Management of symptomatic peripheral artery disease: Claudication

INTRODUCTION — 

Intermittent 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, location and extent of disease, and their socioeconomic circumstances [1-3].

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 other causes of arterial obstruction (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. The differential diagnosis of claudication and the management of these disorders are discussed separately. (See "Lower extremity peripheral artery disease: Clinical features and diagnosis", section on 'Differential diagnosis of PAD'.)

RISK FOR DISEASE PROGRESSION

Progression to limb-threatening events — 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 chronic limb-threatening ischemia (CLTI). 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 overall low risk of progression for most patients with lower extremity claudication:

●Stable claudication – 70 to 80 percent

●Worsening claudication – 10 to 20 percent

●Progression to CLTI – 1 to 2 percent annually

While these data are commonly cited, the risk for progression can be higher, particularly in those with risk factors [4-6]. In a long-term study of 1244 patients with intermittent claudication, the cumulative 10-year risks of development of ischemic ulceration and ischemic rest pain were 23 and 30 percent, respectively [6]. Predictors of progression to CLTI included diabetes, a lower initial ankle-brachial index, and a greater number of pack-years of smoking. The PORTRAIT (Patient‐Centered Outcomes Related to Treatment Practices in Peripheral Arterial Disease: Investigating Trajectories) registry, which enrolled 1275 patients with new or an exacerbation of PAD symptoms, demonstrated that multiple social determinants of health influence clinical progression and well-being at one year after initiation of treatment [1].

Revascularization (endovascular, surgical bypass) in patients with claudication can increase the progression to CLTI. In a systematic review, the estimated risk of major amputation following revascularization was approximately 7 percent over five years and 12 percent over 10 years [7].

Other cardiovascular events — Intermittent claudication as a manifestation of PAD is a strong marker for generalized atherosclerosis and portends cardiovascular and cerebrovascular morbidity and mortality [8-10]. In older studies, the 5- and 10-year mortality rates among patients with intermittent claudication were 30 to 42 and 50 to 65 percent, respectively [11,12]. In a later study that compared all-cause and cardiovascular mortality in patients with and without PAD, all-cause and cardiovascular mortality at five years was 21 and 7.5 percent, which was similar for symptomatic and asymptomatic patients with PAD, but significantly greater compared with patients who did not have PAD for whom all-cause and cardiovascular mortality was 9.5 and 2.4 percent, respectively [13].

The degree of impairment in symptomatic patients may also predict mortality [13-17]. In a meta-analysis of lower extremity performance, a shorter maximum walking distance was associated with increased five-year cardiovascular (unadjusted risk ratio [RR] 2.54, 95% CI 1.86 to 3.47) and all-cause mortality (unadjusted RR 2.23 95% CI 1.85 to 2.69) [16]. Slower walking velocity; lower Walking Impairment Questionnaire stair-climbing score; and poor hip extension, knee flexion, and plantar flexion strength were also associated with increased mortality.

Other effects — Patients living with intermittent claudication voice uncertainty about their PAD, how risk factors work, and whether lifestyle changes, particularly walking, would help. They also express dissatisfaction with the lack of empathy from the medical professionals encountered, with feelings of being dismissed and left on their own [18,19]. Added to this, most patients with intermittent claudication are considered to have "insufficient" knowledge or "health literacy" about PAD. Freely available online patient education materials have varying quality and are often written at a level higher than the average adult in the United States can understand [20-22]. Patients with "sufficient" health literacy report significantly higher self-efficacy and quality of life and are more physically active compared with patients with "insufficient" health literacy [3]. (See 'Patient perspective topic' below and 'Information for patients' below.)

Symptoms of anxiety and depression are prevalent among patients with PAD. Moreover, patients with atypical leg symptoms or pain at rest admit to more impaired mood than patients without those symptoms. Patients with symptoms of moderate-to-severe depression reported more barriers to physical activity practice compared with patients without signs of depression. While depression symptoms are associated with personal barriers to exercise, anxiety symptoms are not. Importantly, for the management of claudication, the beneficial effects of supervised exercise therapy occur regardless of depression and anxiety [23-29]. However, patients with signs of depression have a significantly shorter pain-free walking distance and total walking distance compared with patients with no signs of depression. Pain-free walking distance and total walking distance were similar between patients with and without signs of anxiety.

Patients with intermittent claudication have been reported to have a relative increase in the incidence of tumor and tumor-associated death, probably due to a high prevalence of smoking [30].

