INTRODUCTION — Claudication (derived from the Latin word for limp) is defined as a reproducible discomfort of a defined group of muscles that is induced by exercise and relieved with rest. The symptoms result from an imbalance between the supply and demand for blood flow due to peripheral artery disease (PAD). (See "Clinical features and diagnosis of lower extremity peripheral artery disease".)
The management of the patient with claudication due to PAD, including medical therapy and indications for intervention, will be reviewed here. The management of limb-threatening ischemia (rest pain, ulcers, gangrene) and techniques for reconstruction and their outcomes are discussed elsewhere. (See "Management of chronic limb-threatening ischemia" and "Endovascular techniques for lower extremity revascularization" and "Lower extremity surgical bypass techniques".)
The management of exertional leg pain from arterial obstruction due to other diseases (eg, aneurysm thrombosis, embolism), arterial compression (eg, popliteal entrapment syndrome), or musculoskeletal disorders (eg, lumbar spine stenosis, adductor bursitis, spine or hip osteoarthritis) differs from PAD and is discussed elsewhere. (See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Differential diagnosis of PAD'.)
OVERVIEW — Once a patient is diagnosed with claudication due to peripheral artery disease (PAD), a rational approach to treatment takes into account the patient's age and medical comorbidities, daily activities and limitations, severity of symptoms, and location and extent of disease.
Patients with claudication are classified as having mild, moderate, or severe disease in the Rutherford system, or based on walking distance in the Fontaine system. With stage 2a claudication the patient can walk a distance of greater than 650 feet (200 meters); with stage 2b claudication the patient can walk less than 650 feet (200 meters). (See "Classification of acute and chronic lower extremity ischemia", section on 'Rutherford' and "Classification of acute and chronic lower extremity ischemia", section on 'Fontaine'.)
Initial therapy — Most patients with a diagnosis of claudication should be treated initially with a medical therapy regimen because PAD reflects a systemic disease of atherosclerosis and must include risk factor modification and exercise therapy (ideally supervised exercise therapy) and pharmacologic therapy (algorithm 1), rather than vascular intervention or surgery, given the potential for complications related to revascularization, which can include amputation [1]. Periodic reevaluation of symptoms will determine the effectiveness of these therapies. A selected subset of patients may be appropriate for initial intervention. (See 'Medical management' below and 'Exercise therapy' below and 'Ongoing evaluation and follow-up' below and 'Referral for possible intervention' below.)
Although PAD and its severity is an important marker for cardiovascular risk, symptoms of claudication are associated with a low risk of progression to limb-threatening lower extremity ischemia. Natural history studies show that most patients with claudication remain stable, particularly if they stop smoking. The following limb outcomes at five years demonstrate the low risk of progression for patients with lower extremity claudication [2,3] (see "Epidemiology, risk factors, and natural history of lower extremity peripheral artery disease", section on 'Natural history and progression of PAD'):
●Stable claudication: 70 to 80 percent
●Worsening claudication: 10 to 20 percent
●Progression to critical limb ischemia: 1 to 2 percent
There is less improvement in walking capacity with current pharmacologic therapies compared with exercise training. Continued smoking restricts improvements in pain-free walking symptoms that might otherwise be seen with an exercise program [4], and with continued smoking, patients are also less likely to benefit from the pharmacologic agents discussed below. (See 'Pharmacologic therapy to improve walking' below.)
Functional improvements with a medical therapy regimen that includes exercise therapy tend to be more durable than percutaneous intervention as an initial treatment strategy [5-7].
Systematic reviews identified trials performed between 1996 and 2015 (including the CLEVER and ERASE trials [8-10]) comparing treatment strategies (supervised exercise therapy, intervention [angioplasty/stenting], medical therapy, or combinations) in patients with stable claudication [11,12]. A combination of percutaneous transluminal angioplasty (PTA) and exercise (supervised exercise therapy or exercise advice) may produce the greatest changes in walking distance compared with exercise alone or PTA alone. A handful of trials have also found significant quality-of-life improvements for those undergoing intervention [8-10,13-16].
●Among trials comparing supervised exercise therapy alone with intervention alone (five in each meta-analysis), there were no differences in exercise capacity (maximum walking distance, pain-free walking distance) or differences in future revascularization or amputation [5-9,17-24].
●Among trials comparing intervention with no specific treatment (except advice to exercise) maximum walking distance and pain-free walking distances were improved for the intervention group [11]. However, long-term follow-up in two studies did not show any differences [18,19,25-28].
●Among trials that compared supervised exercise therapy alone with patients who underwent supervised exercise therapy combined with endovascular therapy, there were no clear differences between groups for maximum walking distance (standard mean difference [SMD] 0.26, 95% CI -0.13 to 0.64) or pain-free walking distance (SMD 0.33, 95% CI -0.26 to 0.93) [7,10,21-23,29]. In one of the trials that had longer follow-up, PTA, supervised exercise, or combined treatment were compared in 178 patients with claudication related to femoropopliteal disease [7]. With long-term follow-up (mean 5.2 years, range 3.8 to 7.4 years), those who had angioplasty (with or without exercise) had a significantly higher ankle-brachial index (ABI), but no significant differences were observed between the groups for treadmill walking distances, restenosis rates, new ipsilateral and contralateral lesions on duplex imaging, or quality-of-life outcomes [21].
●Two studies comparing intervention plus pharmacotherapy (cilostazol) compared with pharmacotherapy alone provided data showing a small effect on maximum walking distance (SMD 0.38, 95% CI 0.08-0.68) and a moderate effect on pain-free walking distance (SMD 0.63, 95% CI 0.33-0.94) in favor of combination therapy [16].
A separate trial that included a cost analysis found no significant differences in functional outcomes between supervised exercise therapy, PTA, or a combination of supervised exercise therapy and PTA [22]. However, supervised exercise was the more cost-effective first-line treatment for claudication.
Criteria for intervention — Multidisciplinary guidelines suggest that the following criteria need to be satisfied when considering intervention (percutaneous or surgical) in patients with claudication [2,3,30-35]:
●The patient is significantly disabled by claudication, resulting in an inability to perform normal work or other activities that are important to the patient. This criterion reflects the symptom variability among patients with claudication and of the impact of these symptoms on the quality of life. In addition, there may be substantial differences between patient and physician assessments of the quality of life.
●The patient has not had or is not predicted to have an adequate response to exercise rehabilitation and pharmacologic therapy.
●The characteristics of the lesion permit appropriate intervention at low risk with a high likelihood of initial and long-term success.
●The projected natural history and prognosis of the patient should be taken into account.
●The patient is able to benefit from an improvement in claudication (ie, exercise is not limited by another cause, such as angina, heart failure, chronic obstructive pulmonary disease, or orthopedic problems).
A major concern with intervention in patients with claudication is that some patients may suffer complications that worsen their symptoms. In-stent restenosis, stent fracture, vessel or graft thrombosis, infection, and embolization are complications of percutaneous or surgical intervention that have been associated with the risk of developing limb-threatening ischemia.
