patients with IC. Second, for patients who have not completed exercise therapy, invasive therapy might provide net a benefit for selected patients with IC who are nonsmokers, are taking optimal medical therapy, are considered to have a low physiologic and technical risk, and who are experiencing severe lifestyle limitations and/or a short walking distance. Third, considering the long-term durability of the currently available technology, invasive interventions for femoropopliteal disease should be reserved for patients with severe lifestyle limitations and a short walking distance. Fourth, in the common femoral segment, open common femoral endarterectomy will provide greater net benefit than endovascular intervention for the treatment of IC. Finally, in the infrapopliteal segment, invasive intervention for the treatment of IC is of unclear benefit and could be harmful.

• 23 Patients with intermittent claudication have lifestyle- or vocation-limiting symptoms and have undergone a trial of medical therapy and exercise therapy (supervised). For medical therapy, cilostazol should be employed for ≥3 months to improve absolute claudication distance. Per the 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease ( 4 ), to be effective, exercise therapy should constitute a supervised, structured program of exercise lasting for 30 to 45 min, 3 times/week, for a minimum of 12 weeks.
• 24 Popliteal artery aneurysmal disease is not included.
• 25 Common femoral artery disease is not included.
• 26 The superficial femoral artery (SFA) extends from its ostium after bifurcation of the common femoral artery to the adductor canal.
• 27 The below-the-knee segment extends from the origin of the anterior tibial artery to the pedal arch.
• 28 The trifurcation refers to the division of the popliteal artery into the anterior tibial artery and the tibioperoneal trunk, which subsequently divides into the posterior tibial and peroneal arteries.
• 29 Two-year survival is an estimate based upon patient characteristics and comorbidities: age ≥80 years, body mass index <18.0 kg/m 2 , nonambulatory status, hemodialysis, cerebrovascular disease, left ventricular ejection fraction <40%, Rutherford class 5 or 6.

Two medications, pentoxifylline and cilostazol, are Food and Drug Administration approved for treating walking impairment due to symptomatic PAD. Pentoxifylline, a methylxanthine derivative, increases red blood cell deformability (improved rheology), thereby potentially increasing arterial and microcirculatory flow and tissue oxygen concentration. However, a systematic review concluded that benefits of pentoxifylline for intermittent claudication symptoms were uncertain and based on poor-quality trials. The largest trials of pentoxifylline had effects on pain-free and maximal treadmill walking distance ranging from 0% to 14% benefit without improved quality of life or patient perceived walking ability. Clinical practice guidelines recommend against pentoxifylline for PAD due to lack of efficacy (class, no benefit; level of evidence B-R).

Cilostazol promotes vasodilation, particularly in femoral arteries, and has antiplatelet and antithrombotic activities. It is initiated at 50 mg twice daily and increased to 100 mg twice daily if tolerated. In a meta-analysis of 8 trials of 2247 people with PAD and claudication, cilostazol was associated with a 43-m improvement in treadmill walking distance compared with placebo (95% CI, 18.27-67.95). In a meta-analysis of 6 trials of 1533 patients, cilostazol was associated with a 31.4-m improvement in the initial pain-free treadmill walking distance compared with placebo (95% CI, 22.4-40.5). These improvements in treadmill walking were modest compared with benefits of supervised exercise. Up to 30% of patients prescribed cilostazol may experience adverse effects, including headache, diarrhea, abnormal stools, dizziness, and heart palpitations. Cilostazol and several of its metabolites inhibit phosphodiesterase III. Because some phosphodiesterase III inhibitors were associated with increased mortality in people with heart failure, a black box warning against prescribing cilostazol exists for patients with PAD who have heart failure of any severity.

Peripheral artery disease patients who continue smoking have greater rates of adverse lower extremity outcomes. Patients should be helped to quit smoking, including with pharmacotherapy (ie, varenicline, bupropion, or nicotine replacement therapy) and referred to a smoking cessation program (AHA/ACC class I, level of evidence A).

Two medications, pentoxifylline and cilostazol, are Food and Drug Administration approved for treating walking impairment due to symptomatic PAD. Pentoxifylline, a methylxanthine derivative, increases red blood cell deformability (improved rheology), thereby potentially increasing arterial and microcirculatory flow and tissue oxygen concentration. However, a systematic review concluded that benefits of pentoxifylline for intermittent claudication symptoms were uncertain and based on poor-quality trials. The largest trials of pentoxifylline had effects on pain-free and maximal treadmill walking distance ranging from 0% to 14% benefit without improved quality of life or patient perceived walking ability. Clinical practice guidelines recommend against pentoxifylline for PAD due to lack of efficacy (class, no benefit; level of evidence B-R).

Cilostazol promotes vasodilation, particularly in femoral arteries, and has antiplatelet and antithrombotic activities. It is initiated at 50 mg twice daily and increased to 100 mg twice daily if tolerated. In a meta-analysis of 8 trials of 2247 people with PAD and claudication, cilostazol was associated with a 43-m improvement in treadmill walking distance compared with placebo (95% CI, 18.27-67.95). In a meta-analysis of 6 trials of 1533 patients, cilostazol was associated with a 31.4-m improvement in the initial pain-free treadmill walking distance compared with placebo (95% CI, 22.4-40.5). These improvements in treadmill walking were modest compared with benefits of supervised exercise. Up to 30% of patients prescribed cilostazol may experience adverse effects, including headache, diarrhea, abnormal stools, dizziness, and heart palpitations. Cilostazol and several of its metabolites inhibit phosphodiesterase III.