INITIAL MEDICAL THERAPY AS PREFERRED APPROACH — 

For most patients with claudication, in agreement with major Society Guidelines, we recommend initial medical treatment (algorithm 1) rather than initial revascularization [31-33]. Medical treatment of patients with claudication includes strategies to reduce cardiovascular disease progression and future cardiovascular events, including atherosclerosis risk factor modification, therapies targeted specifically at improving walking ability, such as exercise therapy for those who can participate, and possibly pharmacologic therapies. (See 'Cardiovascular risk reduction' below and 'Therapies to improve walking distance' below.)

A management strategy 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 [34] (see 'Progression to limb-threatening events' above). It is also generally more cost-effective as a first-line treatment for claudication [35,36]. Improvement in walking capacity is generally better for supervised versus unsupervised exercise therapy and for exercise therapy compared with available pharmacologic therapies. (See 'Effectiveness' below.)

Periodic re-evaluation of symptoms will determine their effectiveness for a particular patient. A selected subset of patients may be appropriate for initial revascularization. (See 'Referral for possible intervention' below.)

Durability of medical therapy — Systematic reviews and meta-analyses of randomized trials comparing treatment strategies (supervised exercise therapy, intervention [angioplasty/stenting], medical therapy, or combinations) support supervised exercise therapy in combination with medical management in patients with stable claudication [37-40]. Functional improvements associated with medical management that include exercise therapy tend to be more durable compared with intervention as an initial treatment strategy and are associated with less morbidity and mortality. Although some trials show that a combination of angioplasty and exercise (supervised exercise therapy or exercise advice) produces the greatest initial changes in walking distance compared with exercise alone or angioplasty alone [41-46], the early benefits of revascularization diminish in the longer term [47-53].

In a 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 when supervised exercise therapy was included in the regimen [38]. Supervised exercise therapy and endovascular revascularization plus supervised exercise therapy were both effective at improving maximal walking distances over the intermediate term but not beyond this.

●The Invasive Revascularization or Not in Intermittent Claudication (IRONIC) Trial randomized patients with mild-to-severe intermittent claudication to revascularization, best medical therapy and structured exercise therapy (the revascularization group) or best medical therapy and structured exercise therapy (the nonrevascularization-group) [50]. Revascularization provided a benefit for maximum walking distance (standard mean difference [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 [46]. However, at five years of follow-up, the early benefit seen in patients in the revascularization group was lost, and long-term improvement in health-related quality of life or walking capacity was similar to that of nonrevascularization treatment. Revascularization was not a cost-effective treatment option from a payer/health care point of view [54].

●In a multicenter trial from seven vascular clinics in Sweden between 2010 and 2020, one hundred patients were randomly assigned to primary stenting and best medical treatment or best medical treatment alone and were followed for 60 months [53]. In patients with intermittent claudication caused by isolated superficial femoral artery lesions, primary stenting improved quality of life up to 36 months from treatment compared with best medical treatment alone, but these benefits were no longer detectable at 60 months. There were no differences in progression to chronic limb-threatening ischemia, amputation (2.1 versus 1.9 percent), or mortality (14.6 versus 15.4 percent) between groups.

●In a trial with longer follow-up, angioplasty, supervised exercise, or combined treatment were compared in 178 patients with claudication related to femoropopliteal disease [55]. 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, 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 [51].

Early vascular intervention for claudication is often associated with subsequent vascular intervention [56-58]. In a review of a national database including over 50,000 patients with intermittent claudication, primary endovascular or open surgical treatment had a higher risk of subsequent revascularization relative to patients treated 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 higher mortality risk (endovascular: HR 1.38, 95% CI 1.29-1.48; open surgery HR 1.49, 95% CI 1.34-1.65) [52]. In a review of the Vascular Quality Initiative, female patients had higher reintervention rates and were less often medically optimized preoperatively compared with their male counterparts [59]. However, in the SUPER trial [43], supervised exercise therapy and endovascular therapy improved maximal walking distances on a treadmill- and disease-specific quality of life. After a mean of 5.5 years, 49 percent of supervised exercise therapy patients required intervention for intermittent claudication, and 27 percent of endovascular therapy patients underwent re-intervention.

CARDIOVASCULAR RISK REDUCTION — 

Cardiovascular risk reduction includes lifestyle modifications and pharmacologic therapies aimed at reducing the risk of future major adverse cardiovascular events (MACE) and major adverse limb events (MALE). General strategies for risk reduction in patients with PAD are reviewed elsewhere. Specific considerations for patients with claudication are reviewed below. (See "Overview of lower extremity peripheral artery disease", section on 'General approach by PAD severity'.)

