Lower Extremity Arterial Disease

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Chapter 109

Lower Extremity Arterial Disease

Decision Making and Medical Treatment

Jessica P. Simons, Andres Schanzer

Based on a chapter in the seventh edition by John W. York and Spence M. Taylor

The management of lower extremity peripheral artery disease (PAD) represents one of the most challenging problems for the vascular specialist. Although its worldwide prevalence is unknown, it is estimated that 8 to 12 million Americans are affected by lower extremity PAD.13 A clear association between the prevalence of PAD and increased age has been established.4,5 In an analysis of 2381 patients who participated in the United States National Health and Nutrition Examination Survey, the prevalence of PAD was found to be 4.3% overall, with prevalences of 0.9% in patients between the ages of 40 and 49 years, 2.5% in patients between the ages of 50 and 59 years, 4.7% in patients between the ages of 60 and 69 years, and 14.5% in patients more than age 69 years.4 The prevalence of PAD is expected to increase in the United States and worldwide as the population ages, cigarette smoking persists, and the epidemics of diabetes mellitus (DM), hypertension, and obesity grow.5

Each year, more than 100,000 of these patients will undergo some form of arterial revascularization. Decisions regarding the management of lower extremity PAD pose a unique challenge because of the complex interplay of factors that must be considered, including the underlying pathology, anatomic defects, degree of ischemia, availability of conduits, comorbid conditions, functional status, ambulation potential, and suitability of anatomy for successful revascularization. Appropriate management of lower extremity PAD requires a firm understanding of these factors for good decision making.

Patients with lower extremity ischemia are typically divided into two groups—those with intermittent claudication and those with critical limb ischemia (CLI)—depending on symptoms at presentation. Claudication and CLI are managed differently because of major differences in their natural histories and expected clinical outcomes after treatment. In general, there is more consensus among clinicians regarding decision making for CLI because the natural history of untreated CLI more frequently leads to limb loss than does claudication. Appropriate decision making requires a basic understanding of the systemic nature of the disease. Patients with CLI often have severe associated cardiovascular comorbidities and are generally older and in poorer health than those with claudication. Treatment must therefore be structured accordingly. In contrast, patients with claudication typically seek treatment for the relief of lifestyle limiting pain with ambulation. These patients exhibit a more benign natural history with respect to limb viability, with amputation rates of 1% to 7% at 5 years and clinical deterioration of the limb in only 25%.68 As with CLI, claudication is a marker of significant systemic atherosclerosis, with associated cardiovascular mortality rates at 1, 5, and 10 years as high as 12%, 42%, and 65%, respectively.68 All patients with PAD require medical management of their cardiovascular disease, and many also benefit from either endovascular or open revascularization, as discussed later.

Medical Management

Because atherosclerosis is a systemic disease, the initial treatment of lower extremity PAD should include risk factor modification in an effort to limit progression of the atherosclerotic process. Pharmacologic treatment geared toward the relief of symptoms and the stabilization of existing atherosclerosis is also essential. Patients presenting with PAD are at significantly increased risk for premature cardiovascular events, including myocardial infarction (MI), stroke, and death.9,10 Detection of occult PAD is an important indirect marker for systemic atherosclerosis.11 Any patient older than 40 years who has an ankle-brachial index (ABI) of less than 0.90 has significant PAD, even in the absence of symptoms.12 An ABI of less than 0.90 is 95% sensitive in identifying angiographically confirmed PAD (Fig. 109-1).5,13 Interestingly, more than 50% of patients with an abnormal ABI fail to show typical symptoms of claudication or CLI because of the coexistence of other major comorbidities, a condition sometimes referred to as “chronic subclinical lower extremity ischemia.” There is wide agreement that risk factor modification is indicated for any patient with lower extremity PAD, regardless of symptom presence or severity. Several guidelines have been published5,1416,76 regarding the use of screening for PAD, including a recent systematic review.77 However, endovascular or surgical intervention for asymptomatic disease has not been shown to provide any benefit over waiting until the development of symptoms.14 The natural history of asymptomatic PAD is also not well studied. Citing population-based studies, the Trans Atlantic Inter Society Consensus (TASC II) authors5 concluded that the ratio of asymptomatic to symptomatic PAD patients is as high as 3 : 1 (Fig. 109-2). Unfortunately, there are currently no data available to accurately predict which patients will develop symptoms in the future.