MEDICAL MANAGEMENT
Cardiovascular risk modification — Risk factors for atherosclerosis and risk factor reduction are discussed separately. (See "Epidemiology, risk factors, and natural history of lower extremity peripheral artery disease" and "Overview of established risk factors for cardiovascular disease".)
Smoking cessation — We agree with the guideline recommendations regarding smoking cessation [2,3,31,33-36] (see "Overview of smoking cessation management in adults"):
●All patients should be strongly advised to stop smoking by their physicians.
●All patients should be offered pharmacotherapy, behavior modification, referral to a smoking cessation program, and counseling.
●All patients who are smokers or former smokers should be asked about the status of tobacco use at every visit.
It is not clear whether cessation of cigarette smoking reduces the severity of claudication symptoms. In one study that looked at pain-free and total walking distance outcomes, smoking cessation led to a nonsignificant increase in total walking distance [37]. However, smoking cessation does appear to favorably alter the progression of PAD [38-40]. As an example, a review of 343 patients with claudication compared the clinical outcomes among those who quit smoking (39 patients) with those who continued to smoke (304 patients) [40]. Rest pain, a sign of limb-threatening ischemia, did not occur in patients who stopped smoking but developed in 16 percent of patients who continued to smoke.
Exercise therapy — We recommend an exercise therapy program as part of the initial treatment regimen for patients with claudication based upon randomized trials demonstrating significant improvements in walking parameters for those who participate (algorithm 1) [41,42]. Patients should be referred to a claudication exercise rehabilitation program, if possible, depending upon insurance coverage or personal resources. Home and community-based therapy are also effective for improving walking tolerance but are less effective than supervised exercise and are associated with a high dropout rate, underscoring the need for ongoing psychological support [43-50].
There are several mechanisms by which exercise training may improve claudication, although the available data are insufficient to make conclusions regarding the relative importance of each [51-58]:
●Increased calf blood flow
●Improved endothelial function increases endothelial-dependent dilation
●Reduced local inflammation (induced by muscle ischemia) by decreasing free radicals
●Improvements in muscle architecture
●Improvements in muscle mitochondrial capacity
●Improved muscular strength and endurance, and increased exercise pain tolerance
●Induction of vascular angiogenesis
●Improved mitochondrial and muscle function and muscle metabolism
●Reduced red cell aggregation and blood viscosity
Many studies have evaluated the effects of an exercise rehabilitation program for reducing the symptoms of claudication. A systematic review and meta-analysis (Cochrane) identified 27 trials that compared exercise with usual care or placebo [59]. In a meta-analysis of nine of the trials (391 participants), exercise significantly improved pain-free walking distance (mean difference [MD] 82.1 meters [269 feet]; 95% CI 71.7-92.5) and maximum walking distance (MD 120.4 meters [395 feet]; 95% CI 50.8-189.9). Exercise did not improve the ankle-brachial index. In a Bayesian network meta-analysis comparing the change in physical activity between baseline and follow-up treatments, supervised exercise therapy improved daily physical activity levels in patients with intermittent claudication [60]. Home-based exercise therapy appeared to have a similar benefit, while invasive treatment failed to significantly improve physical activity compared with control.
Although not well studied, exercise ability may be related to survival in PAD patients. In one meta-analysis, a shorter maximum walking distance was associated with increased five-year cardiovascular and all-cause mortality [61,62]. However, in the Cochrane review above [59], a meta-analysis of five trials found no effect for exercise on mortality, when compared with placebo or usual care (relative risk [RR] 0.92, 95% CI 0.39-2.17).
A systematic review identified favorable effects for supervised exercise therapy on modifiable cardiovascular risk factors in patients with intermittent claudication [63]. In the short term, systolic and diastolic blood pressure were improved, but no effect was seen in midterm studies; however, supervised exercise therapy contributed to lowering low-density lipoprotein cholesterol and total cholesterol levels. No effect for supervised exercise therapy was identified for heart rate, triglycerides, high-density lipoprotein cholesterol, glucose, glycated hemoglobin, body weight, body mass index, or cigarette smoking.
Types and prescription — Patients with peripheral vascular disease have impaired muscle strength and walking ability, resulting in progressive functional impairment and poorer quality of life. Leg strength is linearly correlated with lower extremity ankle-brachial index and with functional performance in patients with peripheral artery disease [64].
Treadmill exercise — Despite the evidence of benefit, issues remain concerning the optimal regimen for exercise rehabilitation [65,66]. In general, exercise should be performed for a minimum of 45 to 60 minutes at least three times per week for a minimum of 12 weeks. During each session, an exercise level that is of sufficient intensity to elicit claudication should be achieved. Guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) recommend initiation of exercise at an intensity that induces onset of claudication within 3 to 5 minutes and moderate to moderately severe claudication within 8 to 10 minutes [67,68]. (See 'High-intensity versus low-intensity exercise' below.)
Supervised exercise programs generally consist of a series of sessions lasting 45 to 60 minutes per session, using a treadmill. Including warm-up and cool-down periods of 5 to 10 minutes each, the initial session usually includes 35 minutes of intermittent walking. Walking is then increased by five minutes each session until 50 minutes of intermittent walking can be accomplished. Ideally, the patient attends at least three sessions per week, with a program length greater than three months [3]. Each session is supervised on a one-to-one basis by an exercise physiologist, physical therapist, or nurse. The supervisor monitors the patient's claudication threshold and other cardiovascular parameters. During supervised exercise, the development of new arrhythmias, symptoms that might suggest angina, or the continued inability of the patient to progress to an adequate level of exercise require physician review and examination of the patient. Most patients who eventually respond to a supervised exercise protocol can expect improvement within two months, but the benefits of exercise diminish if exercise training stops.
Alternative modes of exercise — Although most trials have used lower extremity exercise (eg, treadmill or walking), other forms of exercise have been investigated for improving walking performance in patients with PAD [69-78]. These include upper-arm ergometry [75,79-81], cycling [69], and resistance/strength training [76-78,82-86]. For patients with claudication who cannot participate in a walking program, we suggest using an alternative strategy for exercise therapy, which can be beneficial for improving walking ability and functional status.
A systematic review and meta-analysis included ten trials comparing supervised exercise therapy with alternative modes of exercise training (eg, cycling, upper extremity exercise) or combinations of modes in patients with claudication [87]. Among the included trials, there were no significant differences for maximum walking distance or pain-free walking distance.
Among the alternative modalities, lower extremity resistance training may be the most promising. Resistance training using loads approaching 90 percent of one-repetition maximum (RM) induces vasodilation and reactive hyperemia and improves several clinical parameters (eg, maximal strength, VO2 max) without evidence of adverse effects such as worsening pain [76-78,82-86]. In an early trial that included 29 patients with disabling claudication, 12 weeks of strength training were less effective compared with 12 weeks for supervised treadmill exercise [78]. A later trial randomly assigned 156 patients with PAD (with and without claudication) to a six-month program of either supervised treadmill exercise or lower extremity resistance training, or to a control group [76]. Lower extremity resistance training intervention did not improve six-minute walking distance in PAD participants, but it did improve maximal treadmill walking time and quality-of-life measures, particularly stair climbing ability. This mode of exercise may be useful for those who are unable to participate in a walking program. Suggestions for muscle strengthening in older adults are reviewed separately. (See "Physical activity and exercise in older adults", section on 'Muscle strengthening'.)
