Medical management of claudication

Medical management of claudication

Author
Emile R Mohler, III, MD
Section Editor
Denis L Clement, MD, PhD
Deputy Editor
Gordon M Saperia, MD, FACC



Last literature review version 16.2: May 2008 | This topic last updated: March 25, 2008 (More)


INTRODUCTION — Patients with compromise of blood flow to the extremities most commonly present with pain of a muscle group. Intermittent claudication (derived from the Latin word for limp) is defined as a reproducible discomfort of a defined group of muscles which is induced by exercise and relieved with rest. The symptoms result from an imbalance between supply and demand of blood flow that fails to satisfy ongoing metabolic requirements. (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease").

Once claudication is suspected clinically, the diagnosis is confirmed and the disease is localized using noninvasive tests. (See "Noninvasive diagnosis of peripheral arterial disease").

Once the diagnosis is established, the patient can be treated medically with risk factor modification, exercise, and pharmacology or with percutaneous intervention or surgery. The medical management of claudication will be reviewed here. The indications for percutaneous intervention and surgery are discussed separately. (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease" and see "Indications for surgery in the patient with claudication").

RISK FACTOR MODIFICATION — The principal risk factors for the development of peripheral arterial disease (PAD) are cigarette smoking, diabetes mellitus, hypertension, and hyperlipidemia. One study of 6450 subjects estimated that 69 percent of the occurrence of PAD is attributable to these cardiovascular risk factors, with cigarette smoking being the most important factor [1] . In contrast, moderate alcohol consumption reduces the risk of PAD and intermittent claudication, as it does the risk of coronary disease. (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease", section on Risk factors, and see "Cardiovascular benefits and risks of moderate alcohol consumption").

In addition to the shared risk factors, patients with peripheral arterial disease are also at high risk for coronary and cardiovascular events and mortality [2-4] . As a result, the third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel [ATP] III) considered PAD as a coronary heart disease risk equivalent, thereby elevating it to the highest risk category [5] .

The overall approach to secondary prevention of cardiovascular disease is discussed separately. (See "Secondary prevention of cardiovascular disease: Risk factor reduction").

Cigarette smoking — Cessation of cigarette smoking reduces the progression of disease as shown by lower amputation rates and lower incidences of rest ischemia among those who quit [6-8] . One study of 343 patients with intermittent claudication, for example, compared the clinical outcomes among those who quit smoking (39 patients) with those who continued to smoke (304 patients) [8] . No patient who ceased smoking developed rest pain, which occurred in 16 percent of those who continued to smoke.

It is not clear whether smoking cessation reduces the severity of symptoms of claudication. In a meta-analysis that looked at pain free and total walking distance outcomes, smoking cessation was only found to be useful in nonrandomized trials [9] .

We agree with the following recommendations regarding smoking cessation made in the 2007 TASC II consensus document on the management of PAD [10] . (See "Management of smoking cessation").

• All patients should be strongly advised to stop smoking by their physicians
• All patients should be offered nicotine replacement and group counseling sessions
• Many patients may benefit from the addition of antidepressant drug therapy


Diabetes mellitus — No controlled trials have directly evaluated the effects of antidiabetic therapy upon the natural history of PAD. Aggressive control of blood sugar in both type 1 and type 2 diabetes reduces the risk of microvascular complications (eg, nephropathy, retinopathy, and neuropathy) [11,12] . However, in the Diabetes Control and Complications Trial of patients with type 1 diabetes, intensive insulin therapy had no effect upon the risk of PAD [13] . The results were similar in the United Kingdom Prospective Diabetes Study of patients with type 2 diabetes [12] . (See "Glycemic control and vascular complications in type 1 diabetes mellitus", section on Recommendations, and see "Glycemic control and vascular complications in type 2 diabetes mellitus").

We largely agree with the 2007 TASC II consensus document on the management of PAD, which recommends aggressive control of blood glucose levels with an A1C goal of <7.0 percent and as close to 6.0 percent as possible [10] . Less stringent goals may be appropriate for some patients (eg, older patients and those with comorbid conditions). (See "Glycemic control and vascular complications in type 2 diabetes mellitus").

Hypertension — Hypertension is a major risk factor for PAD. However, there are no data evaluating whether antihypertensive therapy alters the progression of claudication. Nevertheless, hypertension should be controlled in these patients to reduce morbidity from cardiovascular and cerebrovascular disease.

There has been past concern involving the use of beta blockers in the treatment of hypertension among patients with intermittent claudication, but there appears to be no adverse effect of beta-1 selective blockers on claudication symptoms [14-16] . As a result, these drugs are not contraindicated in patients with PAD [17] .

The HOPE trial suggested that the angiotensin converting enzyme (ACE) inhibitor ramipril provided added protection against cardiovascular events in patients with cardiovascular disease, including PAD [18] . Cardiovascular benefit was also seen in patients with PAD at baseline [19] . However, these benefits are likely to be a consequence of blood pressure reduction in this placebo-controlled trial, rather than a specific benefit of ACE inhibition. (See "Choice of antihypertensive drug and blood pressure goal in patients at increased risk for a cardiovascular event").