Risk Factor Modification

The risk factors associated with PAD are similar to those classically linked with coronary artery disease. Investigators from the Framingham Heart Study who analyzed “factors of risk” for coronary artery disease were the first to identify demographic and comorbid factors independently associated with systemic atherosclerosis.17,18 Numerous reports since then have confirmed that advanced age, tobacco use, diabetes, dyslipidemia, and hypertension are the primary risk factors associated with PAD (Fig. 109-3). More recent studies have identified non-Hispanic black race,4,19 chronic renal insufficiency,4,20 and elevated homocysteine levels21,22 as additional factors associated with the onset of PAD. All patients with the diagnosis of PAD require appropriate risk factor modification, regardless of whether more aggressive therapy is also being contemplated. Risk factor modification is discussed in detail in the section on Atherosclerotic Risk Factors and is summarized here.


Smoking has been associated with lower extremity ischemia since the early 1900s and arguably remains the most important risk factor for its development. Smoking cessation has been shown to reduce the risk of MI and death in patients with PAD and to delay the progression of lower extremity symptoms from claudication to CLI and limb loss.2325 The physiologic effects of smoking are incompletely understood; however, several pathologic processes have been implicated. Nicotine inhalation has been demonstrated to reduce high-density lipoprotein (HDL) levels, increase platelet aggregation, decrease prostacyclin, increase levels of thromboxane, and promote vasoconstriction.26 Each of these effects contributes to the development and progression of atherosclerotic disease.

Although the beneficial effects of smoking cessation have been clearly demonstrated,27 the role of smoking cessation in the treatment of intermittent claudication is less clear. Treadmill studies have demonstrated an increase in pain-free ambulation distances in some but not all patients after smoking cessation.5 Nonetheless, smoking cessation should be the goal in all patients with lower extremity ischemia to reduce their risk of cardiovascular events and limit the progression of lower extremity PAD. The importance of smoking cessation extends to patients who have undergone lower extremity revascularization because there is a threefold increased risk of graft failure in smokers compared with nonsmokers.28

The role of the physician is to educate patients about the consequences of this high-risk behavior, provide emotional support, and prescribe pharmacologic aids aimed at treating the addiction. Structured smoking cessation programs have demonstrated a 22% cessation rate at 5 years, compared with 5% in patients who attempt to stop smoking independently.27 The addition of pharmacologic agents, such as bupropion, have increased smoking cessation rates in randomized studies of patients with PAD, achieving 3-, 6-, and 12-month abstinence rates of 34%, 27%, and 22%, respectively, compared with 15%, 11%, and 9% in control groups.28 More recently, varenicline (Chantix, Pfizer Inc., New York, NY) has been approved for use in the United States, with remarkable early results. This pharmacologic agent acts as a partial agonist of the α4β2 nicotine acetylcholine receptor and was developed for the sole purpose of treating tobacco addiction. It stimulates the release of dopamine in sufficient quantities to reduce nicotine craving while minimizing the effects of withdrawal. Randomized studies of varenicline have shown continuous abstinence rates of 44% and 22% at 12 and 52 weeks, respectively, versus 17% and 8% in control groups.29 Despite the promise of these new pharmacologic agents, the prognosis for smoking cessation in most patients continues to be poor. Tobacco addiction tends to be inexorable and is characterized by frequent relapses and poor long-term cessation rates (see Chapter 27).

Diabetes Mellitus

The association between DM and atherosclerotic vascular disease is well documented.3033 Diabetes is widely prevalent among patients with lower extremity ischemia. It has been estimated that each incremental 1% increase in glycosylated hemoglobin is associated with a 28% increase in risk for PAD.13 Atherosclerosis in individuals with DM occurs as a consequence of arterial wall degeneration due to alterations in nitric oxide availability to endothelial cells and the stimulation of proatherogenic activity in vascular smooth muscle cells by the reduction of phosphatidylinositol-3 kinase. Diabetes also alters blood component activity via enhanced platelet aggregation, increased blood viscosity, and elevation of fibrinogen levels.34