Antithrombotic therapy — We agree with major cardiovascular consensus guidelines that recommend antithrombotic therapy for secondary prevention of atherosclerotic cardiovascular disease in patients with symptomatic lower extremity PAD [32,33,60]. In randomized trials, antithrombotic therapy reduces the risk of future MACE and MALE [61-71].

Aspirin is commonly prescribed. Alternative antithrombotic therapies may provide additional benefits in selected patients with claudication. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

These include:

●Clopidogrel rather than aspirin (see 'Aspirin, clopidogrel' below)

●Rivaroxaban in addition to aspirin (see 'Rivaroxaban' below)

For patients with claudication, we select the specific agent based on the patient's symptoms and risk.

Aspirin, clopidogrel — For most patients with claudication (mild-to-moderate symptoms, no high-risk comorbidities), either aspirin or clopidogrel monotherapy is appropriate [72]. The most common oral dose of aspirin is 81 mg orally once daily, and for clopidogrel, 75 mg orally once daily. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

●The effectiveness of antiplatelet therapy for the secondary prevention of adverse cardiovascular events (eg, myocardial infarction [MI], stroke, vascular death) was demonstrated in the Antithrombotic Trialists' Collaboration [69-71]. Specifically among patients with PAD, in a meta-analysis that included 18 trials involving 5269 patients (symptomatic and asymptomatic PAD), aspirin therapy (alone or in combination with dipyridamole) was associated with a nonsignificant reduction for the primary composite endpoint of nonfatal MI, nonfatal stroke, and cardiovascular death, but a significant reduction in the secondary outcome of nonfatal stroke (relative risk [RR] 0.66, 95% CI 0.47-0.94) [62]. There were no significant differences in other individual secondary outcomes (nonfatal MI, major bleeding).

●In the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, clopidogrel (75 mg/day) had a modest, although significant, advantage over aspirin (325 mg/day) for reducing the risk of the combined outcome of ischemic stroke, MI, or vascular death in 19,185 patients with a recent stroke, MI, or symptomatic PAD (RR reduction 8.7 percent, 95% CI 0.3-16.5) [63]. In a subgroup analysis, the benefit of clopidogrel over aspirin was mainly driven by patients with PAD, in whom there was a 23.8 percent RR reduction (95% CI 8.9-36.2).

Rivaroxaban — Data suggest additional benefit in reducing MACE and MALE for aspirin combined with low-dose rivaroxaban (a direct oral anticoagulant), particularly in individuals with PAD, although with an increased risk for bleeding [64-68]. A clinically important question is whether the observed improvements in cardiac and limb outcomes outweigh the risk of bleeding, and if so, for which patients? For patients with severe symptoms, at risk for MALE (eg, prior revascularization) or MACE (ie, high-risk comorbidities [heart failure, diabetes, kidney insufficiency, polyvascular disease]), the benefits of reducing these risks may justify the increased risk of bleeding associated with rivaroxaban. In these high-risk groups, we suggest low-dose rivaroxaban (2.5 mg orally twice daily) plus aspirin (100 mg orally once daily) provided the patient has a low baseline risk for bleeding. Rivaroxaban may also provide the added benefit of improving functional outcomes. This issue is discussed below. (See 'Therapies to improve walking distance' below and 'Benefits not firmly established' below.)

●A multicenter trial (COMPASS) randomly assigned over 27,000 patients with stable coronary artery disease or PAD to a low dose of rivaroxaban (2.5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban (5 mg twice daily) plus placebo, or aspirin (100 mg once a day) plus placebo [66]. In a prespecified subgroup analysis among 7470 subjects with PAD, the composite endpoint of cardiovascular death, MI, or stroke was significantly reduced for rivaroxaban plus aspirin compared with aspirin alone (5 versus 7 percent; hazard ratio [HR] 0.72, 95% CI 0.57-0.90), as was MALE (1 versus 2 percent; HR 0.54, 95% CI 0.35-0.82) [67]. Rivaroxaban alone, compared with aspirin alone, did not significantly reduce the composite endpoint, but there was a trend toward reduced MACE. Rivaroxaban increased the risk of major bleeding (3 versus 2 percent; HR 1.61, 95% CI 1.12-2.31), whether used alone or in combination.