Background: Peripheral arterial disease (PAD) affects between 4% and 12% of people aged 55 to 70 years, and 20% of people over 70 years. A common complaint is intermittent claudication (exercise-induced lower limb pain relieved by rest). These patients have a three- to six-fold increase in cardiovascular mortality.  Cilostazol is a drug licensed for the use of improving claudication distance and, if shown to reduce cardiovascular risk, could offer additional clinical benefits. This is an update of the review first published in 2007.

Objectives: To determine the effect of cilostazol on initial and absolute claudication distances, mortality and vascular events in patients with stable intermittent claudication.

Search Methods: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and AMED databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registries, on 9 November 2020.

Selection Criteria: We considered double-blind, randomised controlled trials (RCTs) of cilostazol versus placebo, or versus other drugs used to improve claudication distance in patients with stable intermittent claudication.

Data Collection And Analysis: Two authors independently assessed trials for selection and independently extracted data. Disagreements were resolved by discussion. We assessed the risk of bias with the Cochrane risk of bias tool. Certainty of the evidence was evaluated using GRADE. For dichotomous outcomes, we used odds ratios (ORs) with corresponding 95% confidence intervals (CIs) and for continuous outcomes we used mean differences (MDs) and 95% CIs. We pooled data using a fixed-effect model, or a random-effects model when heterogeneity was identified. Primary outcomes were initial claudication distance (ICD) and quality of life (QoL). Secondary outcomes were absolute claudication distance (ACD), revascularisation, amputation, adverse events and cardiovascular events.

Main Results: We included 16 double-blind, RCTs (3972 participants) comparing cilostazol with placebo, of which five studies also compared cilostazol with pentoxifylline. Treatment duration ranged from six to 26 weeks. All participants had intermittent claudication secondary to PAD. Cilostazol dose ranged from 100 mg to 300 mg; pentoxifylline dose ranged from 800 mg to 1200 mg. The certainty of the evidence was downgraded by one level for all studies because publication bias was strongly suspected. Other reasons for downgrading were imprecision, inconsistency and selective reporting. Cilostazol versus placebo Participants taking cilostazol had a higher ICD compared with those taking placebo (MD 26.49 metres; 95% CI 18.93 to 34.05; 1722 participants; six studies; low-certainty evidence). We reported QoL measures descriptively due to insufficient statistical detail within the studies to combine the results; there was a possible indication in improvement of QoL in the cilostazol treatment groups (low-certainty evidence). Participants taking cilostazol had a higher ACD compared with those taking placebo (39.57 metres; 95% CI 21.80 to 57.33; 2360 participants; eight studies; very-low certainty evidence). The most commonly reported adverse events were headache, diarrhoea, abnormal stools, dizziness, pain and palpitations. Participants taking cilostazol had an increased odds of experiencing headache compared to participants taking placebo (OR 2.83; 95% CI 2.26 to 3.55; 2584 participants; eight studies; moderate-certainty evidence).Very few studies reported on other outcomes so conclusions on revascularisation, amputation, or cardiovascular events could not be made. Cilostazol versus pentoxifylline There was no difference detected between cilostazol and pentoxifylline for improving walking distance, both in terms of ICD (MD 20.0 metres, 95% CI -2.57 to 42.57; 417 participants; one study; low-certainty evidence); and ACD (MD 13.4 metres, 95% CI -43.50 to 70.36; 866 participants; two studies; very low-certainty evidence). One study reported on QoL; the study authors reported no difference in QoL between the treatment groups (very low-certainty evidence). No study reported on revascularisation, amputation or cardiovascular events. Cilostazol participants had an increased odds of experiencing headache compared with participants taking pentoxifylline at 24 weeks (OR 2.20, 95% CI 1.16 to 4.17; 982 participants; two studies; low-certainty evidence). AUTHORS'

Conclusions: Cilostazol has been shown to improve walking distance in people with intermittent claudication. However, participants taking cilostazol had higher odds of experiencing headache. There is insufficient evidence about the effectiveness of cilostazol for serious events such as amputation, revascularisation, and cardiovascular events. Despite the importance of QoL to patients, meta-analysis could not be undertaken because of differences in measures used and reporting. Very limited data indicated no difference between cilostazol and pentoxifylline for improving walking distance and data were too limited for any conclusions on other outcomes.

Peripheral artery disease (PAD) is common and associated with significant morbidity and mortality. Optimal medical management of PAD is required for each patient, irrespective of the decision regarding lower extremity revascularization. The goals include reducing cardiovascular morbidity and mortality and improving quality of life. The approach should consist of aggressive and individualized risk factor modification including smoking cessation, antiplatelet therapy, a statin, and an angiotensin-converting enzyme inhibitor. Exercise is critical for cardiovascular health and highly effective for improving claudication symptoms. Cilostazol may be considered for symptomatic treatment in certain patients.

Revascularization is indicated when there are limiting symptoms in spite of an exercise program and medical therapy and there is a reasonable likelihood that symptoms can be reduced (including absence of other conditions that might limit functional capacity, such as heart failure or lung disease); it is also indicated for limb salvage in the context of critical limb ischemia. Commonly performed revascularization procedures for peripheral artery disease are shown in Figure 3 and Figure S2 in the Supplementary Appendix. An individualized approach should be adopted to select a revascularization strategy for each patient on the basis of the patient’s preferences, anatomical factors, the availability of appropriate conduits, and operative risk. Supervised exercise may serve as a useful adjunct to revascularization. In a trial involving 212 patients with claudication, those who were randomly assigned to endovascular revascularization and supervised exercise had a longer maximal walking distance at 12 months than did those who were randomly assigned to exercise alone (1237 vs. 955 m).