There is some evidence that ACE inhibitor therapy may increase increase walking distance in selected patients with PAD. (See "Angiotensin inhibition" below).

We agree with the 2007 American Heart Association statement on the treatment of blood pressure in ischemic heart disease and the 2007 European Society of Hypertension-European Society of Cardiology (ESH-ESC) guidelines on the management of hypertension which recommended a goal BP below 130/80 mmHg in patients with established coronary artery disease or a coronary risk equivalent (carotid artery disease, peripheral arterial disease, or abdominal aortic aneurysm) [20,21] . The 2007 TASC II consensus document set a higher goal (<140/90 mmHg) [10] . (See "Choice of antihypertensive drug and blood pressure goal in patients at increased risk for a cardiovascular event").

Hyperlipidemia — A number of cholesterol lowering trials in patients with hyperlipidemia and coronary and/or PAD have evaluated the effects on PAD. Initial studies, performed before the availability of statins, showed regression or less progression of femoral atherosclerosis with lipid-lowering therapy [22-24] and a lower incidence of intermittent claudication and limb-threatening ischemia in patients with hyperlipidemia who were treated with partial ileal bypass surgery [25] . A 2000 Cochrane meta-analysis of mostly older trials that specifically evaluated patients with lower limb atherosclerosis concluded that lipid-lowering therapy reduced disease progression (as measured by angiography) and helped alleviate symptoms [26] .

Subsequent studies confirmed these benefits in patients treated with statin therapy. Regression of femoral atherosclerosis [27] , a lower rate of new or worsening intermittent claudication [28] , and improvements in walking distance and pain-free walking time [29-31] have all described. The range of findings can be illustrated by the following observations:

• A post-hoc analysis of the Scandinavian Simvastatin Survival Study (4S), which included 4444 patients with angina or previous myocardial infarction and a baseline plasma total cholesterol between 212 and 309 mg/dL (5.5 and 8.0 mmol/L), found that treatment with 20 to 40 mg/day of simvastatin reduced the incidence of new or worsening intermittent claudication by 38 percent (2.3 versus 3.6 percent with placebo [28] .
• A randomized, double-blind trial included 354 patients with claudication attributable to PAD who were assigned to atorvastatin (10 or 80 mg/day) or placebo [30] . At 12 months, there was a significant improvement in pain-free walking time with high-dose atorvastatin (63 versus 38 percent with placebo [81 versus 39 seconds]) and in community-based physical activity with both doses of atorvastatin. There was no change in ankle-brachial index (ABI).


Statin therapy may also reduce the incidence of cardiovascular events in patients with PAD [32-34] . This was suggested by a study of 515 patients who were admitted for peripheral vascular interventional therapy (mean ABI 0.51) [32] . Statin use was recorded. At a median follow-up of 21 months, 65 patients died. Patients treated with a statin had a significant reduction in all-cause mortality (adjusted hazard ratio 0.52) and in death or nonfatal myocardial infarction (adjusted hazard ratio 0.48). A similar reduction in all-cause mortality in patients with PAD who are treated with statins (hazard ratio 0.46) was noted in a larger prospective observational cohort study [33] .

The evidence for benefit and the appropriate goals for cholesterol lowering in patients with all forms of cardiovascular disease are discussed separately. (See "Intensity of lipid lowering therapy in secondary prevention of coronary heart disease").

We agree with the following recommendations regarding lipid control made in the 2007 TASC II consensus document on the management of PAD [10] :

• All patients with PAD should have their LDL-cholesterol lowered to <100 mg/dL (2.6 mmol/L).
• In patients with PAD and atherosclerosis in other circulatory beds it is reasonable to lower the LDL-cholesterol to <70 mg/dL (1.8 mmol/L).


Risk factor summary — The risk factors for PAD are similar to those for other forms of atherosclerotic vascular disease and PAD is associated with an increased risk of coronary, cerebrovascular, and renovascular disease. As a result, PAD is considered a coronary heart disease equivalent, thereby elevating it to the highest risk category [5] .

The 2005 American College of Cardiology/American Heart Association (ACC/AHA) practice guidelines on PAD and the 2007 TASC II consensus document on the management of PAD recommended smoking cessation, lipid lowering with statin therapy, and treatment of diabetes and hypertension [10,17] . These secondary prevention recommendations are discussed elsewhere. (See "Secondary prevention of cardiovascular disease: Risk factor reduction").

MEDICAL VERSUS INTERVENTIONAL THERAPY — Therapy for intermittent claudication may involve medical, percutaneous, and/or surgical approaches [35] . Most patients with intermittent claudication, except for those with critical limb ischemia, are treated initially with medical therapy.