●In the Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) trial, 6564 patients with PAD who had undergone prior revascularization were randomly assigned to rivaroxaban (2.5 mg twice a day) plus aspirin, or placebo plus aspirin [61]. Low-dose rivaroxaban plus aspirin reduced the composite endpoint of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or death from cardiovascular causes (17.3 versus 19.9 percent; HR 0.85, 95% CI, 0.76-0.96); the incidence of acute limb ischemia (5.2 versus 7.8 percent; HR 1.42, 95% CI 1.10-1.84); and the need for index-limb revascularization for recurrent limb ischemia (20 versus 22.5 percent; HR 0.88, 95% CI 0.79-0.99). Major bleeding, as defined according to the Thrombolysis in Myocardial Infarction (TIMI) classification, was 2.7 percent in the rivaroxaban group and 1.9 percent in the placebo group (HR 1.43, 95% CI 0.97-2.10). The incidence of International Society on Thrombosis and Haemostasis (ISTH) major bleeding was significantly increased for the rivaroxaban group compared with the placebo group (5.94 versus 4.06 percent; HR 1.42, 95% CI 1.10-1.84). Approximately 14 percent of patients discontinued treatment prematurely, which may have had an impact on the observed benefits and risks. Concomitant clopidogrel treatment, which was permitted for up to six months after the intervention, did not affect the primary efficacy or safety outcomes [73]. However, there was a trend toward more ISTH major bleeding within 365 days with clopidogrel use >30 days compared with shorter durations.

Other antiplatelet agents — Other antiplatelet agents (ticagrelor, vorapaxar) have also been studied specifically in the PAD patient population [74-81].

●Ticagrelor – Some trials suggest that ticagrelor may provide benefits for preventing cardiovascular events, although with an increased risk for bleeding [75-78,80].

•In the Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial, 13,885 patients with predominantly symptomatic PAD were randomly assigned to single-agent therapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily) [79,80,82]. The rate of ischemic stroke was significantly reduced for ticagrelor compared with clopidogrel (1.9 versus 2.4 percent; HR 0.78, 95% CI 0.62-0.98), but there were no significant differences between the groups for the composite primary outcome (cardiovascular death, MI, or ischemic stroke; 10.8 versus 10.6 percent) or other outcomes (death, MI, acute limb ischemia, the need for revascularization, major bleeding). However, more patients receiving ticagrelor discontinued treatment due to dyspnea or minor bleeding.

•In the PEGASUS-TIMI 54 trial, 21,162 patients with prior MI one to three years prior were randomly assigned to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo, all on a background of low-dose aspirin [75]. Among PAD patients with prior MI (1143 patients; 5 percent of the total), ticagrelor reduced the absolute rate of a MACE by 4.1 percent and significantly reduced the risk for peripheral revascularization (HR 0.63, 95% CI 0.43-0.93). However, there was a 0.12 percent absolute excess of major bleeding.

●Vorapaxar – Vorapaxar is a novel antagonist of protease-activated receptor (PAR-1), which is located on platelets, vascular endothelium, and smooth muscle and is the primary receptor for thrombin on human platelets [83]. In the Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis in Myocardial Infarction 50 (TRA2°P-TIMI 50), among patients with symptomatic lower extremity PAD, vorapaxar (administered with other antiplatelet agents) reduced the rate of first acute limb ischemia events, particularly among those who had undergone revascularization [84-87]. Moderate or severe bleeding (GUSTO criteria) occurred in significantly more patients who received vorapaxar compared with placebo (4.2 versus 2.5 percent; HR 1.66, 95% CI 1.43 to 1.93).

Other anticoagulants — No added benefit has been established for vitamin K antagonists for those with PAD [88,89]. In the Warfarin and Antiplatelet Vascular Evaluation (WAVE) trial, a combination of warfarin (target international normalized ratio 2 to 3) plus antiplatelet therapy was not more effective compared with aspirin alone for preventing cardiovascular morbidity in patients with PAD [88].

Lifestyle modifications and other therapies

Smoking cessation — We agree with guideline recommendations regarding smoking and vaping cessation, in general, and in particular in patients with PAD [31-33]. Numerous epidemiologic and observational studies have shown that smoking cessation reduces adverse cardiovascular events and the risk of limb loss in patients with PAD. However, smoking cessation interventions in people with PAD do not appear to be as effective for achieving smoking cessation compared with the general population [90]. (See "Overview of lower extremity peripheral artery disease", section on 'Smoking cessation'.)

Continued smoking restricts improvements in pain-free walking symptoms that might otherwise be seen with an exercise program [91] (see 'First-line therapy: Exercise' below), and with continued smoking, patients are also less likely to benefit from the pharmacologic therapies discussed below. (See 'Second-line therapies' below.)