Although the microvascular complications of diabetic retinopathy and nephropathy appear to be a consequence of uncontrolled DM, the effect of intensive blood glucose control on macrovascular complications is unclear. The Diabetes Control and Complications Trial evaluated 1441 patients with type 1 diabetes and compared conventional therapy with intensive insulin therapy. Tighter glucose control regimens exhibited only a nonstatistically significant trend toward a reduction in cardiovascular events and had no demonstrable effect on the incidence of PAD.35 Additional studies have demonstrated similar findings; strict glucose control reduced microvascular complications but failed to significantly decrease macrovascular complications.36,37 Despite these findings, many experts continue to believe that strict glucose control in PAD patients is important to prevent further atherosclerotic complications. The current American Diabetes Association guidelines recommend hemoglobin A1c levels less than 7% as a treatment goal for all patients with DM. They further suggest that the goal of therapy should be to maintain glucose control as close to normal as possible (hemoglobin A1c <6%) without inducing significant hypoglycemia (see Chapter 28).5


The Framingham Offspring Study showed, and other studies confirmed, that hypertension is associated with a two- to threefold increased risk of PAD.38,39 Hypertension is also a risk factor for stroke, coronary artery disease, congestive heart failure, and chronic renal insufficiency. Current guidelines recommend a target blood pressure of less than 140/90 mm Hg in high-risk groups, such as those with documented PAD, and less than 130/80 mm Hg in patients who also have diabetes or renal insufficiency.40,41

The specific pharmacologic agent chosen for blood pressure control is less important than the maintenance of a normotensive state.42 All drugs that are effective at reducing systemic blood pressure decrease the risk of cardiovascular events. Most patients require multiple agents for adequate blood pressure control. Angiotensin-converting enzyme (ACE) inhibitors are particularly beneficial, as shown in the Heart Outcomes Prevention Evaluation (HOPE) study. Patients with adequate blood pressure control using the ACE inhibitor, ramipril, experienced a reduction in subsequent stroke, MI, and vascular-related mortality.43 Subgroup analysis of 4046 patients with PAD found a 22% risk reduction in patients randomized to ramipril compared with placebo. This finding was independent of the absolute reduction in blood pressure, leading the Food and Drug Administration (FDA) to approve ACE inhibitors as a cardioprotective drug in high-risk groups (see Chapter 30).


Total serum cholesterol levels greater than 200 mg/dL (5.18 mmol/L) are associated with an increased risk of cardiac-related events, especially in combination with a low HDL fraction (<40 mg/dL [1.04 mmol/L] in men; <50 mg/dL [1.30 mmol/L] in women) and an elevated low-density lipoprotein (LDL) level (>130 mg/dL [3.37 mmol/L]).4446 Lipid-lowering agents, specifically 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (“statins”), have been shown to decrease the risk of MI-related death in high-risk patients.47 The beneficial effects of statin therapy are pleomorphic and appear to be independent of their lipid-lowering properties; they work by stabilizing existing atherosclerotic plaques, decreasing oxidative stress, and reducing vascular inflammation.48 Statin therapy may also protect against thrombosis by altering the lipid content of platelets, thereby decreasing platelet aggregability.

The direct benefits of statin therapy on cardiac-related events have been demonstrated in multiple well-designed studies.4951 Until recently, however, the effects of lipid management on PAD had been studied only in subgroup analyses of larger comprehensive coronary artery disease trials. For example, subgroup analysis of high-risk patients with PAD enrolled in the Heart Protection Study and treated with simvastatin found significant reductions in cardiovascular events (MI, stroke, vascular-related death).47 Perhaps more significantly, Feringa et al52 demonstrated in their cohort study of 1374 patients with lower extremity PAD that intense statin therapy (target LDL levels <70 mg/dL [1.81 mmol/L]) was independently associated with improved survival over a mean follow-up of 6 years. Benefits have also been seen in studies that have not evaluated a specific target LDL level; in the PREVENT III cohort183 of 1404 patients who underwent lower extremity bypass for CLI, use of any statin therapy (regardless of specific agent or specific dose) was associated with a significant 1-year survival benefit.184

The modulation of HDL cholesterol, although less well studied, is also believed to play an important role in dyslipidemia management in patients with PAD.46 Well-designed studies have found that adding niacin to conventional statin therapy results in regression of atherosclerotic plaques in patients with femoral artery stenosis and a decrease in the intima-media thickness of carotid artery plaques.53 These beneficial effects were observed in addition to a documented pronounced reduction in the progression of coronary artery disease. These PAD-specific benefits occur independently of lipid control. Improvements in leg function, ABI, walking performance, symptoms of claudication, and perioperative and long-term mortality have been demonstrated.54