High-intensity versus low-intensity exercise — The optimal intensity of exercise is uncertain. Walking exercise that induces ischemic leg symptoms has been referred to as high-intensity walking exercise compared with low-intensity walking exercise, which does not induce ischemic symptoms.
While high-intensity walking exercise is recommended [30,67,68], many, but not all, studies have suggested that exercise treadmill training should be performed to near-maximal claudication levels [88,89]. However, few trials have directly compared the relative benefits or harms of walking to different levels of claudication. In an early meta-analysis, use of near-maximal pain during training as a claudication pain endpoint was an independent predictor of improvement in walking distance [90]. A later meta-analysis reported similar outcomes for participants who walked to a mild claudication level compared with those who walked to a severe level of claudication [88]. A small trial comparing high- versus low-intensity exercise also reported similar outcomes [91]. However, a later larger trial, the Low-Intensity Exercise Intervention in PAD (LITE) trial, reported a benefit for high-intensity exercise. In the LITE trial, 305 patients with claudication were randomly assigned to unsupervised, remotely monitored walking exercise that was either low-intensity or high-intensity, or to a non-exercise control for 12 months [92]. The patients using high-intensity exercise benefited the most. The within-group mean change in six-minute walking distance at 12 months was significantly increased for the high-intensity compared with low-intensity group (34.5 versus -6.4 meters). The mean group change was similar for the low-intensity group and the nonexercise group. Adverse events rates were low and similar between the groups. Based on these trials, we recommend an exercise program in which the patient is counseled to walk to the point that claudication symptoms occur, then to rest; when the pain is relieved, to walk again, repeating this cycle for 45 to 60 minutes. We support guidelines from the ACC/AHA guidelines that recommend that supervised exercise protocols should be initiated at an intensity that induces onset of claudication within 3 to 5 minutes and moderate to moderately severe claudication within 8 to 10 minutes.
Supervised versus unsupervised exercise — Although we suggest supervised exercise therapy where available, unsupervised exercise (particularly a structured program) may be the only option when access to supervised programs is limited by transportation, availability, insurance coverage, or other cost-related issues [8,93-97]. The relative effectiveness of supervised versus unsupervised exercise has been evaluated in systematic reviews [43,89,94,98-100]. Walking is the dominant form of exercise training for each group. Supervised exercise therapy showed a greater improvement in maximal treadmill walking distance compared with unsupervised exercise therapy; however, there were no significant effects on the measured quality-of-life parameters between the study groups.
Active feedback has also been incorporated into supervised training regimens [4,101]. A multicenter trial in a community setting with physical therapists staffing outpatient vascular surgery clinics randomly assigned 304 patients to supervised exercise training with accelerometer feedback, supervised training without feedback, or unsupervised walking at home following instruction [101]. Supervised exercise training significantly improved walking distance (360 meters with feedback, 310 meters without feedback) compared with unsupervised walking at home (110 meters) (figure 1). In this study, improvements in quality-of-life measures corresponded to improvements in walking distance. In a trial that compared home-based exercise intervention using a wearable activity monitor and coaching over the phone, there were no significant improvements in walking distance [102].
CMS coverage — The Centers for Medicare & Medicaid Services (CMS) in the United States has determined that the evidence is sufficient to cover supervised exercise therapy for beneficiaries with intermittent claudication (IC) for the treatment of symptomatic PAD. The summary for this decision is as follows [103].
Up to 36 sessions over a 12-week period are covered if all of the following components of a supervised exercise therapy program are met. The supervised exercise therapy program must:
●Consist of sessions lasting 30 to 60 minutes comprising a therapeutic exercise-training program for PAD in patients with claudication;
●Be conducted in a hospital outpatient setting or a physician's office;
●Be delivered by qualified auxiliary personnel necessary to ensure benefits exceed harms, and who are trained in exercise therapy for PAD; and
●Be under the direct supervision of a physician, physician assistant, or nurse practitioner/clinical nurse specialist who must be trained in both basic and advanced life support techniques.
Beneficiaries must have a face-to-face visit with the physician responsible for PAD treatment to obtain the referral for supervised exercise therapy. At this visit, the beneficiary must receive information regarding cardiovascular disease and PAD risk factor reduction, which could include education, counseling, behavioral interventions, and outcome assessments.
Medicare Administrative Contractors have the discretion to cover supervised exercise therapy beyond 36 sessions over 12 weeks and may cover an additional 36 sessions over an extended period of time. A second referral is required for these additional sessions. There is a zero-value professional relative value unit (RVU) component associated with this new code and a minimal facility RVU component. The presence of the code does not mean it will be reimbursed or covered by federal, state, and nongovernmental payers.
Supervised exercise therapy is non-covered for beneficiaries with absolute contraindications to exercise as determined by their primary physician.
Pharmacologic therapy to improve walking — Specific pharmacologic therapy of claudication is aimed at improving symptoms and increasing walking distance in patients with lifestyle-limiting claudication, particularly if risk modification and exercise therapy have not been effective and revascularization cannot be offered or is declined by the patient [3,30,34,35,104,105]. For patients with lifestyle-limiting claudication, we suggest a therapeutic trial (three to six months) of either cilostazol or naftidrofuryl depending upon availability (algorithm 1). Naftidrofuryl has fewer side effects than cilostazol and, where available, can be tried first. If the effect is not sufficient, then changing to cilostazol is warranted. Naftidrofuryl is not available in the United States, and cilostazol may have limited availability outside the United States.
A number of other pharmacologic agents have been evaluated, but firm evidence of decreased pain with ambulation or increased walking distance (total or pain-free) is available for only cilostazol and naftidrofuryl. Statin therapy may also improve walking parameters. Other pharmacologic therapies aimed at reducing progression and complications associated with atherosclerotic disease are also discussed above. (See 'Cardiovascular risk modification' above.)
For other agents, a benefit has not been firmly established. It is important to note that pharmacologic therapy is less beneficial for those who do not quit smoking and do not participate in an exercise therapy program. (See 'Smoking cessation' above and 'Exercise therapy' above.)
Beneficial
Cilostazol — Cilostazol is a phosphodiesterase inhibitor that suppresses platelet aggregation and is a direct arterial vasodilator, but its mechanism of action for improving walking distance in patients with claudication is not known [106]. Benefits to therapy are noted as early as four weeks after the initiation of therapy [107,108]. Cilostazol (100 mg twice daily) should be taken a half hour before or two hours after eating, because high-fat meals markedly increase absorption. Several drugs such as diltiazem and omeprazole, as well as grapefruit juice, can increase serum concentrations of cilostazol if taken concurrently [109]. Cilostazol may be taken safely with aspirin and/or clopidogrel without an additional increase in bleeding time [110]. Side effects for cilostazol noted in clinical studies included headache, loose and soft stools, diarrhea, dizziness, and palpitations [107,111-113]. Nonsustained ventricular tachycardia has been reported. Because other oral phosphodiesterase inhibitors used for inotropic therapy have caused increased mortality in patients with advanced heart failure, cilostazol is contraindicated in heart failure of any severity [109]. (See "Inotropic agents in heart failure with reduced ejection fraction", section on 'Intravenous phosphodiesterase-3 inhibitors'.)