It is not clear whether cessation of cigarette smoking reduces the severity of claudication symptoms. In a review that looked at pain-free and total walking distance outcomes with smoking cessation, total walking distance was increased but was not statistically significant [92]. However, smoking cessation does appear to favorably alter the progression of PAD [93-95]. 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) [95]. Rest pain, a sign of limb-threatening ischemia, did not occur in patients who stopped smoking but developed in 16 percent of those who continued to smoke.

Statins and other pharmacologic therapies — Lipid-lowering therapy with at least a moderate dose of a statin, irrespective of the baseline low-density lipoprotein cholesterol, is recommended for all patients with atherosclerotic cardiovascular disease [33]. (See "Management of low-density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

PCSK9 inhibitors and ezetimibe effectively lower low-density lipoprotein cholesterol levels, which is a major risk factor for PAD progression, potentially reducing the risk of MACE and MALE in patients with PAD [96,97]. We agree with guidelines that recommend considering PCSK9 inhibitors and ezetimibe in high-risk patients with PAD and elevated low-density lipoprotein cholesterol levels, especially those with a history of MACE. The overall efficacy of statins in patients with PAD is reviewed separately. (See "Overview of lower extremity peripheral artery disease", section on 'Lipid-lowering therapy'.)

Whether statin therapy improves walking distance is discussed below. (See 'Benefits not firmly established' below.)

Other therapies aimed at reducing cardiovascular risk include control of blood pressure, control of glucose, and proper diet to maintain a healthy weight. These are reviewed separately. (See "Overview of lower extremity peripheral artery disease", section on 'Antihypertensive therapy' and "Overview of lower extremity peripheral artery disease", section on 'Lifestyle modification'.)

THERAPIES TO IMPROVE WALKING DISTANCE

First-line therapy: Exercise — We recommend an exercise therapy program as part of the initial treatment regimen for patients with claudication based on randomized trials demonstrating significant improvements in walking parameters for those who participate (algorithm 1) [98,99]. (See 'Durability of medical therapy' above and 'Effectiveness' below.)

Patients with claudication should be referred to a supervised treadmill exercise rehabilitation program, if possible, depending on insurance coverage or personal resources. Home and community-based therapy are also effective for improving walking tolerance but less effective than supervised exercise and are associated with a high dropout rate, underscoring the need for ongoing psychological support [100-107]. (See 'Effectiveness' below.)

Patients with PAD 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 PAD [108]. 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 [109-116]:

●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

Effectiveness — 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 [117]. 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 [118].

The relative effectiveness of supervised versus unsupervised exercise has been evaluated in systematic reviews [37,100,118-122]. 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. (See 'Active feedback and wearable monitors' below.)

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 [47,119,123-126]. The relative effectiveness of unsupervised versus supervised exercise has been evaluated in systematic reviews [37,100,119-122]. 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.

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 [15,16]. However, in the Cochrane review above [117], a meta-analysis of five trials found no effect of 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 of supervised exercise therapy on modifiable cardiovascular risk factors in patients with intermittent claudication [127]. 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 of 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 prescriptions — 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 [33,128,129]. 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. (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 [130,131]. 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.

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 requires 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. Supervised exercise therapy has been described as having a 30 percent failure rate and will require additional intervention to ameliorate claudication [43].

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.

Many, but not all, studies have suggested that exercise treadmill training should be performed to near-maximal claudication levels [120,132,133]. However, few trials have directly compared the relative benefits or harms of walking to different levels of claudication. In an early meta-analysis, the use of near-maximal pain during training as a claudication pain endpoint was an independent predictor of improvement in walking distance [134]. 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 [133]. A small trial comparing high- versus low-intensity exercise also reported similar outcomes [135]. However, a subsequent 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 nonexercise control, for 12 months [136]. 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 the 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 event 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 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines that recommend that supervised exercise protocols should be initiated at an intensity that induces the onset of claudication within three to five minutes and moderate to moderately severe claudication within 8 to 10 minutes [33,128].

Active feedback and wearable monitors — Active feedback has been incorporated into both supervised and unsupervised training regimens [91,137]. While still under study, the available data suggest that active feedback or the use of wearable monitors is beneficial. The Society for Vascular Surgery (SVS) has developed a mobile device application (ie, SVS SET) that was designed to fill the gap when supervised therapy is not locally available or is not covered by insurance.

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 [137]. 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.