The medical management of moderate to severe intermittent claudication secondary to PAD involves two modalities in addition to risk factor modification as described above:

• Exercise training or rehabilitation
• Pharmacologic therapy


The indications for revascularization and the choice between percutaneous intervention and surgery are discussed in detail separately. Two important criteria for revascularization are severe disability that limits the patient's ability to work or to perform other activities that are important to the patient, and failure (or predicted failure) to respond to exercise rehabilitation and pharmacologic therapy. (See "Clinical features, diagnosis, and natural history of lower extremity peripheral arterial disease" and see "Indications for surgery in the patient with claudication").

EXERCISE REHABILITATION — Several studies have demonstrated the benefit of exercise rehabilitation programs in reducing symptoms of claudication [36-39] . A meta-analysis that considered only randomized, controlled trials found that exercise produced a significant increase in maximum walking time (mean difference 6.5 minutes); the benefit was greater than that seen with angioplasty at six months (mean difference 3.3 minutes) [36] .

These trials utilized leg exercise (eg, treadmill or walking). The effect of upper limb exercise was assessed in a subsequent trial in which 104 patients with stable peripheral arterial disease were randomly assigned to twice weekly aerobic exercise training with upper limb or lower limb exercise or a nonexercise training control group [40] . At six months, upper and lower limb exercise were associated with similar increases in claudication distance (51 and 57 percent), maximal walking distance (29 and 31 percent), and peak oxygen consumption.

There are several mechanisms by which exercise training may improve claudication, although the available data are insufficient to make conclusions regarding their relative importance [41] :

• Improved endothelial dysfunction via increases in nitric oxide synthase and prostacyclin [42] . (See "Endothelial dysfunction").
• Reduced local inflammation that is induced by muscle ischemia by decreasing free radicals [43] .
• Increased exercise pain tolerance [40] .
• Induction of vascular angiogenesis [44] .
• Improved muscle metabolism by favorable effects on muscle carnitine metabolism and other pathways [45] .
• Reductions in blood viscosity and red cell aggregation [46] .

Although less well studied, exercise may also improve survival. This issue was addressed in a prospective observational study of 225 men and women with PAD evaluated in whom physical activity was measured with a vertical accelerometer [47] . Patients were followed for a mean duration of 57 months at which time 75 patients (33 percent) had died. Individuals in the highest quartile of accelerometer-measured activity had a significantly lower mortality than those in lowest quartile (hazard ratio 0.29, 95% CI 0.10-0.83).

Exercise prescription — Patients should be referred to a claudication exercise rehabilitation program. These programs consist of a series of sessions lasting 45 to 60 minutes per session, involving use of either a motorized treadmill or a track to permit each patient to achieve symptom-limited claudication. 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, surrounded by warm-up and cool down sessions of five to ten minutes each.

Ideally, the patient attends at least three sessions per week, with a program length greater than three months [17] . Each session is supervised on a one-to-one basis by an exercise physiologist, physical therapist, or nurse. The supervising provider monitors the individual patient's claudication threshold and other cardiovascular limitations for adjustment of workload. During this supervised rehabilitation program, 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 may require physician review and examination of the patient.

Most patients who eventually respond to a supervised exercise protocol can expect improvement within two months. Motivated patients achieve the best results. Supervised exercise training programs are not covered by medical insurance. The benefits of exercise diminish when exercise training stops.

Despite the evidence of benefit, issues remain concerning the optimal regimen for exercise rehabilitation. In a trial cited above, for example, the improvement in claudication distance with an exercise regimen was similar with lower limb and upper limb exercise [40] . In addition, the optimal intensity of exercise is uncertain.

In an initial randomized trial addressing the issue of intensity of exercise, a regimen of low-intensity exercise for six months produced similar improvements in claudication distance and health-related quality of life as high-intensity exercise (40 versus 80 percent of maximal exercise capacity) [48] .

Another issue is the value of unsupervised exercise, which may be particularly important when access to supervised programs is limited by cost, transportation, or availability. In an observational study of 417 patients with peripheral arterial disease, those patients who reported self-directed walking for exercise ≥3 times per week walked more city blocks per week (as measured by an accelerometer) and had a significantly lower annual decline in six minute walking distance than those who walked one to two times per week or did not exercise (-48 versus -57 and -79 feet per year) [49] . Similar benefit was noted in patients who walked ≥90 minutes per week compared to a shorter duration of exercise. Benefit from exercise was also seen in the subset of patients who were asymptomatic as manifested by smaller annual declines in six minute walking performance.

The relative efficacy of supervised and unsupervised exercise in patients with intermittent claudication have been compared in eight randomized trials, which were included in a 2006 meta-analysis [50] . Walking was the dominant form of exercise training in both groups. The primary end point was maximal treadmill walking distance before and after a three month period of training. Supervised exercise led to a significantly greater improvement of approximately 150 meters (30 to 35 percent difference in improvement). However, quality of life measures (secondary end points) were not significantly different between the two groups.

PHARMACOLOGIC THERAPY — Pharmacologic therapy of claudication is aimed at symptomatic relief or slowing progression of the natural disease. A number of drugs have been evaluated but, as will be seen, the evidence of benefit is convincing only for antiplatelet agents, usually aspirin, and cilostazol [17,51] .