The efficacy of cilostazol has been demonstrated in several meta-analyses [114-117]. In one of these, 2702 patients with stable moderate-to-severe claudication who received cilostazol (100 mg cilostazol twice daily for 12 to 24 weeks) were compared with placebo [114]. Significantly greater increases in maximal walking distances (MWDs) and pain-free walking distances (PFWDs) were seen in patients treated with cilostazol (MWD: 67 versus 50 percent increase from baseline, PFWD: 40 versus 22 percent). In a later systematic review that compared cilostazol with naftidrofuryl and pentoxifylline, cilostazol appeared to be slightly less effective than naftidrofuryl but more effective than pentoxifylline [116].
Naftidrofuryl — Naftidrofuryl (600 mg daily orally), which is currently available in Europe, can be used for treatment of claudication [35]. Naftidrofuryl has fewer side effects than cilostazol and, where available, can be tried first. If the effect is not sufficient, then changing to cilostazol is warranted.
Naftidrofuryl is a 5-hydroxytryptamine-2-receptor antagonist [118-120]. The mechanisms of action of this drug are unclear, but it is thought to promote glucose uptake and increase adenosine triphosphate levels. Systematic reviews have consistently identified significant and clinically meaningful improvements in walking distance after initiation of naftidrofuryl therapy [37,116,121]. The later of these performed a network meta-analysis and found that the percentage change from baseline for mean walking distance increased 60 percent compared with placebo, and pain-free walking distance increased 49 percent compared with placebo, differences that were greater for naftidrofuryl compared with cilostazol or pentoxifylline [116].
Benefit not firmly established
Medical therapies — Medical therapies with benefits that have not been firmly established for improving claudication symptoms include statin therapy, antiplatelet agents, and pentoxifylline. Nevertheless, statin therapy and antiplatelet therapy are recommended to reduce the risk for future cardiovascular events. (See 'Cardiovascular risk modification' above.)
●Statin therapy – A number of trials in patients with hyperlipidemia and coronary heart disease or PAD have evaluated the effects of lipid-lowering trials on the natural history of PAD [122-125]. Initial studies, performed before the availability of statins, showed regression or less progression of femoral atherosclerosis with lipid-lowering therapy [126-130], and a lower incidence of claudication and limb-threatening ischemia in patients with hyperlipidemia who were treated with surgery [131]. A 2007 Cochrane meta-analysis that specifically evaluated patients with lower extremity PAD concluded that lipid-lowering therapy reduced disease progression (as measured by arteriography) and may help alleviate symptoms and improve total walking distance and pain-free walking distance [122]. There was no effect on ankle-brachial index.
●Antiplatelet agents – The preponderance of data on currently available antiplatelet agents indicate only a modest improvement or no improvement in claudication symptoms can be expected and that a significant benefit may not be seen with aspirin alone. These agents are also associated with negative side effects that limit their usefulness, especially compared with the therapies discussed above (cilostazol and naftidrofuryl). Thus, the main indication for antiplatelet therapy remains the secondary prevention of coronary heart disease and stroke. (See 'Beneficial' above.)
Among three trials identified in a systematic review evaluating walking distance [132-134], antiplatelet therapy significantly improved pain-free walking distance compared with placebo (mean difference 78 feet) [135]. In five trials, the risk of revascularization was also reduced by antiplatelet treatment compared with placebo (RR 0.65, 95% CI 0.43-0.97) [136-140]. These trials used ticlopidine, picotamide, or indobufen. These agents are not available in the United States but may be available internationally. Ticlopidine is associated with a substantially increased risk of leukopenia and thrombocytopenia, requiring close hematologic monitoring for at least three months. Other potential side effects of antiplatelet therapy include bleeding, dyspepsia, diarrhea, nausea, anorexia, rash, purpura, and dizziness.
●Pentoxifylline – The available data indicate that the benefit of pentoxifylline is marginal, particularly in light of more effective therapies such as cilostazol and naftidrofuryl, which are discussed above [116]. (See 'Beneficial' above.)
Pentoxifylline is a rheologic modifier approved for use in the United States for the symptomatic relief of claudication. Its putative mechanisms of action include increased deformability of red blood cells and blood viscosity, decreases in fibrinogen concentration, and reduced platelet adhesiveness. Studies investigating the efficacy of pentoxifylline have yielded conflicting results [141-146], leading to variable recommendations for its use by various society guidelines [3,34,35,105]. One meta-analysis found that pentoxifylline improved walking distance by 29 meters compared with placebo [145]. In a later systematic review, the percentage improvement in total walking distance for pentoxifylline over placebo ranged from 1.2 to 156 percent, and for pain-free walking distance the difference ranged from -34 to 74 percent [146]. Improvements in walking distances associated with pentoxifylline are generally substantially less than those achieved with a supervised exercise program [147] or cilostazol [148].
Compression therapy — Intermittent mechanical (non-pneumatic) calf compression has been used to treat claudication. In a trial that randomly assigned 30 patients with stable claudication to active intermittent compression claudication distance or medical therapy alone, absolute claudication distance (42 percent) and postexercise (but not resting) ankle-brachial index percent at one month were significantly increased [149]. Treatment effects were maintained or further improved after cessation of therapy at three months; postexercise ankle-brachial index was maintained.
Ineffective — Therapies with no proven clinical benefit for improving symptoms of claudication and that thus are not recommended [3,105] include anticoagulants (eg, warfarin, low-molecular-weight heparin) [150], hormone replacement therapy [151-153], Ginkgo biloba [3,33,154,155], Padma 28 [3,30,33,156], garlic [157], and vitamin E supplementation [3,158]. Chelation therapy also does not improve claudication distance in PAD [3,159].
Intermittent vacuum therapy alternately applies negative pressure and atmospheric pressure to the lower extremities. In a Dutch study, 78 patients undergoing supervised exercise therapy were randomly assigned to an intervention group receiving intermittent vacuum therapy treatment (-50 mBar negative pressure) or a control group receiving a sham treatment (-5 mBar negative pressure) over 12 sessions of 30 minutes during a six-week period [160]. Walking distance was similar between the groups, and both groups had a similar improvement in quality of life at 6 and 12 weeks follow-up. Thus, intermittent vacuum therapy did not confer any additional beneficial effects in patients with intermittent claudication undergoing a standardized supervised exercise therapy program.
Investigational — Pharmacologic therapies under investigation for the treatment of symptoms of peripheral artery disease are reviewed separately. (See "Investigational therapies for treating symptoms of lower extremity peripheral artery disease".)
ONGOING EVALUATION AND FOLLOW-UP — After initial counseling, follow-up should be scheduled at three months to assess risk reduction strategies and the effectiveness of exercise therapy and medical therapies for reducing symptoms (algorithm 1) [30].
Patients who show improvement and who are satisfied with their progress can be scheduled for annual vascular examination, which should include ankle-brachial index testing. In the interim, repeat noninvasive vascular studies are not needed unless there is a significant change in symptoms [161].
