Version May 2024
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. Once a patient is diagnosed with claudication due to peripheral artery disease (PAD), the approach to treatment needs to account for the severity of symptoms, the patient's daily activities and limitations, their age and medical comorbidities, and location and extent of disease.
The general management of the patient with claudication due to PAD is reviewed. The indications for intervention (endovascular, surgical) and techniques for lower extremity revascularization and their outcomes are reviewed separately. (See "Approach to revascularization for claudication due to peripheral artery disease" 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 in separate topic reviews. The differential diagnosis of these is discussed elsewhere. (See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Differential diagnosis of PAD'.)
APPROACH TO MANAGEMENT — For most patients with claudication, we recommend an initial medical treatment regimen that includes cardiovascular risk reduction, including smoking cessation, exercise therapy (for those who can participate), and possibly pharmacologic therapy (algorithm 1), rather than initial revascularization [1-3]. Medical management that includes exercise therapy is effective and does not have the potential risks associated with complications of intervention, which can worsen symptoms or lead to amputation [4]. It also more cost-effective as a first-line treatment for claudication [5,6]. Improvement in walking capacity is generally better for supervised compared with nonsupervised exercise therapy, and exercise therapy compared with available pharmacologic therapies. Periodic reevaluation of symptoms will determine the effectiveness of these therapies for a particular patient. A selected subset of patients may be appropriate for initial revascularization. (See 'Referral for possible intervention' below and "Approach to revascularization for claudication due to peripheral artery disease", section on 'Clinical criteria for revascularization'.)
Risk for progression and risk modification — Although PAD and its severity is an important marker for cardiovascular risk, symptoms of claudication are associated with an overall 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 [3,7]:
●Stable claudication: 70 to 80 percent
●Worsening claudication: 10 to 20 percent
●Progression to critical limb ischemia: 1 to 2 percent
Risk factors for atherosclerosis and strategies to reduce the future risk for cardiovascular events are discussed separately. (See "Epidemiology, risk factors, and natural history of lower extremity peripheral artery disease", section on 'Epidemiology and risk factors' and "Overview of lower extremity peripheral artery disease", section on 'Risk factor modification'.)
Evidence supporting initial medical therapy — Systematic reviews of 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) support an initial conservative approach in patients with stable claudication [11,12].
In some but not all trials, a combination of percutaneous transluminal angioplasty (PTA) and exercise (supervised exercise therapy or exercise advice) produced the greatest initial changes in walking distance compared with exercise alone or PTA alone, and a handful of trials also reported significant quality-of-life improvements for those undergoing intervention [8-10,13-17]. However, these and other meta-analyses report diminishing benefits of revascularizations in the longer term [18].
●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 [5,8,9,19-28].
●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 [23,24,29-32].
●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) [5,10,21,26,27,33]. 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 [21]. 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 [26].
●In the Invasive Revascularization or Not in Intermittent Claudication (IRONIC) Trial, which compared intervention plus pharmacotherapy (cilostazol) with pharmacotherapy alone, intervention provided a benefit for 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 [17].
Functional improvements with a medical therapy regimen that includes exercise therapy tend to be more durable compared with endovascular intervention as an initial treatment strategy and are associated with less morbidity and mortality [19-21]. In a review of a national database including over 50,000 patients with intermittent claudication, primary treatments included supervised exercise therapy in 72 percent, endovascular treatment in 22 percent, and surgery in 6 percent. Patients who underwent primary endovascular or open surgical treatment had a higher risk of subsequent revascularization compared with supervised exercise therapy (endovascular: hazard ratio [HR] 1.44, 95% CI 1.37-1.51; open surgery: HR 1.45, 95% CI 1.34-1.57), and a higher mortality risk (endovascular: HR 1.38, 95% CI 1.29-1.48; open surgery HR 1.49, 95% CI 1.34-1.65).
In a later network meta-analysis, the mean differences in walking distance compared with baseline for short (<1 year) and intermediate (1 to <2 years) follow-up were greatest for supervised exercise therapy and supervised exercise therapy combined with endovascular treatment [18]. At long-term (>2 years) follow-up, none of the tested treatments improved mean walking distance compared with controls. Similarly, in the IRONIC trial [34], which randomly assigned patients with mild-to-severe intermittent claudication to either revascularization plus best medical therapy and structured exercise therapy (revascularization) or best medical therapy and structured exercise therapy (nonrevascularization), no long-term improvement in health-related quality-of-life or walking capacity was seen for a revascularization compared with a nonrevascularization strategy. Revascularization was also not a cost-effective treatment option from a payer/health care point of view. In a separate trial that included a cost analysis also found no significant differences in functional outcomes between supervised exercise therapy, PTA, or a combination of supervised exercise therapy and PTA [5]. However, in this study, supervised exercise was more cost-effective as a first-line treatment for claudication.
SMOKING CESSATION — We agree with the guideline recommendations regarding smoking cessation, in general, and in particular in patients with peripheral artery disease [3,7,35-39]. (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.
Continued smoking restricts improvements in pain-free walking symptoms that might otherwise be seen with an exercise program [40], and with continued smoking, patients are also less likely to benefit from the pharmacologic agents discussed below. (See 'Pharmacologic therapy to improve walking' below.)