The benefits of drug therapy aimed to risk factor modification are discussed above. (See "Risk factor modification" above).

Antiplatelet agents — The preponderance of data on the use of currently available antiplatelet agents indicate that no or only a modest improvement in claudication symptoms can be expected and that a significant benefit may not be seen with aspirin alone. Thus, the main indication for aspirin therapy is for secondary prevention of coronary disease and stroke. (See "Benefits of aspirin in cardiovascular disease").

Aspirin — The Antithrombotic Trialists' Collaboration overview analyzed the results of randomized trials of antiplatelet therapy among more than 135,000 high-risk patients with prior evidence of cardiovascular disease, including myocardial infarction, stroke, transient ischemic attacks, unstable angina, stable angina, revascularization surgery, angioplasty, atrial fibrillation, valvular disease, and PAD [52] . Moderate dose aspirin (75 to 325 mg/day) was most commonly prescribed.

Among 26 trials of patients with intermittent claudication, 12 with peripheral grafting, and four with peripheral angioplasty, antiplatelet therapy was associated with a significant reduction in the risk of nonfatal myocardial infarction, nonfatal stroke, or vascular death (5.8 versus 7.1 percent, odds reduction 23 percent) (show table 3). The magnitude of benefit was similar in the three groups.

However, the data on aspirin alone do not suggest a statistically significant benefit in the broad PAD population, including asymptomatic patients. The overall benefit of antiplatelet therapies in the Antithrombotic Trialists' Collaboration data was driven by data from trials using ticlopidine, clopidogrel and dipyridamole [52,53] .

The Physicians Health Study, a primary prevention study, found that 325 mg of aspirin every other day decreased the need for peripheral artery surgery [54] . However, no difference was noted between the aspirin and placebo groups in the development of claudication.

Aspirin plus dipyridamole — The combination of aspirin and dipyridamole was found to increase the pain-free walking distance and resting limb blood flow in a study of 54 patients with intermittent claudication [55] . Another study in 296 patients with intermittent claudication found an improved coagulation profile and ankle/brachial index with therapy but did not report if walking distance improved with combined therapy [56] .

Ticlopidine and clopidogrel — Ticlopidine, an inhibitor of platelet aggregation. appears to modestly increase walking distance in patients with intermittent claudication [57] . However, the drug is associated with a substantial risk of leukopenia and thrombocytopenia, requiring close hematologic monitoring for at least three months. Other potential side effects include bleeding, dyspepsia, diarrhea, nausea, anorexia, rash, purpura, and dizziness. The usual dose of ticlopidine is 250 mg twice daily, with food.

Clopidogrel is a similar but safer drug. The CAPRIE trial found that clopidogrel (75 mg/day) had a modest, although significant advantage over aspirin (325 mg/day) for the prevention of stroke, myocardial infarction (MI), and PAD in 19,185 patients with a recent stroke, MI, or PAD (annual rate of 5.3 versus 5.8 percent) [58] .

Comparison of antiplatelet agents — A meta-analysis of randomized studies with antiplatelet agents found that ticlopidine had the best evidence of efficacy (ie, improvement in walking distance, reduction in occlusion and/or improvement in mortality) [59] . In addition, as noted above, the CAPRIE trial found that clopidogrel was more effective than aspirin in preventing vascular events [58] .

Nevertheless, aspirin is generally considered the antiplatelet drug of choice because of the high incidence of comorbid coronary disease, the benefits of aspirin in preventing myocardial infarction, and its lower cost.

Summary — We agree with the following recommendations for antiplatelet therapy from the TASC II consensus document for the management of PAD [10] :

• All symptomatic patients and asymptomatic patients with evidence for atherosclerosis in other circulatory beds should be prescribed an antiplatelet drug. Asymptomatic patients without evidence for atherosclerotic disease elsewhere may be considered for antiplatelet therapy.
• Aspirin is the agent of choice; clopidogrel may be used if aspirin cannot be tolerated or in the subgroup of patients with symptomatic PAD.


Warfarin — Warfarin has not been shown to improve cardiovascular outcomes in patients with PAD. (See "Secondary prevention of cardiovascular disease: Risk factor reduction", section on Warfarin).

Cilostazol — Cilostazol is a phosphodiesterase inhibitor approved by the FDA for the treatment of intermittent claudication. It suppresses platelet aggregation and is a direct arterial vasodilator [60] . The efficacy of cilostazol has been demonstrated in several studies [61-64] and in a meta-analysis of eight randomized, placebo-controlled trials that included 2702 patients with stable moderate to severe claudication [65] . In the meta-analysis, treatment with 100 mg twice daily for 12 to 24 weeks increased maximal and pain-free walking distances by 50 and 67 percent respectively [65] . Benefit may be noted as early as four weeks [63] .