Referral for possible intervention — If the patient has been compliant with risk reduction strategies, yet six months to one year of exercise therapy and adjunctive pharmacotherapy have failed to provide satisfactory improvement, referral for possible intervention can be suggested (algorithm 1). (See 'Criteria for intervention' above and "Approach to revascularization for claudication due to peripheral artery disease", section on 'Clinical criteria for revascularization'.)
Noncompliance, particularly continued smoking, remains a significant issue in treating patients with peripheral artery disease (PAD) [162]. Those who continue to smoke should be counseled again of the increased risk for PAD progression [40]. Most vascular practitioners are generally reluctant to suggest intervention (open or percutaneous) in patients with claudication who continue to smoke because of overall worse outcomes.
Vascular imaging — Vascular imaging is used to define vascular anatomy prior to intervention. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Duplex ultrasound'.)
INTERVENTIONS FOR CLAUDICATION — For patients who are significantly disabled by claudication, intervention may be an option (algorithm 1), provided the patient meets the above criteria. (See 'Criteria for intervention' above and "Approach to revascularization for claudication due to peripheral artery disease", section on 'Clinical criteria for revascularization'.)
Options include percutaneous intervention, surgical bypass, or a combination of these.
●Percutaneous intervention involves accessing typically the femoral artery with an arterial sheath and passing various wires or catheters to guide the placement of an expandable balloon and/or stent, or other devices. Balloon angioplasty results in a "controlled" dissection of the arterial media, widening the lumen of the stenosed vessel. Adjunctive stenting may be needed if the vessel does not remain patent or the dissection progresses. (See "Endovascular techniques for lower extremity revascularization".)
●Surgical revascularization involves identifying an appropriate vessel above and another below the arterial obstruction onto which to suture a graft to bypass the obstruction. The graft can be autogenous vein or prosthetic material. (See "Lower extremity surgical bypass techniques".)
Options for revascularization depend upon the level of obstruction.
●Aortoiliac disease – Aortoiliac disease is also called inflow disease. Claudication resulting from disease in this location often tends to be more disabling (buttock or thigh claudication), and the threshold to intervene when treating claudication for inflow disease is generally lower than for more distal disease (algorithm 1). Options for treating aortoiliac disease include iliac artery angioplasty and stenting, aortoiliac bypass, and aortofemoral bypass, among others. (See "Endovascular techniques for lower extremity revascularization", section on 'Aortoiliac'.)
●Femoropopliteal disease – Disease below the inguinal ligament is also called outflow disease. Calf claudication is usually due to a lesion in the superficial femoral or popliteal artery and can be treated using balloon angioplasty/stenting of the femoral or superficial femoral artery, or surgical bypass such as femoral to above-knee popliteal bypass or femoral to below-knee bypass. Rarely, a more distal bypass may be needed to treat symptoms of claudication, but more typically, symptoms more severe than claudication (rest pain, ischemic ulcers) result from multiple lesions and disease of the tibial vessels. (See "Endovascular techniques for lower extremity revascularization", section on 'Femoropopliteal' and "Lower extremity surgical bypass techniques".)
Choice of initial intervention — Determining whether percutaneous or surgical revascularization is the more appropriate initial intervention for patients with claudication depends upon the location and extent of disease, and the patient's risk for the intervention (algorithm 1). (See "Endovascular techniques for lower extremity revascularization" and "Approach to revascularization for claudication due to peripheral artery disease".)
Given the widespread availability of percutaneous procedures, guidelines have recommended initial percutaneous revascularization, reserving surgery for when arterial anatomy is not favorable for a percutaneous approach, provided the patient has an acceptable risk for surgery [34,35,68,163]. Lesions that display unfavorable anatomy for a percutaneous approach have one or more of the following features:
●Long-segment stenosis
●Multifocal stenoses
●Eccentric, calcified stenosis
●Long segment occlusions
These features reflect more extensive disease and are typically associated with more severe symptoms. The Inter-Society Consensus for the Management of Peripheral Artery Diseases (TASC II) presented a scheme that classified iliac, femoral, and popliteal lesions as type A, B, C, or D, which was based upon overall success rates for treating a lesion using endovascular or surgical means at the time the classification was created [35]. Short segment disease (type A) was more likely to be successfully treated with an endovascular intervention compared with long segment occlusion (type D). The details of the TASC classification are reviewed in detail elsewhere. (See "Classification of acute and chronic lower extremity ischemia", section on 'TASC classification'.)
The TASC II general guidelines are given below [34,35]. The location of the lesion, along with the patient's comorbidities, fully informed patient preference, and the operator's long-term success rates, must be considered when making treatment recommendations. Endovascular intervention for aortoiliac ("inflow") lesions tends to have better long-term outcomes compared with interventions for infrainguinal ("outflow") lesions.
●Endovascular therapy is the treatment of choice for TASC type A lesions.
●Endovascular treatment is preferred over surgical treatment for TASC type B lesions. Patients with Type B lesions who fail endovascular management may also benefit from surgery.
●Patients with type C lesions who are not good-risk candidates for surgery may also benefit from percutaneous intervention, but for good-risk candidates, surgery is preferred. However, the choice depends on lesion location (see above regarding inflow versus outflow lesions).
●Surgery is the treatment of choice for Type D lesions. However, the choice depends on lesion location (see above regarding inflow versus outflow lesions).
With advancements in balloons, stents, and delivery systems, percutaneous intervention can be offered to poor surgical candidates with more extensive PAD. Compared with lower extremity bypass, endovascular interventions are associated with fewer periprocedural complications but higher rates of restenosis, which can usually be managed with repeat intervention [164]. In one retrospective review, risk factors for restenosis in femoropopliteal lesions included diabetes, no stent use, chronic total occlusion, and poor below-the-knee runoff [165]. For the patient who remains disabled following initial attempts at percutaneous revascularization, surgical bypass may be an option, but, in general, surgery should be reserved for low-risk patients with disabling symptoms who can be expected to tolerate the procedure and live long enough to enjoy the improved quality of life. The same criteria are used in patients with diabetes, even though they are at higher risk for a worse outcome. Patients who benefit most from elective surgical revascularization are generally under 70 years of age, are nondiabetic, and have little evidence of disease distal to the primary lesion [166].
This general approach may differ in very young patients (<40 years of age) with claudication. Symptoms in this group of patients are typically due to a more aggressive atherosclerotic disease process than that experienced by the majority of older patients with claudication. The aggressive nature of atherosclerosis in young individuals was demonstrated in a retrospective series of 29 vascular reconstructions in patients under the age of 40, 76 percent of which were for intermittent claudication [167]. The following results were noted:
●Average mortality rate at 10 years following initial surgery was 31 percent
●Initial vascular reconstructions failed in 72 percent, with an amputation rate of 17 percent
●At the end of the follow-up period, only 25 percent of surviving patients were asymptomatic
These results suggest that one should be cautious before considering revascularization (endovascular, surgical) for patients in this group.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Occlusive carotid, aortic, mesenteric, and peripheral atherosclerotic disease".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Peripheral artery disease and claudication (The Basics)")
●Beyond the Basics topics (see "Patient education: Peripheral artery disease and claudication (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●The management of patients with claudication due to atherosclerotic disease is aimed at lowering the risk of cardiovascular disease progression and complications and improving claudication symptoms. Medical management involves risk factor modification, exercise, and possibly pharmacologic therapy to improve walking distance. Vascular intervention may be indicated for some patients with debilitating claudication. (See 'Introduction' above and 'Overview' above.)