Aortoiliac angioplasty and stenting (Fig. S1 in the Supplementary Appendix) have high procedural success rates (approximately 96%) and a 3-year patency rate of approximately 82%. Stent placement is generally avoided in the common femoral artery, owing to the risk of biomechanical stress-related stent fractures and the potential for interference with future arterial access. Endovascular intervention in the superficial femoral artery is associated with high rates of restenosis, and several technologies to limit restenosis, including drug-eluting or covered stents and drug-coated balloons, are being evaluated (Figure 3). Endovascular therapy of isolated infrapopliteal disease is not recommended for claudication. Patients should receive dual antiplatelet therapy for at least 30 days or for a longer period if a drug-eluting stent is placed.

Surgical bypass (Fig. S2 in the Supplementary Appendix) should be considered when an endovascular approach has failed or is not feasible from an anatomical standpoint.

Figure 3:
Caption: Major Arteries of the Legs and Endovascular Procedures for Treatment of Peripheral Artery Disease.
Description: Balloon angioplasty, stenting (with balloon-expandable or self-expanding stents), and atherectomy are common endovascular procedures. Drug-eluting or covered stents and drug-coated balloons are being evaluated to reduce the rate of restenosis.

Guidelines from the AHA/ACC 1 and the Society for Vascular Surgery 61 recommend best medical treatment as the first-line treatment for claudication, with revascularization reserved for only refractory cases. These recommendations are based on data showing that there is a relatively low likelihood of limb loss associated with mild PAD 189 and that long-term improvements in symptomatology may be limited. 190 For example, recent data from the Invasive Revascularization or Not in Intermittent Claudication trial demonstrated that, after 5 years of follow-up, revascularization for claudication lost any early benefit and did not result in long-term health-related quality of life compared with best medical therapy. 190 Despite guidelines recommending medical management as the first-line therapy for claudication, recent registry data from the Vascular Quality Initiative demonstrate that 27% of all open bypass procedures and even a higher percentage of endovascular interventions are performed for claudication. 191 It is possible that many of the patients undergoing revascularization for claudication experienced severe claudication symptoms and that conservative management failed. For instance, in the CLEVER study (Claudication: Exercise Versus Endoluminal Revascularization), 192 the revascularization group and the supervised exercise therapy group had better 18-month outcomes than optimal medical care alone. Quality improvement initiatives aimed at reducing unnecessary procedures are emerging to address outlier behavior in the overuse of invasive interventions for mild disease. 177 , 193 Higher-quality data about the benefits of revascularization for severe claudication symptoms are needed.

Symptom improvement after endovascular treatment for claudication is related to vessel patency, and long-term patency is greater in the aortoiliac than in the femoropopliteal segment.58 Furthermore, factors associated with lower vessel patency include longer lesion length, occlusion rather than stenosis, the presence of multiple and diffuse lesions, poor-quality runoff, diabetes, CKD, renal failure, and smoking.59, 60, 61, 62

* The CLEVER (Claudication: Exercise Versus Endoluminal Revascularization) trial, which enrolled patients with aortoiliac disease and compared endovascular therapy with SET and with medications alone, showed that endovascular therapy and supervised exercise had improved walking time compared with medication alone at 6 months.11,12 Other RCTs that included patients with aortoiliac disease have shown improvement in QOL, as assessed by questionnaires and time to onset of claudication, may be superior with endovascular treatment in combination with a medical and exercise treatment plan, compared with medical treatment alone.7,8,15 The ERASE (Endovascular Revascularization And Supervised Exercise) trial randomized patients with claudication and aortoiliac and femoropopliteal disease to endovascular revascularization plus supervised exercise or supervised exercise alone.9 After 1 year, patients in both groups had significant improvements in walking distances and health-related QOL, with greater improvements in the combined-therapy group.9 The long-term comparative effectiveness of 1) endovascular revascularization versus SET and 2) medical therapy versus SET and medical therapy without revascularization for aortoiliac disease is unknown.

Revascularization for Claudication: Aortoiliac and Femoropopliteal Disease (Excluding Common Femoral Artery Disease)

* 4.

Multiple RCTs have compared endovascular procedures with various combinations of medical treatment with or without supervised or unsupervised exercise programs for patients with aortoiliac and/or femoropopliteal disease and claudication.7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 Although these trials have used different endpoints and enrolled patients with anatomic disease distribution at different levels, overall, these studies have shown the effectiveness of revascularization to improve walking performance and QOL in patients with claudication.8,10,23,30 Combining revascularization with either supervised exercise or pharmacotherapy results in greater improvements in these endpoints than exercise or medical therapy alone.9,10,23,24,56 In a network meta-analysis of 37 trials (15 of which included endovascular therapy) that randomized 2,983 patients over a mean weighted follow-up of 12 months to best medical therapy, SET, endovascular therapy (12 trials), or endovascular therapy plus SET (8 trials), the combination of endovascular therapy plus SET outperformed other treatment modalities with respect to walking performance and QOL.57 Symptom improvement after endovascular treatment for claudication is related to vessel patency, and long-term patency is greater in the aortoiliac than in the femoropopliteal segment.58

More than 70% of patients prefer to have an active role in determining their treatment plan for claudication.46, 47, 48 Such discussions should be undertaken when considering whether to undergo a revascularization procedure, its timing, and approach for revascularization (ie, endovascular or surgical), and should take into account the patient’s goals, treatment preferences, and perception of risk. Patient engagement is also essential to facilitate smoking cessation, medication adherence, and participation in structured exercise.
Endovascular therapy typically involves the displacement or removal of stenotic or occlusive atherosclerotic disease using catheter-based techniques. Endovascular techniques for claudication include PTA (sometimes referred to as “plain-old balloon angioplasty”); drug-coated balloon angioplasty; bare-metal, drug-eluting, and covered stents; lithotripsy; and atherectomy. Endovascular tools are selected based upon lesion characteristics (eg, anatomic location, lesion length, degree of calcification), operator experience, and the range of available technologies. The appropriateness of particular endovascular therapies for the treatment of claudication is beyond the scope of this document but has been addressed in other multisocietal statements.49, 50, 51
Surgical revascularization for claudication most commonly involves the removal of plaque from diseased arteries (endarterectomy) or bypass around narrowed or occluded segments, sometimes performed in combination with endovascular treatments (“hybrid approaches”). Assessment of options for bypass conduit is performed as part of evaluation for surgical revascularization.