Currently, the American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend an LDL cholesterol level of less than 100 mg/dL (2.59 mmol/L) in patients with PAD and an even lower level (<70 mg/dL [1.8 mmol/L]) in high-risk patients with more generalized atherosclerosis. In patients with PAD who have elevated triglycerides, precluding the accurate calculation of serum LDL levels, a non-LDL cholesterol level less than 130 mg/dL (3.37 mmol/L) is recommended (Table 109-1) (see Chapter 29).5,5557


The important influence of homocysteine metabolism on premature atherosclerosis was suspected in the 1990s when a distinct group of young patients with advanced atherosclerosis and no other established risk factors was investigated.58 Plasma levels of homocysteine are regulated in part by B vitamins, and vitamin supplementation lowers plasma homocysteine levels.59 Thus, low levels of folate and vitamin B6 are also associated with the risk of PAD, perhaps through the modulation of homocysteine levels.60 Elevated circulating homocysteine results in endothelial dysfunction and injury, followed by platelet activation and thrombus formation. Other effects of hyperhomocysteinemia include the production of hydrogen peroxide (which mediates endothelial injury), increases in factors XII and V, decreases in protein C, and inhibition of thrombomodulin and heparin sulfate. Early studies found elevated homocysteine to be an independent risk factor for coronary artery disease and stroke.61 More recently, however, studies, such as the Vitamin Intervention for Stroke Prevention Trial, have questioned the actual impact of abnormal homocysteine metabolism on premature atherosclerosis, because they failed to show a benefit of high-dose folic acid therapy on stroke prevention.62 Other randomized controlled trials by Liem et al63 and Wrone et al64 failed to show a beneficial impact of folic acid administration on cardiovascular endpoints in patients with stable coronary artery disease and end-stage renal disease.

Despite these recent reports, serologic evaluation for elevated homocysteine levels is still recommended for patients with family histories of multiple thrombotic events, patients with premature cardiovascular symptoms in the absence of conventional risk factors, and selected patients with coronary artery disease, PAD, stroke, deep venous thrombosis, and pulmonary embolism. Supplemental B vitamins or folic acid therapy may be worthwhile; however, level I data that show a benefit in the prevention of cardiovascular disease are lacking (see Chapter 26).5

Platelets and Thrombosis

Antiplatelet therapy is now widely accepted among physicians for the treatment of cardiovascular disease, and it has been shown to reduce the risk of nonfatal MI, ischemic stroke, and vascular-related death. It should be used in all patients with PAD. The Antiplatelet Trialists’ Collaboration included 102,459 patients with cardiovascular disease (MI, stroke, PAD, or other vascular disease) and concluded that the risk of fatal or nonfatal cardiovascular events in patients treated with antiplatelet therapy was 9.5%, compared with 11.9% in the untreated control group.65 Subgroup analysis of patients with claudication in this study revealed an 18% to 23% reduction in cardiovascular-related events.

Clopidogrel (Plavix, Bristol-Myers Squibb, New York, NY) is the only antiplatelet agent approved by the FDA for the secondary prevention of atherosclerotic vascular disease, including PAD. The primary supporting data were derived from the findings of the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, which randomized more than 19,000 patients with known cardiovascular disease to receive either daily clopidogrel (75 mg) or aspirin (325 mg).66 Endpoints of stroke, MI, or death were examined. Clopidogrel was associated with an overall 8.7% reduction in the composite endpoint. In a subgroup analysis of 6452 PAD patients, a relative cardiovascular risk reduction of 24% was found in the clopidogrel group compared with the aspirin group. Clopidogrel was well tolerated, with few adverse effects.66

The Clopidogrel for High Atherothrombotic Risk, Ischemic Stabilization, Management, and Avoidance (CHARISMA) investigators attempted to answer the question of whether dual antiplatelet therapy with aspirin and clopidogrel was superior to aspirin alone in preventing stroke, MI, and death in a broad population of patients at risk for cardiovascular events. In this randomized study of 15,603 patients, there was no significant difference in the composite outcome of MI, stroke, and death between the two groups.68 In the group that received dual antiplatelet therapy, there was a significantly greater rate of moderate bleeding (transfusion required) with a relative risk of 1.62 (2.1% compared with 1.3%).