●Claudication is associated with an increased risk of coronary, cerebrovascular, and renovascular disease, and peripheral artery disease (PAD) is considered to be a coronary heart disease risk equivalent. To reduce the risk for cardiovascular disease progression and complications, we recommend a secondary prevention strategy that includes antiplatelet therapy (aspirin 75 to 162 mg/day or clopidogrel 75 mg/day), smoking cessation, control of blood sugar and blood pressure, lipid-lowering therapy, and dietary modification (as needed) to achieve the goals set in national guidelines. (See 'Cardiovascular risk modification' above and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Overview of vascular intervention and surgery for vascular anomalies".)
●For most patients with claudication, we recommend an initial medical treatment regimen that includes risk reduction, exercise therapy (for those who can participate), and possibly pharmacologic therapy, rather than initial vascular intervention (Grade 1B). Symptoms of claudication are associated with a low risk of progression to limb-threatening lower extremity ischemia, and a major concern with intervention is that some patients may suffer complications that worsen their symptoms. A subset of patients with severe claudication and inflow disease may benefit from early vascular intervention. (See 'Overview' above and 'Initial therapy' above and 'Interventions for claudication' above and "Approach to revascularization for claudication due to peripheral artery disease", section on 'Clinical evaluation'.)
•For patients who can participate in exercise therapy, we suggest supervised rather than unsupervised exercise therapy, where available (Grade 1B). The value of an unsupervised exercise program is less well studied but can still generally be recommended for patients who cannot participate in a supervised exercise program. Exercise therapy should follow a high-intensity regimen and be performed for a minimum of 30 to 45 minutes at least three times per week for a minimum of 12 weeks prior to reevaluation. During each session, an exercise level that is of sufficient intensity to elicit claudication should be achieved. (See 'Exercise therapy' above.)
•For most patients with lifestyle-limiting claudication who do not have an improvement in symptoms with risk modification and exercise therapy, we suggest a therapeutic trial of naftidrofuryl or cilostazol (100 mg twice daily) depending upon availability (Grade 2B). Naftidrofuryl has fewer side effects, and, where both are available, naftidrofuryl can be tried first. If the effect is not sufficient, then changing to cilostazol is appropriate. (See 'Pharmacologic therapy to improve walking' above.)
●We suggest follow-up after three months to assess the effectiveness of the initial medical therapy regimen for reducing symptoms. Patients who show improvement and who are satisfied with their progress can be scheduled for annual vascular examination. For patients who have been compliant with risk reduction strategies, yet six months to one year of exercise therapy and adjunctive pharmacotherapy have failed to provide satisfactory improvement, referral for possible revascularization is appropriate. (See 'Ongoing evaluation and follow-up' above and 'Referral for possible intervention' above and 'Criteria for intervention' above and "Approach to revascularization for claudication due to peripheral artery disease", section on 'Clinical criteria for revascularization'.)
●Options for revascularization include percutaneous intervention, surgical bypass, or a combination of these, and the choice depends upon the level of obstruction (aortoiliac, femoropopliteal) and severity of disease, and the patient's risk for the intervention. We agree with major cardiovascular society guidelines that recommend an initial attempt at percutaneous revascularization, reserving surgery for when arterial anatomy is not favorable for a percutaneous approach, provided the patient has an acceptable risk for surgery. (See 'Interventions for claudication' above and "Approach to revascularization for claudication due to peripheral artery disease", section on 'Clinical evaluation'.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Emile R Mohler, III, MD (deceased), who contributed to an earlier version of this topic review.
1 : Risk of major amputation in patients with intermittent claudication undergoing early revascularization.
2 : 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
3 : 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.
4 : Optimizing supervised exercise therapy for patients with intermittent claudication.
5 : Long-term clinical effectiveness of supervised exercise therapy versus endovascular revascularization for intermittent claudication from a randomized clinical trial.
6 : Is percutaneous transluminal angioplasty better than exercise for claudication? Preliminary results from a prospective randomised trial.
7 : Early outcomes from a randomized, controlled trial of supervised exercise, angioplasty, and combined therapy in intermittent claudication.
8 : Supervised exercise, stent revascularization, or medical therapy for claudication due to aortoiliac peripheral artery disease: the CLEVER study.
9 : 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.
10 : Endovascular Revascularization and Supervised Exercise for Peripheral Artery Disease and Intermittent Claudication: A Randomized Clinical Trial.
11 : Endovascular revascularisation versus conservative management for intermittent claudication.
12 : Comparative Efficacy of Endovascular Revascularization Versus Supervised Exercise Training in Patients With Intermittent Claudication: Meta-Analysis of Randomized Controlled Trials.
13 : Primary Stenting of the Superficial Femoral Artery in Patients with Intermittent Claudication Has Durable Effects on Health-Related Quality of Life at 24 Months: Results of a Randomized Controlled Trial.
14 : Exercise training for health-related quality of life in peripheral artery disease: a systematic review and meta-analysis.
15 : Two-year results from a randomized clinical trial of revascularization in patients with intermittent claudication.
16 : Improved quality of life after 1 year with an invasive versus a noninvasive treatment strategy in claudicants: one-year results of the Invasive Revascularization or Not in Intermittent Claudication (IRONIC) Trial.
17 : Exercise training versus angioplasty for stable claudication. Long and medium term results of a prospective, randomised trial.
18 : The constitutive procoagulant and hypofibrinolytic state in patients with intermittent claudication due to infrainguinal disease significantly improves with percutaneous transluminal balloon angioplasty.
19 : The EXercise versus Angioplasty in Claudication Trial (EXACT): reasons for recruitment failure and the implications for research into and treatment of intermittent claudication.
20 : Intermittent claudication: clinical effectiveness of endovascular revascularization versus supervised hospital-based exercise training--randomized controlled trial.
21 : Long-term outcomes of a randomized clinical trial of supervised exercise, percutaneous transluminal angioplasty or combined treatment for patients with intermittent claudication due to femoropopliteal disease.
22 : Economic analysis of a randomized trial of percutaneous angioplasty, supervised exercise or combined treatment for intermittent claudication due to femoropopliteal arterial disease.
23 : Randomized clinical trial of percutaneous transluminal angioplasty, supervised exercise and combined treatment for intermittent claudication due to femoropopliteal arterial disease.
24 : Treatment efficacy of intermittent claudication by surgical intervention, supervised physical exercise training compared to no treatment in unselected randomised patients I: one year results of functional and physiological improvements.
25 : The Oslo balloon angioplasty versus conservative treatment study (OBACT)--the 2-years results of a single centre, prospective, randomised study in patients with intermittent claudication.
26 : Beneficial effects of 1-year optimal medical treatment with and without additional PTA on inflammatory markers of atherosclerosis in patients with PAD. Results from the Oslo Balloon Angioplasty versus Conservative Treatment (OBACT) study.