Cilostazol appears to be more effective than pentoxifylline. This was illustrated in a trial of 698 patients randomly assigned to cilostazol (100 mg twice daily), pentoxifylline (400 mg three times daily), or placebo for 24 weeks [66] . The increase in mean maximal walking distance over baseline with pentoxifylline and placebo was the same (30 and 34 percent, respectively), but the increase with cilostazol was significantly greater (54 percent).

Side effects noted in clinical studies included headache, loose and soft stools, diarrhea, dizziness and palpitations [61-64] . 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 [67,68] . (See "Inotropic agents in heart failure due to systolic dysfunction", section on Phosphodiesterase inhibitors).

Based upon the evidence of benefit, a therapeutic trial (three to six months) of cilostazol (100 mg orally twice daily) is recommended (in the absence of heart failure) to improve symptoms and increase walking distance in patients with lifestyle-limiting claudication, particularly if antiplatelet agents and exercise rehabilitation are ineffective and revascularization cannot be offered or is declined by the patient [10,17,51] .

Cilostazol should be taken one-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 [67] . Cilostazol may be taken safely with aspirin and/or clopidogrel without an additional increase in bleeding time [69] .

Pentoxifylline — Pentoxifylline (Trental) is a rheologic modifier approved by the Food and Drug Administration (FDA) for the symptomatic relief of claudication [70,71] . Its putative mechanism of action includes an increase in red blood cell deformity, and decreases in fibrinogen concentration, platelet adhesiveness, and whole-blood viscosity.

Studies investigating the efficacy of pentoxifylline have yielded conflicting results [71-74] . A meta-analysis found that pentoxifylline improved walking distance by 29 meters compared with placebo [74] . The improvement was approximately 50 percent in the placebo group, while pentoxifylline provided an additional 30 percent. The benefit was substantially less than that achieved with a supervised exercise program (123 percent increase in peak walking time in one study) [38] . In addition, pentoxifylline is less effective than cilostazol [66] .

The available data indicate that the benefit of pentoxifylline is marginal and not well established [17] . The Seventh ACCP Consensus Conference recommended against the use of pentoxifylline [18] , while the ACC/AHA guidelines concluded that pentoxifylline (400 mg three times per day) may be considered a second-line drug to cilostazol to improve walking distance [17] .

The 2007 TASC II consensus document on the management of PAD makes no recommendation on the use of pentoxifylline [10] .

Other rheologic modifiers — Hemodilution therapy for reducing the plasma viscosity involves removing blood and replacing it with a colloidal solution of hydroxyethyl starch (HES) or a low-molecular-weight dextran (LMWD) one to two times weekly for several weeks. This approach has resulted in some improvement in pain free walking distance in clinical trials [75,76] , but the relatively small benefit achieved does not warrant routine use of this therapy.

Naftidrofuryl — Naftidrofuryl is a 5-hydroxytryptamine-2-receptor antagonist that is currently available only in Europe [77-79] . The mechanisms of action of this drug are unclear but it is thought to promote glucose uptake and increase adenosine triphosphate levels. A meta-analysis of four trials showed an increase in the time to initial pain development on treadmill walking over a three to six month period [9] .

The 2007 TASC II consensus document on the management of PAD concluded that naftidrofuryl (600 mg/day orally) can be considered for the treatment of intermittent claudication [10] .

Angiotensin inhibition — As mentioned above, data from the HOPE trial suggested that ramipril therapy provided cardiovascular benefit in patients with PAD at baseline [19] . However, these benefits are likely to be a consequence of blood pressure reduction in this placebo-controlled trial, rather than a specific benefit of ACE inhibition. (See "Hypertension" above).

A separate issue is whether angiotensin inhibition might provide symptomatic benefit in patients with intermittent claudication. This was evaluated in a small randomized trial in which 40 older patients with intermittent claudication were assigned to ramipril (10 mg once daily) or placebo for 24 weeks [80] . After adjustment for baseline values, ramipril therapy was associated with a significant 227 second increase in pain-free walking time and a significant 451 second increase in maximum walking time; no changes were noted in the placebo group.

The generalizability of this initial observation is unclear since there were strict inclusion criteria, including superficial femoral artery stenosis or occlusion. Patients with diabetes, hypertension, or coronary heart disease and those with a history of ACE inhibitor therapy were excluded. Further studies are required before the use of ACE inhibitors for claudication can be recommended.

Buflomedil — Buflomedil is an alpha adrenolytic agent with vasoactive and hemorrheologic properties. It is available for use in Europe but not the United States.

The best available data in peripheral arterial disease comes from the LIMB trial, which evaluated the long-term efficacy and safety of buflomedil in 2078 patients with intermittent claudication and an ankle-brachial index between 0.30 and 0.80 who were randomly assigned to either placebo or buflomedil at 300 or 150 mg daily (adjusted to the creatinine clearance) [81] . At a median follow-up of 2.8 years, the rate of the primary outcome (composite end point of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, symptomatic deterioration of PAD, or leg amputation) was significantly lower in patients who received buflomedil (9.1 versus 12.4 percent); this benefit was primarily due to a reduction in symptomatic deterioration. There were no important differences in safety outcomes.