A third antiplatelet drug, picotamide, was studied for the treatment of cardiovascular disease. Picotamide is an inhibitor of thromboxane A2 synthase and thromboxane-endoperoxide receptors. The Drug Evaluation in Atherosclerotic Vascular Disease in Diabetics (DAVID) study demonstrated that picotamide was more effective than aspirin alone in reducing overall mortality at 24 months in patients with PAD and type 2 diabetes.67

Two recent trials analyzed the benefit of aspirin for primary prevention in at-risk patients. The Antithrombotic Trialists’ Collaboration performed a meta-analysis of low-dose aspirin in the primary prevention of several cardiovascular endpoints and the incidence of major bleeding events. They found that aspirin therapy yielded a 12% proportional reduction in serious vascular events (0.51% aspirin versus 0.57% control per year; P = 0.0001), but also increased major gastrointestinal and extracranial bleeding events (0.10% versus 0.07% per year; P < .0001).69 The authors concluded that aspirin was of uncertain value for primary prevention when weighed against the risk of adverse bleeding events. Similarly, the Aspirin for Asymptomatic Atherosclerosis Trialists group conducted a randomized controlled trial on the use of low-dose aspirin for primary prevention of cardiovascular events in patients with diminished ABIs on screening examination.70 For the primary endpoint of fatal or nonfatal MI, stroke, or revascularization, they found no difference between groups (13.7 events per 1000 person-years in the aspirin group versus 13.3 in the placebo group; hazard ratio, 1.03; 95% confidence interval [CI], 0.84-1.27). There were no significant differences for any of the secondary endpoints, including major hemorrhage. They concluded there was no significant benefit to low-dose aspirin in the primary prevention of major vascular events in this at-risk, but clinically asymptomatic population.

Exercise Therapy for Claudication

Multiple reports have clearly demonstrated improvements in pain-free ambulation and overall walking performance with structured exercise training.5,7173 Data from more than 20 randomized trials have confirmed that exercise therapy is the best initial treatment of intermittent claudication.73 The benefits of exercise extend beyond improvement in the symptoms of claudication. Regular aerobic exercise reduces cardiovascular risk by lowering cholesterol and blood pressure and by improving glycemic control. In most patients, claudication initiates a downward spiral of cardiovascular deconditioning that can result in an annual mortality rate as high as 12%.73 Ambulation distance can decline at a rate of 8.4 m/yr beginning with symptom onset.74 This cycle can be halted and even reversed with exercise training. In a recent report from Japan, Sakamoto et al75 showed that the implementation of structured exercise resulted in a 5-year cardiovascular event-free survival rate of 80.5% in patients with PAD, compared with 56.7% in untreated matched controls.

The current ACC/AHA guidelines support supervised exercise for the treatment of intermittent claudication as a level IA recommendation.76 The guidelines suggest that exercise training, in the form of walking, should be performed for a minimum of 30 to 45 minutes per session, three to four times per week, for a period not less than 12 weeks. During each session, the patient should be encouraged to walk until the limit of lower extremity pain tolerance is reached, followed by a short period of rest until pain relief is obtained, then a return to exercise. This cycle should be followed for the duration of the session. As the pain-free interval of ambulation increases, the level of exercise should be increased (Box 109-1).71

Box 109-1

Key Components of A Structured Exercise Program for Claudication

* These general guidelines should be individualized and based on the results of treadmill stress testing and the patient’s clinical status. A full discussion of the exercise precautions for persons with concomitant diseases can be found elsewhere for patients with diabetes (Ruderman N, Devlin JT, Schneider S, Kriska A: Handbook of exercise in diabetes. Alexandria, VA, 2002, American Diabetes Association), hypertension (ACSM’s guidelines for exercise testing and prescription. In: Franklin BA, ed. Baltimore, MD, 2000, Lippincott, Williams & Wilkins), and coronary artery disease (Guidelines for Cardiac Rehabilitation and Secondary Prevention/American Association of Cardiovascular and Pulmonary Rehabilitation. Champaign, IL: Human Kinetics; 1999).

(From Stewart KJ, et al: Exercise training for claudication. N Engl J Med 347:1941-1951, 2002.)

Although exercise therapy appears to be easy to implement, effectiveness is often limited by poor patient compliance. Studies have shown the superiority of clinic-based exercise programs over home-based programs.5 However, effective exercise training is not possible in up to 34% of patients because of comorbid medical conditions, and an additional 30% of patients simply refuse to participate in exercise training.5 In addition, supervised exercise training programs are usually not covered by third-party insurance plans, including Medicare. Therefore, although exercise therapy in motivated patients offers proven benefits, its effectiveness is applicable to only about one third of patients presenting with intermittent claudication.