27 : Is intermittent claudication improved by percutaneous transluminal angioplasty? A randomized controlled trial.
28 : Randomised controlled trial of percutaneous transluminal angioplasty for intermittent claudication.
29 : The adjuvant benefit of angioplasty in patients with mild to moderate intermittent claudication (MIMIC) managed by supervised exercise, smoking cessation advice and best medical therapy: results from two randomised trials for stenotic femoropopliteal and aortoiliac arterial disease.
30 : Society for Vascular Surgery practice guidelines for atherosclerotic occlusive disease of the lower extremities: management of asymptomatic disease and claudication.
31 : 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteriesEndorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS).
32 : Effect of supervised exercise therapy for intermittent claudication in patients with diabetes mellitus.
33 : 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.
34 : ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC).
35 : Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).
36 : AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation endorsed by the World Heart Federation and the Preventive Cardiovascular Nurses Association.
37 : Treatment of intermittent claudication with physical training, smoking cessation, pentoxifylline, or nafronyl: a meta-analysis.
38 : The effect of postoperative smoking on femoropopliteal bypass grafts.
39 : The measured effect of stopping smoking on intermittent claudication.
40 : Cessation of smoking in patients with intermittent claudication. Effects on the risk of peripheral vascular complications, myocardial infarction and mortality.
41 : Exercise for intermittent claudication.
42 : Supervised vs unsupervised exercise for intermittent claudication: A systematic review and meta-analysis.
43 : Supervised exercise therapy versus home-based exercise therapy versus walking advice for intermittent claudication.
44 : Supervised exercise therapy for intermittent claudication in daily practice.
45 : Home-based walking exercise intervention in peripheral artery disease: a randomized clinical trial.
46 : Availability of supervised exercise programs and the role of structured home-based exercise in peripheral arterial disease.
47 : Systematic review of home-based exercise programmes for individuals with intermittent claudication.
48 : Randomized clinical trial of a brief psychological intervention to increase walking in patients with intermittent claudication.
49 : Cost-effectiveness of exercise therapy in patients with intermittent claudication: supervised exercise therapy versus a 'go home and walk' advice.
50 : Efficacy of quantified home-based exercise and supervised exercise in patients with intermittent claudication: a randomized controlled trial.
51 : Effects of exercise rehabilitation on endothelial reactivity in older patients with peripheral arterial disease.
52 : Physical performance in peripheral arterial disease: a slower rate of decline in patients who walk more.
53 : The evidence for exercise-induced inflammation in intermittent claudication: should we encourage patients to stop walking?
54 : Exercise-induced angiogenesis-related growth and transcription factors in skeletal muscle, and their modification in muscle pathology.
55 : Effect of exercise training on skeletal muscle histology and metabolism in peripheral arterial disease.
56 : Intermittent claudication, exercise, and blood rheology.
57 : A Review of the Potential Local Mechanisms by Which Exercise Improves Functional Outcomes in Intermittent Claudication.
58 : Exercise training for management of peripheral arterial disease: a systematic review and meta-analysis.
59 : Exercise for intermittent claudication.
60 : The Effect of Supervised Exercise, Home Based Exercise and Endovascular Revascularisation on Physical Activity in Patients With Intermittent Claudication: A Network Meta-analysis.
61 : Physical activity during daily life and mortality in patients with peripheral arterial disease.
62 : Association of lower extremity performance with cardiovascular and all-cause mortality in patients with peripheral artery disease: a systematic review and meta-analysis.
63 : A systematic review and meta-analysis of the effects of supervised exercise therapy on modifiable cardiovascular risk factors in intermittent claudication.
64 : Leg strength in peripheral arterial disease: associations with disease severity and lower-extremity performance.
65 : Optimal exercise program length for patients with claudication.
66 : Supervised walking therapy in patients with intermittent claudication.
67 : Optimal Exercise Programs for Patients With Peripheral Artery Disease: A Scientific Statement From the American Heart Association.
68 : 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
69 : Short-term effects of cycle and treadmill training on exercise tolerance in peripheral arterial disease.
70 : The Impact of Walking Exercises and Resistance Training upon the Walking Distance in Patients with Chronic Lower Limb Ischaemia.
71 : The impact of different supervised exercise regimens on endothelial function in patients with intermittent claudication.
72 : The Effects of Walking or Walking-with-Poles Training on Tissue Oxygenation in Patients with Peripheral Arterial Disease.
73 : Nordic pole walking improves walking capacity in patients with intermittent claudication: a randomized controlled trial.
74 : Influence of the Physical Training on Muscle Function and Walking Distance in Symptomatic Peripheral Arterial Disease in Elderly.
75 : Efficacy of arm-ergometry versus treadmill exercise training to improve walking distance in patients with claudication.
76 : Treadmill exercise and resistance training in patients with peripheral arterial disease with and without intermittent claudication: a randomized controlled trial.
77 : Strength training increases walking tolerance in intermittent claudication patients: randomized trial.
78 : Exercise training improves functional status in patients with peripheral arterial disease.
79 : Upper- versus lower-limb aerobic exercise training on health-related quality of life in patients with symptomatic peripheral arterial disease.
80 : Comparison of the effect of upper body-ergometry aerobic training vs treadmill training on central cardiorespiratory improvement and walking distance in patients with claudication.
81 : Upper- vs lower-limb aerobic exercise rehabilitation in patients with symptomatic peripheral arterial disease: a randomized controlled trial.
82 : Effects of walking and strength training on resting and exercise cardiovascular responses in patients with intermittent claudication.
83 : Superiority of treadmill walking exercise versus strength training for patients with peripheral arterial disease. Implications for the mechanism of the training response.
84 : Maximal strength training improves walking performance in peripheral arterial disease patients.
85 : A session of resistance exercise increases vasodilation in intermittent claudication patients.
86 : Concurrent strength and endurance training improves physical capacity in patients with peripheral arterial disease.
87 : Modes of exercise training for intermittent claudication.
88 : A systematic review of randomized controlled trials: Walking versus alternative exercise prescription as treatment for intermittent claudication.
89 : Editor's choice--The effect of supervision on walking distance in patients with intermittent claudication: a meta-analysis.
90 : Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis.
91 : The effect of exercise intensity on the response to exercise rehabilitation in patients with intermittent claudication.
92 : Effect of Low-Intensity vs High-Intensity Home-Based Walking Exercise on Walk Distance in Patients With Peripheral Artery Disease: The LITE Randomized Clinical Trial.
93 : Impact of a supervised strength training or walking training over a subsequent unsupervised therapy period on walking capacity in patients with claudication.
94 : Supervised exercise therapy versus non-supervised exercise therapy for intermittent claudication.
95 : Effect of structured home-based exercise on walking ability in patients with peripheral arterial disease: a meta-analysis.
96 : Unsupervised exercise and mobility loss in peripheral artery disease: a randomized controlled trial.
97 : A Systematic Review of the Uptake and Adherence Rates to Supervised Exercise Programs in Patients with Intermittent Claudication.
98 : Meta-analysis of clinical trials examining the benefit of structured home exercise in patients with peripheral artery disease.