Peripheral artery disease patients who continue smoking have greater rates of adverse lower extremity outcomes. Patients should be helped to quit smoking, including with pharmacotherapy (ie, varenicline, bupropion, or nicotine replacement therapy) and referred to a smoking cessation program (AHA/ACC class I, level of evidence A).

Two medications, pentoxifylline and cilostazol, are Food and Drug Administration approved for treating walking impairment due to symptomatic PAD. Pentoxifylline, a methylxanthine derivative, increases red blood cell deformability (improved rheology), thereby potentially increasing arterial and microcirculatory flow and tissue oxygen concentration. However, a systematic review concluded that benefits of pentoxifylline for intermittent claudication symptoms were uncertain and based on poor-quality trials. The largest trials of pentoxifylline had effects on pain-free and maximal treadmill walking distance ranging from 0% to 14% benefit without improved quality of life or patient perceived walking ability. Clinical practice guidelines recommend against pentoxifylline for PAD due to lack of efficacy (class, no benefit; level of evidence B-R).

Cilostazol promotes vasodilation, particularly in femoral arteries, and has antiplatelet and antithrombotic activities. It is initiated at 50 mg twice daily and increased to 100 mg twice daily if tolerated. In a meta-analysis of 8 trials of 2247 people with PAD and claudication, cilostazol was associated with a 43-m improvement in treadmill walking distance compared with placebo (95% CI, 18.27-67.95). In a meta-analysis of 6 trials of 1533 patients, cilostazol was associated with a 31.4-m improvement in the initial pain-free treadmill walking distance compared with placebo (95% CI, 22.4-40.5). These improvements in treadmill walking were modest compared with benefits of supervised exercise. Up to 30% of patients prescribed cilostazol may experience adverse effects, including headache, diarrhea, abnormal stools, dizziness, and heart palpitations. Cilostazol and several of its metabolites inhibit phosphodiesterase III.

Patients with peripheral arterial disease are at increased risk for all-cause mortality, cardiovascular mortality, and mortality from coronary artery disease. Smoking should be stopped, and hypertension, diabetes mellitus, and dyslipidemia should be treated. Statins reduce the incidence of intermittent claudication and increase exercise duration until the onset of intermittent claudication in patients with peripheral arterial disease and hypercholesterolemia. Antiplatelet drugs, such as aspirin or clopidogrel, angiotensin-converting enzyme inhibitors, and statins, should be given to all patients with peripheral arterial disease. Beta-blockers should be given if coronary artery disease is present. Exercise rehabilitation programs and cilostazol improve exercise time until the onset of intermittent claudication. Indications for lower-extremity angioplasty, preferably with stenting, or bypass surgery are incapacitating claudication interfering with work or lifestyle in patients; limb salvage in patients with limb-threatening ischemia as manifested by rest pain, nonhealing ulcers, infection, or gangrene; and vasculogenic impotence.

The prevalence of peripheral arterial disease (PAD) increases with age. PAD in elderly persons may be asymptomatic, may be associated with intermittent claudication, or may be associated with critical limb ischemia. Other atherosclerotic vascular disorders, especially coronary artery disease (CAD), may coexist with PAD. Elderly persons with PAD are at increased risk for all-cause mortality, cardiovascular mortality, and mortality from CAD. Modifiable risk factors should be treated in persons with PAD such as cessation of cigarette smoking and control of hypertension, dyslipidemia, and diabetes. Statins have been shown to reduce the incidence of intermittent claudication and to improve treadmill exercise duration until the onset of intermittent claudication in persons with PAD and hypercholesterolemia. Antiplatelet drugs such as aspirin or clopidogrel, especially clopidogrel, should be administered to all persons with PAD. Persons with PAD should be treated with angiotensin-converting enzyme inhibitors and also with beta blockers if CAD is present. Cilostazol should be given to persons with intermittent claudication to improve exercise capacity unless heart failure is present. Exercise rehabilitation programs improve exercise time until claudication. Indications for lower extremity angioplasty, preferably with stenting, or bypass surgery are 1) incapacitating claudication in persons interfering with work or lifestyle; 2) limb salvage in persons with limb-threatening ischemia as manifested by rest pain, nonhealing ulcers, and/or infection or gangrene; and 3) vasculogenic impotence. However, amputation should be performed if tissue loss has progressed beyond the point of salvage, if surgery is too risky, if life expectancy is very low, or if functional limitations obviate the benefit of limb salvage.

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. 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. 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.