Pharmacologic Treatment of Claudication

Pharmacologic therapy for intermittent claudication has been the subject of intense research for more than 30 years. To date, only two drugs (pentoxifylline and cilostazol) have achieved FDA approval for the treatment of intermittent claudication in the United States. However, a number of other medications have been investigated, with varying degrees of evidence supporting their efficacy (Table 109-2). These include a number of drugs and supplements with various reported mechanisms of action, such as changes in tissue metabolism (naftidrofuryl, levocarnitine), enhanced nitric oxide production (L-arginine), and vasodilatory effects (statins, buflomedil, prostaglandins, ACE inhibitors, K-134).


In 1984, pentoxifylline (Trental, sanofi-aventis, Paris, France) became the first drug approved by the FDA for the treatment of intermittent claudication. It is a methylxanthine derivative that is thought to improve oxygen delivery because of its rheolytic effect on red blood cell wall flexibility and deformability, ultimately reducing blood viscosity. Pentoxifylline is also believed to inhibit platelet aggregation and to increase fibrinogen levels.78 Early trials of pentoxifylline were promising and showed that maximal treadmill walking distances in patients with claudication were improved by 12% compared with placebo.79 Although walking distances improved, patient discomfort with walking typically persisted. Porter et al79 evaluated the efficacy of pentoxifylline in a multicenter double-blinded study and demonstrated modest improvements in pain-free ambulation distance and maximal walking distance after pentoxifylline administration in patients compared with the control group. These findings were reproduced in several well-designed studies.80,81

Although pentoxifylline has produced a very modest improvement in walking distance in clinical trials of patients with claudication, this improvement appears to be more statistically significant than clinically significant. In clinical practice, although some patients experience substantial long-term symptom relief with pentoxifylline, others do not, and it is impossible to predict patient response without a trial of the drug. Whether these observed improvements are a consequence of a placebo effect is unclear.

Pentoxifylline is well tolerated, safe, and relatively inexpensive. Although its clinical impact has been modest, pentoxifylline represents one of the earliest successful pharmacologic advances for the treatment of claudication. Dosing recommendations for pentoxifylline begin at 400 mg orally three times daily and can be increased as tolerated up to 1800 mg/day. Pentoxifylline can interfere with blood clotting, especially if taken with sodium warfarin. Pentoxifylline has rarely been associated with nausea, headache, anxiety, insomnia, drowsiness, and loss of appetite. Increased blood pressure can occur, so blood pressure should be monitored.7981


Cilostazol (Pletal, Otsuka Pharmaceutical Ltd., Tokyo, Japan) gained FDA approval in 1999 for the treatment of intermittent claudication. Oral administration of this phosphodiesterase III inhibitor increases cyclic adenosine monophosphate (cAMP) and results in a variety of physiologic effects, including the inhibition of smooth muscle cell contraction and platelet aggregation. Cilostazol is also thought to decrease smooth muscle cell proliferation, a process that has been implicated in coronary artery restenosis after percutaneous transluminal angioplasty.82 Finally, cilostazol has a beneficial effect on plasma lipid concentrations, resulting in a decrease in serum triglycerides and an increase in HDL. Although the precise mechanism by which cilostazol improves the symptoms of intermittent claudication is unknown, it is likely a combination of these effects.

Several controlled clinical trials, including a meta-analysis, have confirmed the efficacy of cilostazol.80,83,84 Results have shown increased maximal walking distances up to 50% and significant improvements in health-related quality of life (QoL) measures.83 There is also increasing evidence that cilostazol may modulate the synthesis of vascular endothelial growth factor (VEGF), potentially stimulating angiogenesis in patients with chronic lower extremity ischemia.85

The benefits of cilostazol in the treatment of intermittent claudication were compared with those of pentoxifylline in a randomized controlled trial performed by Dawson et al.80 They found that cilostazol therapy significantly increased maximal walking distance by 107 m (54% increase), compared with a 64-m improvement in the pentoxifylline group (30% increase). There was no difference in maximal walking distance improvement between the pentoxifylline and placebo groups. Regarding the durability of the effect, a recent pooled analysis of nine randomized controlled trials demonstrated a significant benefit in maximal walking distance compared with placebo at 6 months.86

Cilostazol has a moderate but notable adverse effect profile that includes headache, diarrhea, and gastrointestinal discomfort. Its use is contraindicated in patients with congestive heart failure, and high plasma drug levels may result when taken in combination with other medications metabolized by the liver via the cytochrome-P450 pathway: (CYP 3A4 and CYP 2C19).