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 [41]. However, smoking cessation does appear to favorably alter the progression of PAD [42-44]. 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) [44]. 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) [45,46]. (See 'Evidence supporting initial medical therapy' above.)
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 [47-54]. [55]
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 [56-63]:
●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 [64]. 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 [65]. 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 [66,67]. However, in the Cochrane review above [64], 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 [68]. 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 [69].
Independent of the mode of delivery, all exercise programs should be progressive and individually prescribed where possible, considering disease severity, comorbidities, and initial exercise capacity [70]. All patients should aim to accumulate at least 30 min of aerobic activity, at least three times a week, for at least three months, ideally in the form of walking exercise to near-maximal claudication pain. The benefits of exercise diminish when exercise training stops.
Treadmill exercise — Despite the evidence of benefit, issues remain concerning the optimal regimen for exercise rehabilitation [71,72]. 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 [73,74]. (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 [7]. 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 [75-84]. These include upper-arm ergometry [81,85-87], cycling [75], and resistance/strength training [82-84,88-92]. 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. However, in a systematic review, there was no clear difference comparing alternative exercise modes and supervised walking exercise for improving the maximum and pain‐free walking distance in patients with intermittent claudication [93].
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 [93]. 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 [82-84,88-92]. 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 [84]. 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 [82]. 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 [2,73,74], many, but not all, studies have suggested that exercise treadmill training should be performed to near-maximal claudication levels [94,95]. 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 [96]. 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 [94]. A small trial comparing high- versus low-intensity exercise also reported similar outcomes [97]. 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 [98]. 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 [8,99-103]. The relative effectiveness of supervised versus unsupervised exercise has been evaluated in systematic reviews [47,95,100,104-106]. 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 [40,107]. 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 [107]. 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 [108].
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 [109].
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 [2,7,37,38,110,111]. 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 'Risk for progression and 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 [112]. Benefits to therapy are noted as early as four weeks after the initiation of therapy [113,114]. 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 [115]. Cilostazol may be taken safely with aspirin and/or clopidogrel without an additional increase in bleeding time [116]. Side effects for cilostazol noted in clinical studies included headache, loose and soft stools, diarrhea, dizziness, and palpitations [113,117-119]. 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 [115]. (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 [120-123]. 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 [120]. 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 [122].
Naftidrofuryl — Naftidrofuryl (600 mg daily orally), which is currently available in Europe, can be used for treatment of claudication [38]. 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 [124-126]. 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 [41,122,127]. 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 [122].
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 'Risk for progression and 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 [128-131]. Initial studies, performed before the availability of statins, showed regression or less progression of femoral atherosclerosis with lipid-lowering therapy [132-136], and a lower incidence of claudication and limb-threatening ischemia in patients with hyperlipidemia who were treated with surgery [137]. 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 [128]. 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 [138-140], antiplatelet therapy significantly improved pain-free walking distance compared with placebo (mean difference 78 feet) [141]. 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) [142-146]. 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 [122]. (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 [147-152], leading to variable recommendations for its use by various society guidelines [7,37,38,111]. One meta-analysis found that pentoxifylline improved walking distance by 29 meters compared with placebo [151]. 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 [152]. Improvements in walking distances associated with pentoxifylline are generally substantially less than those achieved with a supervised exercise program [153] or cilostazol [154].
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 [155]. 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 [7,111] include anticoagulants (eg, warfarin, low-molecular-weight heparin) [156], hormone replacement therapy [157-159], Ginkgo biloba [7,36,160,161], Padma 28 [2,7,36,162], garlic [163], and vitamin E supplementation [7,164]. Chelation therapy also does not improve claudication distance in PAD [7,165].
Investigational — Pharmacologic and device therapies (eg, negative pressure wound therapy) 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) [2].
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 [166].
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 "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) [167]. Those who continue to smoke should be counseled again of the increased risk for PAD progression [44]. 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.
Interventions for claudication — Options for intervention include percutaneous intervention, surgical bypass, or a combination of these (hybrid procedure).
●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".)
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, among other factors (algorithm 1). Vascular imaging is used to define vascular anatomy to plan intervention. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Duplex ultrasound' and "Advanced vascular imaging for lower extremity peripheral artery disease".)
●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 "Approach to revascularization for claudication due to peripheral artery disease", section on 'Revascularization to restore inflow'.)
●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. (See "Approach to revascularization for claudication due to peripheral artery disease", section on 'Infrainguinal revascularization'.)
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, renal, 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)")
PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Peripheral artery disease".)
SUMMARY AND RECOMMENDATIONS
●Approach to management – 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. 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 debilitating claudication and inflow disease may benefit from early vascular intervention. (See 'Approach to management' above.)
●Risk factor modification – Claudication is associated with an increased risk of coronary, cerebrovascular, and renovascular disease, and peripheral artery disease (PAD) is 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 'Risk for progression and risk modification' above.)
●Supervised exercise therapy – 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.)
●Pharmacologic therapy – 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.)
●Follow-up – We suggest follow-up after three months to assess the effectiveness of the initial medical therapy regimen for improving symptoms. (See 'Ongoing evaluation and follow-up' above.)
•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.
•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.
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Emile R Mohler, III, MD (deceased), who contributed to an earlier version of this topic review.
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