The Society for Vascular Surgery appropriate use criteria (AUC) for the management of intermittent claudication were created using the RAND appropriateness method, a validated and standardized method that combines the best available evidence from medical literature with expert opinion, using a modified Delphi process. These criteria serve as a framework on which individualized patient and clinician shared decision-making can grow. These criteria are not absolute. AUC should not be interpreted as a requirement to administer treatments rated as appropriate (benefit outweighs risk). Nor should AUC be interpreted as a prohibition of treatments rated as inappropriate (risk outweighs benefit). Clinical situations will occur in which moderating factors, not included in these AUC, will shift the appropriateness level of a treatment for an individual patient. Proper implementation of AUC requires a description of those moderating patient factors. For scenarios with an indeterminate rating, clinician judgement combined with the best available evidence should determine the treatment strategy. These scenarios require mechanisms to track the treatment decisions and outcomes. AUC should be revisited periodically to ensure that they remain relevant. The panelists rated 2280 unique scenarios for the treatment of intermittent claudication (IC) in the aortoiliac, common femoral, and femoropopliteal segments in the round 2 rating. Of these, only nine (0.4%) showed a disagreement using the interpercentile range adjusted for symmetry formula, indicating an exceptionally high degree of consensus among the panelists. Post hoc, the term "inappropriate" was replaced with the phrase "risk outweighs benefit." The term "appropriate" was also replaced with "benefit outweighs risk." The key principles for the management of IC reflected within these AUC are as follows. First, exercise therapy is the preferred initial management strategy for all patients with IC. Second, for patients who have not completed exercise therapy, invasive therapy might provide net a benefit for selected patients with IC who are nonsmokers, are taking optimal medical therapy, are considered to have a low physiologic and technical risk, and who are experiencing severe lifestyle limitations and/or a short walking distance. Third, considering the long-term durability of the currently available technology, invasive interventions for femoropopliteal disease should be reserved for patients with severe lifestyle limitations and a short walking distance. Fourth, in the common femoral segment, open common femoral endarterectomy will provide greater net benefit than endovascular intervention for the treatment of IC. Finally, in the infrapopliteal segment, invasive intervention for the treatment of IC is of unclear benefit and could be harmful.

Revascularization for Claudication: Aortoiliac and Femoropopliteal Disease (Excluding Common Femoral Artery Disease)

* 4.

Multiple RCTs have compared endovascular procedures with various combinations of medical treatment with or without supervised or unsupervised exercise programs for patients with aortoiliac and/or femoropopliteal disease and claudication.7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 Although these trials have used different endpoints and enrolled patients with anatomic disease distribution at different levels, overall, these studies have shown the effectiveness of revascularization to improve walking performance and QOL in patients with claudication.8,10,23,30 Combining revascularization with either supervised exercise or pharmacotherapy results in greater improvements in these endpoints than exercise or medical therapy alone.9,10,23,24,56 In a network meta-analysis of 37 trials (15 of which included endovascular therapy) that randomized 2,983 patients over a mean weighted follow-up of 12 months to best medical therapy, SET, endovascular therapy (12 trials), or endovascular therapy plus SET (8 trials), the combination of endovascular therapy plus SET outperformed other treatment modalities with respect to walking performance and QOL.57 Symptom improvement after endovascular treatment for claudication is related to vessel patency, and long-term patency is greater in the aortoiliac than in the femoropopliteal segment.58

Symptom improvement after endovascular treatment for claudication is related to vessel patency, and long-term patency is greater in the aortoiliac than in the femoropopliteal segment.58 Furthermore, factors associated with lower vessel patency include longer lesion length, occlusion rather than stenosis, the presence of multiple and diffuse lesions, poor-quality runoff, diabetes, CKD, renal failure, and smoking.59, 60, 61, 62

* The CLEVER (Claudication: Exercise Versus Endoluminal Revascularization) trial, which enrolled patients with aortoiliac disease and compared endovascular therapy with SET and with medications alone, showed that endovascular therapy and supervised exercise had improved walking time compared with medication alone at 6 months.11,12 Other RCTs that included patients with aortoiliac disease have shown improvement in QOL, as assessed by questionnaires and time to onset of claudication, may be superior with endovascular treatment in combination with a medical and exercise treatment plan, compared with medical treatment alone.7,8,15 The ERASE (Endovascular Revascularization And Supervised Exercise) trial randomized patients with claudication and aortoiliac and femoropopliteal disease to endovascular revascularization plus supervised exercise or supervised exercise alone.9 After 1 year, patients in both groups had significant improvements in walking distances and health-related QOL, with greater improvements in the combined-therapy group.9 The long-term comparative effectiveness of 1) endovascular revascularization versus SET and 2) medical therapy versus SET and medical therapy without revascularization for aortoiliac disease is unknown.

More than 70% of patients prefer to have an active role in determining their treatment plan for claudication.46, 47, 48 Such discussions should be undertaken when considering whether to undergo a revascularization procedure, its timing, and approach for revascularization (ie, endovascular or surgical), and should take into account the patient’s goals, treatment preferences, and perception of risk. Patient engagement is also essential to facilitate smoking cessation, medication adherence, and participation in structured exercise.
Endovascular therapy typically involves the displacement or removal of stenotic or occlusive atherosclerotic disease using catheter-based techniques. Endovascular techniques for claudication include PTA (sometimes referred to as “plain-old balloon angioplasty”); drug-coated balloon angioplasty; bare-metal, drug-eluting, and covered stents; lithotripsy; and atherectomy. Endovascular tools are selected based upon lesion characteristics (eg, anatomic location, lesion length, degree of calcification), operator experience, and the range of available technologies. The appropriateness of particular endovascular therapies for the treatment of claudication is beyond the scope of this document but has been addressed in other multisocietal statements.49, 50, 51
Surgical revascularization for claudication most commonly involves the removal of plaque from diseased arteries (endarterectomy) or bypass around narrowed or occluded segments, sometimes performed in combination with endovascular treatments (“hybrid approaches”). Assessment of options for bypass conduit is performed as part of evaluation for surgical revascularization.

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. 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. 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.