Limitations of the trial included the use of soft end points such as self-reported symptoms and the use of statin therapy in only about 15 percent of patients [82] .

Ginkgo biloba — Ginkgo biloba has been studied in patients with intermittent claudication with modest success. The mechanism by which ginkgo may work in this disorder is unclear, but may involve a number of activities including an antioxidant effect, inhibition of vascular injury, and antithrombotic effects. (See "Clinical use of ginkgo biloba").

In a meta-analysis of eight randomized, double-blind, placebo-controlled trials, patients who received ginkgo biloba extract had a significant increase in pain free walking distance (34 meters) compared with placebo [83] . However, there were a number of problems with the studies, including lack of clarity regarding the randomization procedure. In addition, concerns about recommending herbal products in general remain since these remedies are not regulated by the United States Food and Drug Administration. (See "Overview of herbal medicine", sections on Lack of standardization and Lack of regulation).

The ACC/AHA guidelines concluded that benefit is not well established for ginkgo biloba for the treatment of intermittent claudication [17] .

Ineffective therapies

Estrogen replacement therapy — The effect of estrogen replacement therapy (ERT) on the incidence of PAD is unclear. In a population-based study of 2196 postmenopausal women, ERT for one year or more was associated with a 52 percent decreased risk of peripheral arterial disease (defined as an ankle/arm systolic blood pressure index lower than 0.9) [56] .

In contrast, the Heart and Estrogen/Progestin Replacement Study (HERS) of 2763 postmenopausal women with coronary heart disease found that hormone replacement therapy with estrogen and progesterone did not significantly reduce the incidence of peripheral arterial events (relative hazard 0.87 compared to placebo) [57] . Based upon the latter report, ERT does not appear to have a role in the management of peripheral vascular disease. (See "Postmenopausal hormone therapy and cardiovascular risk").

Chelation therapy — The use of repeated intravenous infusion of EDTA or "chelation therapy" has been advocated by some researchers in the treatment of intermittent claudication. A double-blind, randomized, controlled trial was conducted to evaluate the effectiveness of chelation therapy in patients with intermittent claudication. The main outcome measure was walking distances and ankle/brachial pulse indices. No significant difference between the chelation therapy group and the control group was observed [84] .

The ACC/AHA guidelines concluded that chelation therapy was not beneficial and may be harmful in the treatment of intermittent claudication [17] .

Vitamin E supplementation — Vitamin E has been evaluated in the treatment of coronary heart disease because of its antioxidant properties. (See "Nutritional antioxidants in coronary heart disease").

Several small trials have evaluated its efficacy in the treatment of intermittent claudication; there was no clear evidence of benefit [85] . The ACC/AHA guidelines concluded that vitamin E was not recommended for the treatment of intermittent claudication [17] .

Investigational agents — The following newer agents are currently being investigated in patients with claudication. Their clinical use is not yet recommended.

Verapamil — Vasodilators are not thought to be effective in patients with claudication because they rarely increase blood flow beyond the level produced by maximally tolerated exercise [86] . However, a randomized, double-blind, placebo-controlled crossover trial of 44 patients with stable intermittent claudication reported that treatment of verapamil (120 to 480 mg per day) for four weeks increased mean pain free walking distances by 29 percent and maximal walking distances by 49 percent compared to placebo (show figure 1) [87] . Verapamil had no effect on systolic ankle pressure, ankle/brachial pressure index, peripheral leg temperature or systolic blood pressure, suggesting that its effects are not mediated by improved hemodynamics.

Antichlamydophila therapy — It has been proposed that chronic Chlamydophila (formerly Chlamydia) pneumoniae infection may promote the development of atherosclerosis and clinical trials of antichlamydophila therapy have been performed in a variety of clinical settings. This hypothesis was tested in a randomized, placebo-controlled trial that investigated the efficacy of an antichlamydophila antibiotic, roxithromycin (300 mg/day for 30 days), to prevent progression of peripheral arterial disease (PAD) in 40 men who were seropositive for C. pneumoniae, and had established PAD and at least one carotid plaque detectable by ultrasonography [88] . During 2.7 year follow-up, patients treated with roxithromycin experienced significantly fewer invasive revascularizations (5 versus 29 interventions) compared with placebo, and had significantly less frequent limitation to 200 m walking distance (20 versus 65 percent).

These observations need to be confirmed in a larger trial of patients with PAD, particularly in view of the lack of benefit of antichlamydophila therapy in major trials of patients with coronary disease. (See "Chlamydophila (Chlamydia) pneumoniae infection as a potential etiologic factor in atherosclerosis").