Home-based exercise intervention with regular professional support and encouragement is a safe method of exercise prescription for people with intermittent claudication and can be beneficial in improving functional walking capacity as well as some aspects of quality of life when compared with no exercise [138]. However, home-based therapy is not as effective as hospital-based supervised exercise interventions [118,139-145]. However, structured monitoring with the use of an external wearable activity monitor (WAM) has been shown to improve outcomes in some, but not all [146], studies. Mobile applications (apps) that make use of accelerometers built into modern smartphones or other wearable devices have created an alternative solution for monitoring patients during home-based therapy. WAM interventions improve measures of walking ability (heterogeneous outcomes such as maximum walking distance, distance, and six-minute walking distance), increased daily walking activity (steps/day), cardiovascular metrics (maximum oxygen consumption), and quality of life [147].

Alternative modes of exercise — Although most trials have used lower extremity exercise (eg, treadmill or walking), other forms of exercise have been investigated to improve walking performance in patients with PAD [148-158]. These include upper-arm ergometry [155,159-161], cycling [149], and resistance/strength training [156-158,162-166]. 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 between alternative exercise modes and supervised walking exercises for improving the maximum and pain‐free walking distance in patients with intermittent claudication [148].

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 [148]. 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 [156-158,162-166]. In an early trial that included 29 patients with disabling claudication, 12 weeks of strength training were less effective compared with 12 weeks of supervised treadmill exercise [158]. 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 [156]. Lower extremity resistance training intervention did not improve the 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'.)

Second-line therapies — 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 are refused by the patient [31-33,60,167]. 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 be available only within 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 the progression and complications associated with atherosclerotic disease are discussed above. (See 'Cardiovascular risk reduction' above.)

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 'First-line therapy: Exercise' 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 [168]. Benefits to therapy are noted as early as four weeks after the initiation of therapy [169,170].

●Efficacy – The effectiveness of cilostazol has been demonstrated in several meta-analyses [171-174]. 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 [171]. Significantly greater increases in maximal walking distances and pain-free walking distances were seen in patients treated with cilostazol (maximal walking distance: 67 versus 50 percent increase from baseline, pain-free walking distance: 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 [173].

●Dosing – Cilostazol (100 mg orally 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 [175].

Cilostazol may be taken safely with aspirin or clopidogrel without an additional increase in bleeding time [176]. While there is a theoretical synergistic risk of increased bleeding for cilostazol combined with rivaroxaban, however, no clinical data are available to inform this risk [177].

No dosing adjustment is necessary for adults with kidney function impairment, although metabolite concentrations may be increased. Cilostazol is not appreciably removed by dialysis, and while there is no dose adjustment for those on dialysis provided by the manufacturer, a lower trial dose (eg, 50 mg twice daily) may be prudent [178]. The dose can then be adjusted upward as tolerated.

●Side effects – Side effects of cilostazol noted in clinical studies have included headache, loose and soft stools, diarrhea, dizziness, and palpitations [169,179-181]. 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 [175]. (See "Inotropic agents in heart failure with reduced ejection fraction", section on 'Intravenous phosphodiesterase-3 inhibitors'.)

Naftidrofuryl — Naftidrofuryl (600 mg daily orally) can also be used for the treatment of claudication. 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 [182-184]. The mechanisms of action of this drug are unclear, but it is thought to promote glucose uptake and increase ATP levels. Systematic reviews have consistently identified significant and clinically meaningful improvements in walking distance after initiation of naftidrofuryl therapy [92,173,185]. The later of these performed a network meta-analysis and found that the percentage change from baseline for mean walking distance increased by 60 percent compared with placebo, and pain-free walking distance increased by 49 percent compared with placebo, differences that were greater for naftidrofuryl compared with cilostazol or pentoxifylline [173].

Benefits 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 of future cardiovascular events. (See 'Risk for disease progression' above.)

●Statin therapy – A number of trials in patients with hyperlipidemia and coronary artery disease or PAD have evaluated the effects of lipid-lowering trials on the natural history of PAD [186-189]. Initial studies performed before the availability of statins showed regression or less progression of femoral atherosclerosis with lipid-lowering therapy [190-194], and a lower incidence of claudication and limb-threatening ischemia in patients with hyperlipidemia who were treated with surgery [195]. 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 [186]. There was no effect on the ankle-brachial index.

●Rivaroxaban – Rivaroxaban is a direct oral anticoagulant (factor Xa inhibitor) that has demonstrated benefits for reducing major adverse cardiac events and major adverse limb events in patients with atherosclerotic disease, although with an increased risk for bleeding [61,66,67]. (See 'Rivaroxaban' above.)