Tabled 1

| | Grade| Level of evidence
---|---|---|---
4.1.| We recommend multidisciplinary comprehensive smoking cessation interventions for patients with IC (repeatedly until tobacco use has stopped).| 1| A
4.2.| We recommend statin therapy in patients with symptomatic PAD.| 1| A
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.| 1| B
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.| 1| B
4.5.| In patients with IC due to atherosclerosis, we recommend antiplatelet therapy with aspirin (75-325 mg daily).| 1| A
4.6.| We recommend clopidogrel in doses of 75 mg daily as an effective alternative to aspirin for antiplatelet therapy in patients with IC.| 1| B
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.| 1| C
4.8.| We suggest against using folic acid and vitamin B12 supplements as a treatment of IC.| 2| C
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.| 2| A
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.

The Society for Vascular Surgery appropriate use criteria (AUC) for the management of intermittent claudication were created using the RAND appropriateness method, a validated and standardized method that combines the best available evidence from medical literature with expert opinion, using a modified Delphi process. These criteria serve as a framework on which individualized patient and clinician shared decision-making can grow. These criteria are not absolute. AUC should not be interpreted as a requirement to administer treatments rated as appropriate (benefit outweighs risk). Nor should AUC be interpreted as a prohibition of treatments rated as inappropriate (risk outweighs benefit). Clinical situations will occur in which moderating factors, not included in these AUC, will shift the appropriateness level of a treatment for an individual patient. Proper implementation of AUC requires a description of those moderating patient factors. For scenarios with an indeterminate rating, clinician judgement combined with the best available evidence should determine the treatment strategy. These scenarios require mechanisms to track the treatment decisions and outcomes. AUC should be revisited periodically to ensure that they remain relevant. The panelists rated 2280 unique scenarios for the treatment of intermittent claudication (IC) in the aortoiliac, common femoral, and femoropopliteal segments in the round 2 rating. Of these, only nine (0.4%) showed a disagreement using the interpercentile range adjusted for symmetry formula, indicating an exceptionally high degree of consensus among the panelists. Post hoc, the term "inappropriate" was replaced with the phrase "risk outweighs benefit." The term "appropriate" was also replaced with "benefit outweighs risk." The key principles for the management of IC reflected within these AUC are as follows. First, exercise therapy is the preferred initial management strategy for all patients with IC. Second, for patients who have not completed exercise therapy, invasive therapy might provide net a benefit for selected patients with IC who are nonsmokers, are taking optimal medical therapy, are considered to have a low physiologic and technical risk, and who are experiencing severe lifestyle limitations and/or a short walking distance. Third, considering the long-term durability of the currently available technology, invasive interventions for femoropopliteal disease should be reserved for patients with severe lifestyle limitations and a short walking distance. Fourth, in the common femoral segment, open common femoral endarterectomy will provide greater net benefit than endovascular intervention for the treatment of IC. Finally, in the infrapopliteal segment, invasive intervention for the treatment of IC is of unclear benefit and could be harmful.

Revascularization is indicated when there are limiting symptoms in spite of an exercise program and medical therapy and there is a reasonable likelihood that symptoms can be reduced (including absence of other conditions that might limit functional capacity, such as heart failure or lung disease); it is also indicated for limb salvage in the context of critical limb ischemia. Commonly performed revascularization procedures for peripheral artery disease are shown in Figure 3 and Figure S2 in the Supplementary Appendix. An individualized approach should be adopted to select a revascularization strategy for each patient on the basis of the patient’s preferences, anatomical factors, the availability of appropriate conduits, and operative risk. Supervised exercise may serve as a useful adjunct to revascularization. In a trial involving 212 patients with claudication, those who were randomly assigned to endovascular revascularization and supervised exercise had a longer maximal walking distance at 12 months than did those who were randomly assigned to exercise alone (1237 vs. 955 m).

Aortoiliac angioplasty and stenting (Fig. S1 in the Supplementary Appendix) have high procedural success rates (approximately 96%) and a 3-year patency rate of approximately 82%. Stent placement is generally avoided in the common femoral artery, owing to the risk of biomechanical stress-related stent fractures and the potential for interference with future arterial access. Endovascular intervention in the superficial femoral artery is associated with high rates of restenosis, and several technologies to limit restenosis, including drug-eluting or covered stents and drug-coated balloons, are being evaluated (Figure 3). Endovascular therapy of isolated infrapopliteal disease is not recommended for claudication. Patients should receive dual antiplatelet therapy for at least 30 days or for a longer period if a drug-eluting stent is placed.

Surgical bypass (Fig. S2 in the Supplementary Appendix) should be considered when an endovascular approach has failed or is not feasible from an anatomical standpoint.

Figure 3:
Caption: Major Arteries of the Legs and Endovascular Procedures for Treatment of Peripheral Artery Disease.
Description: Balloon angioplasty, stenting (with balloon-expandable or self-expanding stents), and atherectomy are common endovascular procedures. Drug-eluting or covered stents and drug-coated balloons are being evaluated to reduce the rate of restenosis.

Peripheral artery disease patients who continue smoking have greater rates of adverse lower extremity outcomes. Patients should be helped to quit smoking, including with pharmacotherapy (ie, varenicline, bupropion, or nicotine replacement therapy) and referred to a smoking cessation program (AHA/ACC class I, level of evidence A).

Two medications, pentoxifylline and cilostazol, are Food and Drug Administration approved for treating walking impairment due to symptomatic PAD. Pentoxifylline, a methylxanthine derivative, increases red blood cell deformability (improved rheology), thereby potentially increasing arterial and microcirculatory flow and tissue oxygen concentration. However, a systematic review concluded that benefits of pentoxifylline for intermittent claudication symptoms were uncertain and based on poor-quality trials. The largest trials of pentoxifylline had effects on pain-free and maximal treadmill walking distance ranging from 0% to 14% benefit without improved quality of life or patient perceived walking ability. Clinical practice guidelines recommend against pentoxifylline for PAD due to lack of efficacy (class, no benefit; level of evidence B-R).