99 : The Impact of Supervised Exercise Training on Traditional Cardiovascular Risk Factors in Patients With Intermittent Claudication: A Systematic Review and Meta-Analysis.
100 : Supervised Exercise Therapy and Revascularization for Intermittent Claudication: Network Meta-Analysis of Randomized Controlled Trials.
101 : Multicenter randomized clinical trial of supervised exercise therapy with or without feedback versus walking advice for intermittent claudication.
102 : Effect of a Home-Based Exercise Intervention of Wearable Technology and Telephone Coaching on Walking Performance in Peripheral Artery Disease: The HONOR Randomized Clinical Trial.
103 : Effect of a Home-Based Exercise Intervention of Wearable Technology and Telephone Coaching on Walking Performance in Peripheral Artery Disease: The HONOR Randomized Clinical Trial.
104 : Antithrombotic therapy in peripheral artery disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
105 : Antithrombotic therapy for peripheral artery occlusive disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
106 : Cilostazol: treatment of intermittent claudication.
107 : A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial.
108 : The vascular and biochemical effects of cilostazol in patients with peripheral arterial disease.
109 : Drugs for intermittent claudication.
110 : Managing PAD with multiple platelet inhibitors: the effect of combination therapy on bleeding time.
111 : Cilostazol has beneficial effects in treatment of intermittent claudication: results from a multicenter, randomized, prospective, double-blind trial.
112 : Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease.
113 : 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.
114 : Meta-analysis of results from eight randomized, placebo-controlled trials on the effect of cilostazol on patients with intermittent claudication.
115 : A pooled analysis of the durability and predictors of treatment response of cilostazol in patients with intermittent claudication.
116 : Systematic review of the efficacy of cilostazol, naftidrofuryl oxalate and pentoxifylline for the treatment of intermittent claudication.
117 : Cilostazol for intermittent claudication.
118 : Naftidrofuryl in intermittent claudication: a retrospective analysis.
119 : An evaluation of patients with severe intermittent claudication and the effect of treatment with naftidrofuryl.
120 : Hemorrheological, micro- and macrocirculatory effects of naftidrofuryl in an acute study: a randomized, placebo-controlled, double-blind individual comparison.
121 : Naftidrofuryl for intermittent claudication.
122 : Lipid-lowering for peripheral arterial disease of the lower limb.
123 : Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease.
124 : Effect of simvastatin versus placebo on treadmill exercise time until the onset of intermittent claudication in older patients with peripheral arterial disease at six months and at one year after treatment.
125 : Effects of simvastatin on walking performance and symptoms of intermittent claudication in hypercholesterolemic patients with peripheral vascular disease.
126 : B-mode ultrasound assessment of pravastatin treatment effect on carotid and femoral artery walls and its correlations with coronary arteriographic findings: a report of the Regression Growth Evaluation Statin Study (REGRESS).
127 : Regression and progression of early femoral atherosclerosis in treated hyperlipoproteinemic patients.
128 : Treatment of hyperlipidaemia retards progression of symptomatic femoral atherosclerosis. A randomised controlled trial.
129 : Effects of colestipol-niacin therapy on human femoral atherosclerosis.
130 : Effect of niacin ER/lovastatin on claudication symptoms in patients with peripheral artery disease.
131 : Impact of cholesterol reduction on peripheral arterial disease in the Program on the Surgical Control of the Hyperlipidemias (POSCH).
132 : Clinical efficacy of picotamide in long-term treatment of intermittent claudication.
133 : Efficacy of indobufen in the treatment of intermittent claudication.
134 : Double-blind, controlled, multicenter study of indobufen versus placebo in patients with intermittent claudication.
135 : Antiplatelet agents for intermittent claudication.
136 : Effect of picotamide on the clinical progression of peripheral vascular disease. A double-blind placebo-controlled study. The ADEP Group.
137 : Multicenter double-blind study of ticlopidine in the treatment of intermittent claudication and the prevention of its complications.
138 : Platelet inhibition with Ticlopidine in atherosclerotic intermittent claudication.
139 : Ticlopidine in the treatment of intermittent claudication: a 21-month double-blind trial.
140 : Results of EMATAP: a double-blind placebo-controlled multicentre trial of ticlopidine in patients with peripheral arterial disease.
141 : Trental 400 in the treatment of intermittent claudication: results of long-term, placebo-controlled administration.
142 : Pentoxifylline efficacy in the treatment of intermittent claudication: multicenter controlled double-blind trial with objective assessment of chronic occlusive arterial disease patients.
143 : Pentoxifylline in the treatment of intermittent claudication of the lower limbs.
144 : On the assessment of the efficacy of pentoxifylline (Trental).
145 : Management of intermittent claudication with pentoxifylline: meta-analysis of randomized controlled trials.
146 : Pentoxifylline for intermittent claudication.
147 : Benefit of exercise conditioning for patients with peripheral arterial disease.
148 : A comparison of cilostazol and pentoxifylline for treating intermittent claudication.
149 : A prospective randomized controlled study with intermittent mechanical compression of the calf in patients with claudication.
150 : Anticoagulants (heparin, low molecular weight heparin and oral anticoagulants) for intermittent claudication.
151 : Hormone replacement therapy and peripheral arterial disease: the Rotterdam study.
152 : Peripheral arterial disease in randomized trial of estrogen with progestin in women with coronary heart disease: the Heart and Estrogen/Progestin Replacement Study.
153 : Steroid sex hormones for lower limb atherosclerosis.
154 : Ginkgo biloba for intermittent claudication.
155 : Ginkgo biloba for intermittent claudication.
156 : Padma 28 for intermittent claudication.
157 : Garlic for peripheral arterial occlusive disease.
158 : Vitamin E for intermittent claudication.
159 : Naftidrofuryl for intermittent claudication.
160 : Randomized controlled trial of vacuum therapy for intermittent claudication.
161 : ACCF/ACR/AIUM/ASE/ASN/ICAVL/SCAI/SCCT/SIR/SVM/SVS 2012 appropriate use criteria for peripheral vascular ultrasound and physiological testing part I: arterial ultrasound and physiological testing: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American College of Radiology, American Institute of Ultrasound in Medicine, American Society of Echocardiography, American Society of Nephrology, Intersocietal Commission for the Accreditation of Vascular Laboratories, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Interventional Radiology, Society for Vascular Medicine, and Society for Vascular Surgery.
162 : Rehabilitation in patients with peripheral arterial disease.
163 : Society for Vascular Surgery Practice guidelines for atherosclerotic occlusive disease of the lower extremities management of asymptomatic disease and claudication. Introduction.
164 : The Contemporary Safety and Effectiveness of Lower Extremity Bypass Surgery and Peripheral Endovascular Interventions in the Treatment of Symptomatic Peripheral Arterial Disease.
165 : Shared and differential factors influencing restenosis following endovascular therapy between TASC (Trans-Atlantic Inter-Society Consensus) II class A to C and D lesions in the femoropopliteal artery.
166 : Functional outcome after surgical treatment for intermittent claudication.
167 : Results of vascular reconstructions for atherosclerotic arterial occlusive disease of the lower limbs in young adults.