To evaluate whether rivaroxaban provides any functional improvements in patients with claudication, an open-label trial randomly assigned 88 patients with intermittent claudication (ankle-brachial index ≤0.85) to receive either rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily) or aspirin alone (100 mg once daily) [196]. The total walking distance measured by the six-minute walk test improved by 89 meters in the rivaroxaban-plus-aspirin group compared with 21 meters in the aspirin group for an absolute difference of 68 meters (95% CI 19-116 meters) and a relative improvement of 327 percent (95% CI 94-560). Treadmill walking was similarly improved. No major bleeding events were observed in either group. This trial had some limitations, including a relatively small sample size, which is the likely cause of differing baseline characteristics between the groups (eg, baseline treadmill walking distance) and incomplete reporting of findings. Before rivaroxaban can be recommended specifically for improving physical function, larger double-blind, placebo-controlled studies are needed to validate the walking improvements seen in this trial, as well as trials to directly compare rivaroxaban with established treatments. (See 'Beneficial' above.)

●Antiplatelet agents – The preponderance of data on available antiplatelet agents indicates that 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 for treating claudication, especially compared with the therapies discussed above (ie, cilostazol and naftidrofuryl). Thus, the main indication for antiplatelet therapy remains the secondary prevention of myocardial infarction and stroke. (See 'Antithrombotic therapy' above.)

Among three trials identified in a systematic review evaluating walking distance [197-199], antiplatelet therapy significantly improved pain-free walking distance compared with placebo (mean difference 78 feet) [200]. 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) [201-205]. 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.

In a multicenter trial, 102 patients with claudication were treated with either vorapaxar or placebo in addition to a home exercise program for six months. At six months, there was no significant difference between the vorapaxar and placebo groups in walking performance or quality of life [206].

●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 [173]. (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 reduced blood viscosity, decreases in fibrinogen concentration, and reduced platelet adhesiveness. Studies investigating the efficacy of pentoxifylline have yielded conflicting results [207-213], leading to variable recommendations for its use by various society guidelines [31-33]. One meta-analysis reported that pentoxifylline improved walking distance by 29 meters compared with placebo [212]. 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 [213]. Improvements in walking distances associated with pentoxifylline are generally substantially less than those achieved with a supervised exercise program [214] or cilostazol [215].

Compression therapy — Intermittent mechanical (non-pneumatic) calf compression has been used to treat claudication [216]. 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 [217]. Treatment effects were maintained or further improved after cessation of therapy at three months; postexercise ankle-brachial index was maintained. For the patients with a baseline pain-free walking distance of <200 meters, an increase was found in both pain-free walking distance and maximal walking distance compared with sham treatment. It does not confer any additional beneficial effects for patients undergoing a standardized supervised exercise therapy program [218-220].

Ineffective — Therapies with no proven clinical benefit for improving symptoms of claudication and which are not recommended [167] include vitamin K antagonists and low-molecular-weight heparin [221], hormone replacement therapy [222-224], Ginkgo biloba [225,226], Padma 28 [32,227], garlic [228], and vitamin E supplementation [229]. Chelation therapy also does not improve claudication distance in PAD [230].

Investigational — Pharmacologic and other device therapies (eg, negative pressure wound therapy) under investigation for the treatment of symptoms of PAD 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) [32].

Patients who show improvement and who are satisfied with their progress can be scheduled for an 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 [231].

Referral for possible intervention — Guidelines from the Society for Vascular Surgery, the American College of Cardiology, the American Heart Association, and others recommend that peripheral vascular interventions be limited to patients with lifestyle-limiting symptoms and only after an adequate trial of medical and exercise therapy. 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 'Effectiveness' 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 PAD [232]. Those who continue to smoke should be counseled again about the increased risk for PAD progression [95]. Most vascular practitioners are generally reluctant to suggest intervention (open or endovascular) in patients with claudication who continue to smoke because of overall worse outcomes.

Interventions for claudication — Options for intervention include endovascular or surgical intervention, or a combination of these (ie, hybrid procedure).

●Endovascular intervention – Endovascular intervention typically involves accessing 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 recoils after angioplasty or extension of the dissection occurs. (See "Endovascular techniques for lower extremity revascularization".)

●Surgical revascularization – Surgical revascularization involves identifying an appropriate vessel above and another below the arterial obstruction to suture a graft to bypass the obstruction. The graft can be an autogenous vein or prosthetic material. (See "Lower extremity surgical bypass techniques".)

Determining whether endovascular or surgical revascularization is the more appropriate initial intervention for patients with claudication depends upon the location and extent of the disease and the patient's risk for the intervention, among other factors (algorithm 1). Vascular imaging is used to define vascular anatomy and plan interventions. (See "Advanced vascular imaging for lower extremity peripheral artery disease".)