Cilostazol promotes vasodilation, particularly in femoral arteries, and has antiplatelet and antithrombotic activities. It is initiated at 50 mg twice daily and increased to 100 mg twice daily if tolerated. In a meta-analysis of 8 trials of 2247 people with PAD and claudication, cilostazol was associated with a 43-m improvement in treadmill walking distance compared with placebo (95% CI, 18.27-67.95). In a meta-analysis of 6 trials of 1533 patients, cilostazol was associated with a 31.4-m improvement in the initial pain-free treadmill walking distance compared with placebo (95% CI, 22.4-40.5). These improvements in treadmill walking were modest compared with benefits of supervised exercise. Up to 30% of patients prescribed cilostazol may experience adverse effects, including headache, diarrhea, abnormal stools, dizziness, and heart palpitations. Cilostazol and several of its metabolites inhibit phosphodiesterase III.

Revascularization for Claudication: Aortoiliac and Femoropopliteal Disease (Excluding Common Femoral Artery Disease)

* 4.

Multiple RCTs have compared endovascular procedures with various combinations of medical treatment with or without supervised or unsupervised exercise programs for patients with aortoiliac and/or femoropopliteal disease and claudication.7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 Although these trials have used different endpoints and enrolled patients with anatomic disease distribution at different levels, overall, these studies have shown the effectiveness of revascularization to improve walking performance and QOL in patients with claudication.8,10,23,30 Combining revascularization with either supervised exercise or pharmacotherapy results in greater improvements in these endpoints than exercise or medical therapy alone.9,10,23,24,56 In a network meta-analysis of 37 trials (15 of which included endovascular therapy) that randomized 2,983 patients over a mean weighted follow-up of 12 months to best medical therapy, SET, endovascular therapy (12 trials), or endovascular therapy plus SET (8 trials), the combination of endovascular therapy plus SET outperformed other treatment modalities with respect to walking performance and QOL.57 Symptom improvement after endovascular treatment for claudication is related to vessel patency, and long-term patency is greater in the aortoiliac than in the femoropopliteal segment.58

More than 70% of patients prefer to have an active role in determining their treatment plan for claudication.46, 47, 48 Such discussions should be undertaken when considering whether to undergo a revascularization procedure, its timing, and approach for revascularization (ie, endovascular or surgical), and should take into account the patient’s goals, treatment preferences, and perception of risk. Patient engagement is also essential to facilitate smoking cessation, medication adherence, and participation in structured exercise.
Endovascular therapy typically involves the displacement or removal of stenotic or occlusive atherosclerotic disease using catheter-based techniques. Endovascular techniques for claudication include PTA (sometimes referred to as “plain-old balloon angioplasty”); drug-coated balloon angioplasty; bare-metal, drug-eluting, and covered stents; lithotripsy; and atherectomy. Endovascular tools are selected based upon lesion characteristics (eg, anatomic location, lesion length, degree of calcification), operator experience, and the range of available technologies. The appropriateness of particular endovascular therapies for the treatment of claudication is beyond the scope of this document but has been addressed in other multisocietal statements.49, 50, 51
Surgical revascularization for claudication most commonly involves the removal of plaque from diseased arteries (endarterectomy) or bypass around narrowed or occluded segments, sometimes performed in combination with endovascular treatments (“hybrid approaches”). Assessment of options for bypass conduit is performed as part of evaluation for surgical revascularization.

Occlusive lesions of the FP segment most commonly present with IC involving the calf. Isolated lesions of the crural or foot arteries usually do not cause claudication, although disease involving both segments may cause severe calf claudication and symptoms can involve the foot. In many patients, unilateral calf claudication is well tolerated and may be managed conservatively, as previously described. For patients with more severe symptoms requiring treatment, a trial of exercise therapy, preferably supervised training or approved pharmacologic treatment (cilostazol), or both, should be undertaken before invasive therapy. If these measures are unsuccessful, invasive therapy may be appropriate after a detailed discussion with the patient. As previously noted, this discussion should cover the natural history of IC, the risks and benefits of open surgery and endovascular interventions, an estimate of long-term patency, likelihood of symptom relief, and the implications of failed therapy.
In the last decade, vascular specialists have readily adopted EVT as an attractive alternative to open bypass surgery for infrainguinal occlusive disease. PTA and stenting are the most commonly used EVTs for focal and intermediate-length stenosis. However, the development of other techniques and technologies, such as subintimal angioplasty, devices for crossing and re-entering long-segment total occlusions, stent grafts, and mechanical and laser atherectomy, have made it possible to successfully treat even advanced disease, leading some vascular specialists to advocate an endovascular-first approach for patients undergoing lower extremity revascularization. In most cases, endovascular procedures are well tolerated with minimal complications, require short hospital stays, and result in rapid recovery.
However, endovascular procedures are less durable than surgical bypass and have a greater need for reintervention, especially in cases of diffuse stenosis or long-segment total occlusion of the superficial femoral or popliteal arteries, or both (Table IV).