Propionyl-L-carnitine — The mechanism of action of propionyl-L-carnitine in patients with claudication is thought to be via increased energy metabolism in ischemic muscle [89,90] . A double-blind placebo-controlled study of 245 patients with intermittent claudication found that active therapy resulted in a modest increase in maximal walking distance (73 versus 46 percent with placebo) and time to initial pain on treadmill walking [89,90] . In a follow-up report from this trial, propionyl-L-carnitine, but not placebo, resulted in an improvement in quality of life, emotional status, and physical function among patients with more severely limited walking capacity (<250 meters) at baseline [91] . In contrast, patients with mild functional impairment (walking distance >250 meter) had no response to the drug [92] . Other studies have also found that propionyl-L-carnitine improves exercise performance and functional status in patients with claudication [93] .

The ACC/AHA guidelines concluded that benefit is not well established for propionyl-L-carnitine for the treatment of intermittent claudication [17] .

Defibrotide — Defibrotide is a polydeoxyribonucleotide that stimulates fibrinolysis via increased release of tissue plasminogen activator and prostacyclin and reduced release of plasminogen activator inhibitor from endothelial cells. Defibrotide also decreases beta thromboglobulin and may therefore act by inhibiting platelet aggregation. The results from a placebo-controlled trial study reported an increased maximal treadmill walking distance over a six month period [94] .

Prostaglandin E1 — Prostaglandin E1 (PGE1) is a vasodilator and an inhibitor of platelet aggregation. However, it is rapidly inactivated in the lungs, and must be given intraarterially or intravenously using large doses. PGE1 is experimental and has not been approved for clinical use.

In a study of 80 patients with intermittent claudication, intravenous administration of a prostaglandin E1 prodrug produced a dose related improvement in walking distance and quality of life at four and eight weeks [95] .

A Cochrane review of five studies comparing PGE1 (eg, alprostadil, epoprostenol) with placebo found that significant increases in walking distances were attained with PGE1, which persisted even after termination of treatment [96] . Further randomized trials were recommended to confirm these results.

Prostacyclin — Beraprost is an orally-active prostaglandin I2 (prostacyclin) analog that has antiplatelet and vasodilating properties. Its efficacy was evaluated in the BERCI-2 trial of 549 patients with a pain-free walking distance of 50 to 300 meters that changed by <25 percent during a four week placebo run-in phase [97] . After six months, patients had a >50 percent increase in walking distance on a treadmill and on one or more earlier treadmill test with beraprost (40 mcg three times daily) compared to placebo (44 versus 33 percent). The pain free walking distances increased by 82 and 53 percent, respectively, and the maximum walking distances increased by 60 and 35 percent, respectively. The incidence of critical cardiovascular events (cardiac death, myocardial infarction, coronary revascularization, stroke, transient ischemic attack, or critical or subcritical leg ischemia requiring medical or surgical intervention) was the lower but not statistically significantly so (4.8 versus 8.9 for placebo).

Different results were found in another study of 897 patients, which had the same study design as BERCI-2 [98] . Patients were treated with beraprost (40 mcg three times daily) or placebo after a three week placebo run-in period. At six months, there was no difference between beraprost and placebo in the improvement of mean walking distance or pain free walking distance. There was no significant improvement in quality of life for either group. The reasons for the difference in outcome between BERCI-2 and this study may include a lower incidence of hypertension, diabetes, and lipid disorders and a higher baseline ankle/brachial index in the BERCI-2 study population.

The ACC/AHA guidelines concluded that oral vasodilation prostaglandins were not effective for the treatment of intermittent claudication [17] .

NM-702 — NM-702 is an investigational phosphodiesterase inhibitor that has been shown in phase I and II studies to be well tolerated and to improve treadmill performance. It has the additional potentially beneficial property of inhibiting human platelet thromboxane A2 synthetase.

In a study of safety and efficacy, 386 individuals with clinically stable claudication were randomly assigned to placebo or to NM-702 (4 mg or 8 mg twice daily for 24 weeks) [99] . Statistically significant improvements in treadmill claudication onset and peak walking times were noted. The drug was well tolerated and no unanticipated safety concerns were found.

Mesoglycan — Mesoglycan, a sulfated polysaccharide compound containing the thrombin inhibitors heparan and dermatan sulfate, is available in some European countries. One randomized trial of 242 patients treated for 23 weeks found that a clinical response, defined as ≥50 percent increase over baseline in absolute walking distance, was more frequently achieved with mesoglycan (50 versus 26 percent with placebo) [100] .

Glutathione — Glutathione is an antioxidant that improved pain free walking distance in a randomized, double-blind, placebo-controlled study of 40 patients with intermittent claudication [101] . However, glutathione was administered intravenously twice daily, an obvious disadvantage compared with oral therapies.

Therapeutic angiogenesis — Animal studies have suggested that angiogenic growth factors can stimulate the development of collateral arteries, an approach known as therapeutic angiogenesis [102] . The safety and efficacy of therapeutic angiogenesis in humans is under investigation with variable results in patients with peripheral arterial disease [103-106] . It is also being evaluated in other disorders such as refractory angina and limb-threatening ischemia. (See "Therapeutic angiogenesis for management of refractory angina" and see "Treatment of chronic critical limb ischemia", section on Stimulation of angiogenesis).