●Aortoiliac/common femoral artery – Aortoiliac disease is also referred to as inflow disease. Claudication resulting from the disease in this location often tends to be more disabling (buttock or thigh claudication), and the threshold to intervene for inflow disease when treating claudication 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. Common femoral artery disease is often approached using open surgical techniques often in combination with endovascular or more distal artery bypass. (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 referred to as 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. In only very rare circumstances would a more distal bypass be considered to treat symptoms of claudication [233]. (See "Approach to revascularization for claudication due to peripheral artery disease", section on 'Infrainguinal revascularization'.)

Long-term outcomes — Estimates for limb and cardiovascular outcomes at five years in patients with claudication are as follows:

●Limb morbidity – In the long-term, most patients (70 to 80 percent) will experience stable claudication with worsening claudication occurring in 10 to 20 percent and variable progression to chronic limb-threatening ischemia (CLTI) depending on the initial ankle-brachial index and risk factors (eg, ongoing smoking, diabetes) [33,72]. (See 'Progression to limb-threatening events' above.)

Among those who develop CLTI, outcomes have improved over time, related to improved medical management [234-236] and possibly the more liberal use of endovascular intervention [237]. Even among those without a revascularization option, amputation-free survival has also improved [238]. (See "Management of chronic limb-threatening ischemia", section on 'Ongoing medical therapy and follow-up'.)

●Cardiovascular morbidity and mortality — PAD is strongly associated with cardiac disease (eg, ischemic heart disease, heart failure) and cerebrovascular disease [8,10,239-241]. In a review of over 5000 participants, mortality was 59 percent at 10 years. Among those who died, cardiac and cerebrovascular disease was the main cause of death in 44.6 percent [241].

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 5^th to 6^th 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 10^th to 12^th 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

●Initial management – For most patients with claudication, we recommend initial medical management to manage symptoms, rather than an initial vascular intervention (Grade 1B). Symptoms of claudication are associated with an overall low risk of progression to limb-threatening ischemia, and a major concern with intervention is that some patients may suffer complications that worsen their symptoms or threaten the limb. A subset of patients with debilitating claudication and inflow disease may benefit from early vascular intervention. (See 'Risk for disease progression' above and 'Initial medical therapy as preferred approach' above.)

●Medical therapy – Initial medical management of patients with claudication is aimed at reducing cardiovascular disease progression and complications and improving claudication symptoms. Medical therapy includes risk factor modification and therapies targeted specifically at improving walking ability, such as exercise therapy (for those who can participate) and possibly pharmacologic therapies. Risk reduction includes antithrombotic therapy, lifestyle modifications (smoking cessation, dietary modifications), and control of blood pressure, blood sugar, and lipid levels to achieve the goals set in national guidelines. (See 'Cardiovascular risk reduction' above.)

●Antithrombotic therapy – Antithrombotic therapy is recommended as part of a risk reduction strategy for secondary prevention of atherosclerotic cardiovascular disease. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

Antithrombotic therapy reduces the risk of future major adverse cardiovascular events (MACE) and major adverse limb events (MALE). For patients with claudication, we select the specific agent based on the patient's symptoms and risk. (See 'Antithrombotic therapy' above.)

•For most patients with claudication (mild-to-moderate symptoms, no high-risk comorbidities), either aspirin (75 to 100 mg/day) or clopidogrel (75 mg/day) monotherapy is appropriate. (See 'Aspirin, clopidogrel' above.)

•For patients with severe symptoms, at risk for MALE (eg, prior revascularization) or MACE (ie, one or more high-risk comorbidities [heart failure, diabetes, kidney insufficiency, polyvascular disease]), we suggest low-dose rivaroxaban (2.5 mg orally twice daily) plus aspirin (100 mg orally once daily) provided the patient has a low baseline risk for bleeding (Grade 2B). The benefits of reducing these risks may justify the increased risk of bleeding associated with rivaroxaban. (See 'Rivaroxaban' above.)

●Improving walking ability

•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 re-evaluation. During each session, an exercise level that is of sufficient intensity to elicit claudication should be achieved. (See 'First-line therapy: Exercise' 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 cilostazol (100 mg orally twice daily) or naftidrofuryl, 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 'Second-line therapies' 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 an 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 not provided satisfactory improvement, referral for possible revascularization is appropriate.

•Options for revascularization include endovascular or surgical intervention, or a combination of these (ie, hybrid revascularization). The choice depends on the level of obstruction (aortoiliac, femoropopliteal), the severity of the disease, and the patient's risk for the intervention.

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Emile R Mohler, III, MD, who contributed to an earlier version of this topic review.