The Society for Vascular Surgery appropriate use criteria (AUC) for the management of intermittent claudication were created using the RAND appropriateness method, a validated and standardized method that combines the best available evidence from medical literature with expert opinion, using a modified Delphi process. These criteria serve as a framework on which individualized patient and clinician shared decision-making can grow. These criteria are not absolute. AUC should not be interpreted as a requirement to administer treatments rated as appropriate (benefit outweighs risk). Nor should AUC be interpreted as a prohibition of treatments rated as inappropriate (risk outweighs benefit). Clinical situations will occur in which moderating factors, not included in these AUC, will shift the appropriateness level of a treatment for an individual patient. Proper implementation of AUC requires a description of those moderating patient factors. For scenarios with an indeterminate rating, clinician judgement combined with the best available evidence should determine the treatment strategy. These scenarios require mechanisms to track the treatment decisions and outcomes. AUC should be revisited periodically to ensure that they remain relevant. The panelists rated 2280 unique scenarios for the treatment of intermittent claudication (IC) in the aortoiliac, common femoral, and femoropopliteal segments in the round 2 rating. Of these, only nine (0.4%) showed a disagreement using the interpercentile range adjusted for symmetry formula, indicating an exceptionally high degree of consensus among the panelists. Post hoc, the term "inappropriate" was replaced with the phrase "risk outweighs benefit." The term "appropriate" was also replaced with "benefit outweighs risk." The key principles for the management of IC reflected within these AUC are as follows. First, exercise therapy is the preferred initial management strategy for all patients with IC. Second, for patients who have not completed exercise therapy, invasive therapy might provide net a benefit for selected patients with IC who are nonsmokers, are taking optimal medical therapy, are considered to have a low physiologic and technical risk, and who are experiencing severe lifestyle limitations and/or a short walking distance. Third, considering the long-term durability of the currently available technology, invasive interventions for femoropopliteal disease should be reserved for patients with severe lifestyle limitations and a short walking distance. Fourth, in the common femoral segment, open common femoral endarterectomy will provide greater net benefit than endovascular intervention for the treatment of IC. Finally, in the infrapopliteal segment, invasive intervention for the treatment of IC is of unclear benefit and could be harmful.

Revascularization is indicated when there are limiting symptoms in spite of an exercise program and medical therapy and there is a reasonable likelihood that symptoms can be reduced (including absence of other conditions that might limit functional capacity, such as heart failure or lung disease); it is also indicated for limb salvage in the context of critical limb ischemia. Commonly performed revascularization procedures for peripheral artery disease are shown in Figure 3 and Figure S2 in the Supplementary Appendix. An individualized approach should be adopted to select a revascularization strategy for each patient on the basis of the patient’s preferences, anatomical factors, the availability of appropriate conduits, and operative risk. Supervised exercise may serve as a useful adjunct to revascularization. In a trial involving 212 patients with claudication, those who were randomly assigned to endovascular revascularization and supervised exercise had a longer maximal walking distance at 12 months than did those who were randomly assigned to exercise alone (1237 vs. 955 m).

Aortoiliac angioplasty and stenting (Fig. S1 in the Supplementary Appendix) have high procedural success rates (approximately 96%) and a 3-year patency rate of approximately 82%. Stent placement is generally avoided in the common femoral artery, owing to the risk of biomechanical stress-related stent fractures and the potential for interference with future arterial access. Endovascular intervention in the superficial femoral artery is associated with high rates of restenosis, and several technologies to limit restenosis, including drug-eluting or covered stents and drug-coated balloons, are being evaluated (Figure 3). Endovascular therapy of isolated infrapopliteal disease is not recommended for claudication. Patients should receive dual antiplatelet therapy for at least 30 days or for a longer period if a drug-eluting stent is placed.

Surgical bypass (Fig. S2 in the Supplementary Appendix) should be considered when an endovascular approach has failed or is not feasible from an anatomical standpoint.

Figure 3:
Caption: Major Arteries of the Legs and Endovascular Procedures for Treatment of Peripheral Artery Disease.
Description: Balloon angioplasty, stenting (with balloon-expandable or self-expanding stents), and atherectomy are common endovascular procedures. Drug-eluting or covered stents and drug-coated balloons are being evaluated to reduce the rate of restenosis.

Peripheral artery disease patients who continue smoking have greater rates of adverse lower extremity outcomes. Patients should be helped to quit smoking, including with pharmacotherapy (ie, varenicline, bupropion, or nicotine replacement therapy) and referred to a smoking cessation program (AHA/ACC class I, level of evidence A).

Two medications, pentoxifylline and cilostazol, are Food and Drug Administration approved for treating walking impairment due to symptomatic PAD. Pentoxifylline, a methylxanthine derivative, increases red blood cell deformability (improved rheology), thereby potentially increasing arterial and microcirculatory flow and tissue oxygen concentration. However, a systematic review concluded that benefits of pentoxifylline for intermittent claudication symptoms were uncertain and based on poor-quality trials. The largest trials of pentoxifylline had effects on pain-free and maximal treadmill walking distance ranging from 0% to 14% benefit without improved quality of life or patient perceived walking ability. Clinical practice guidelines recommend against pentoxifylline for PAD due to lack of efficacy (class, no benefit; level of evidence B-R).

Cilostazol promotes vasodilation, particularly in femoral arteries, and has antiplatelet and antithrombotic activities. It is initiated at 50 mg twice daily and increased to 100 mg twice daily if tolerated. In a meta-analysis of 8 trials of 2247 people with PAD and claudication, cilostazol was associated with a 43-m improvement in treadmill walking distance compared with placebo (95% CI, 18.27-67.95). In a meta-analysis of 6 trials of 1533 patients, cilostazol was associated with a 31.4-m improvement in the initial pain-free treadmill walking distance compared with placebo (95% CI, 22.4-40.5). These improvements in treadmill walking were modest compared with benefits of supervised exercise. Up to 30% of patients prescribed cilostazol may experience adverse effects, including headache, diarrhea, abnormal stools, dizziness, and heart palpitations. Cilostazol and several of its metabolites inhibit phosphodiesterase III.