As an example, the TRAFFIC trial evaluated the role of recombinant fibroblast growth factor-2 (rFGF-2) in 190 patients with intermittent claudication due to infrainguinal peripheral artery disease [105] . Patients were randomly assigned to bilateral lower limb arterial infusions of placebo, single dose rFGF-2, or repeat dose rFGF-2 on days 1 and 30. At 90 days, a single infusion of rFGF-2 was associated with a significant increase in peak walking time compared with placebo (increase of 1.77 versus 0.6 minutes compared to baseline); there was no additional benefit from a second infusion. This was a phase II study that was not powered to detect functional improvements in activities of daily living or quality of life.

However, the RAVE trial found no benefit from intramuscular injection of an adenoviral vector transmitting the vascular endothelial growth factor (VEGF) gene in 105 patients with claudication [106] . Changes from baseline in peak walking time, claudication onset time, ankle/brachial index and quality of life were similar at 12 and 26 weeks with two doses of VEGF compared to placebo.

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Claudication"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

RECOMMENDATIONS — The therapy of patients with claudication involves the use of antiplatelet agents, risk factor modification including an exercise program, and possibly medical therapy for improvement in symptoms (show algorithm 1). The following recommendations are generally consistent with the 2004 Seventh American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy [51] , the 2005 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for peripheral arterial disease [17] , the TASC II consensus document on the management of PAD [10] , and the 2006 ACC/AHA guidelines on secondary prevention [107] .

Antiplatelet agents — Antiplatelet agents are warranted in all patients with claudication to reduce the risk of myocardial infarction, stroke, and cardiovascular mortality. Aspirin (75 to 162 mg/day) should be given indefinitely, particularly in patients with clinically evident coronary or cerebrovascular disease [17,51] . Aspirin may be considered in patients without symptoms [10] . (See "Benefits of aspirin in cardiovascular disease").

Clopidogrel (75 mg/day) is an alternative treatment but aspirin is preferred because the much higher cost of clopidogrel is not justified [51,53] by the possible small increase in efficacy shown in the CAPRIE trial [58] . (See "Antiplatelet agents" aboveSee "Antiplatelet agents" above).

Modification of risk factors — The risk factors for PAD are similar to those for other forms of atherosclerotic vascular disease and PAD is associated with an increased risk of coronary, cerebrovascular, and renovascular disease. As a result, PAD is considered as a coronary heart disease risk equivalent, thereby elevating it to the highest risk category [5] .

Because of this risk, secondary prevention modalities, including smoking cessation, lipid lowering with statin therapy, and treatment of diabetes and hypertension, are recommended to the goals set in current national guidelines [10,17] . (See "Risk factor modification" above and see "Secondary prevention of cardiovascular disease: Risk factor reduction" and see "Intensity of lipid lowering therapy in secondary prevention of coronary heart disease").

Asymptomatic patients — Certain patient groups are at higher risk for PAD, such as those ≥70 years of age or ≥50 years of age with a history of smoking and/or diabetes. Such patients should be screened for PAD with measurement of the ankle-brachial index and, if necessary, other tests [17] . Patients with PAD should be treated with same secondary prevention measures as those with claudication [17] . (See "Noninvasive diagnosis of peripheral arterial disease", section on Asymptomatic patients).

Exercise — A supervised exercise program is recommended as part of the initial treatment regimen. It should be performed for a minimum of 30 to 45 minutes at least three times per week for a minimum of 12 weeks [10,17] . During each session, exercise that is of sufficient intensity to elicit claudication is recommended [10] . The value of an unsupervised exercise program is less well studied, but is generally recommended for patients who cannot participate in supervised exercise programs. (See "Exercise rehabilitation" above).

Medical therapy — Among the medical therapies that have been evaluated for the treatment of claudication. Convincing evidence of benefit is available for cilostazol [17,35,51] .

Cilostazol — A therapeutic trial of cilostazol (100 mg orally twice daily) is recommended (in the absence of heart failure) to improve symptoms and increase walking distance in patients with lifestyle-limiting claudication, particularly if the above measures are ineffective and revascularization cannot be offered or is declined by the patient [17,51] . Cilostazol is not recommended for routine use in all patients with claudication because of its cost and modest clinical benefit. (See "Cilostazol" above).

Cilostazol should be taken one-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 [67] . Cilostazol may be taken safely with aspirin and/or clopidogrel without an additional increase in bleeding time [69] .

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 [67,68] . (See "Inotropic agents in heart failure due to systolic dysfunction", section on Phosphodiesterase inhibitors).

Pentoxifylline — The available data indicate that the benefit of pentoxifylline is marginal and not well established [10,17] . (See "Pentoxifylline" above).
Other — The ACC/AHA guidelines concluded that benefit is not well established for ginkgo biloba, L-arginine, and propionyl-L-carnitine in patients with intermittent claudication, and that oral vasodilator prostaglandins are not effective, vitamin E is not recommended, and chelation therapy may be harmful [17] .