The adverse effects of cilostazol can be minimized by initiating a progressive treatment regimen, starting at 50 mg/day for 1 week, increasing to 50 mg twice daily the following week, and finally achieving the standard dose of 100 mg twice daily in week 3. Of the pharmacologic agents used to treat claudication, cilostazol has the most data supporting its clinical use.

Intermittent Pneumatic Compression for Peripheral Artery Disease

Intermittent pneumatic compression (IPC) in combination with appropriate risk factor modification may be a viable method of treatment for patients with unreconstructable vascular disease, for those who are physiologically unfit for surgical intervention, or for patients with intermittent claudication who do not want invasive treatment. IPC involves sequential inflation and deflation of pneumatic pressure cuffs positioned at the foot or calf. Inflation-deflation rates vary according to the system used, each applying a pressure up to 120 mm Hg for 2 to 3 seconds before deflating. This sequence is continued at a rate of three cycles per minute throughout the treatment session. The physiologic effects of IPC are thought to be a consequence of three mechanisms: an increase in the arteriovenous pressure gradient; reversal of vasomotor paralysis; and enhanced release of nitric oxide.108

Sporadic favorable reports describing IPC for lower extremity ischemia, albeit in series with relatively small patient numbers, date from the 1960s. However, several recently published studies described the clinical benefit of IPC for the treatment of intermittent claudication and CLI.108110 In one of these reports, 48 patients with CLI were randomized to receive IPC plus stringent wound care versus stringent wound care alone. With a follow-up of 18 months, the investigators observed limb salvage in 58% of those treated with IPC compared with 17% receiving stringent wound care alone (P < .01).110 These studies showed that although the role of IPC was not completely defined for the treatment of PAD, it might be beneficial in high-risk patients with limited treatment options.

Improvements in limb salvage have also been demonstrated using IPC. Kavros et al110 examined the effects of IPC on patients with chronic CLI or tissue loss in whom limb revascularization was thought to be impossible. These investigators achieved limb salvage with complete wound healing in 14 of 24 patients (54%) who underwent IPC, compared with 4 of 24 patients (17%) who received equivalent wound care but no IPC. Chang et al111 also demonstrated benefits on measures of health-related QoL. They randomized 31 patients with either disabling claudication or CLI and no reconstruction options to a 3-month course of IPC; among the treatment group, there were significant improvements in six of eight domains of health-related QoL, whereas the control group only experienced improvements in two domains. Although data are limited overall, this treatment method may have significant benefits in patients with CLI when combined with dedicated medical management and wound care, particularly in those with limited revascularization options.

Decision Making for Revascularization

Patients with lower extremity PAD present with a wide spectrum of symptoms. Patients may be asymptomatic, may experience only minor exertional leg pain, may experience significant walking impairment, or may present with ulceration or gangrene. The first critical step in decision making for the treatment of PAD, therefore, is to confirm that PAD is the responsible etiology of the patient’s symptoms (see Chapter 108). In brief, noninvasive vascular laboratory testing is indicated for patients with a history consistent with vasculogenic claudication, pain at rest or metatarsalgia, or tissue loss. Measurement of the ABI is the most commonly used PAD screening tool. An ABI of ≤0.90 has been demonstrated to have high sensitivity and specificity for the identification of PAD compared with the gold standard of invasive arteriography (evidence present of a peripheral hemodynamically significant arterial stenosis).5 Complete physical examination will often disclose pulse deficits, but intact pulses at rest do not rule out hemodynamically significant PAD. Once the symptom complex (either claudication or CLI) is determined to be secondary to PAD, decision making depends on symptom severity and whether the symptoms are from acute or chronic lower extremity ischemia. The following discussion relates to chronic lower extremity ischemia; acute ischemia is discussed in Chapters 161 and 162.

Decision making regarding revascularization is based first on symptom status and a sophisticated understanding of the natural history of the patient’s condition. As a result, treatment strategies may be very different for patients with disabling claudication compared with those with CLI because the risk of limb loss is dramatically different for the two conditions. Anatomic classification systems, such as the TASC classification system, may assist in gauging the extent of angiographic disease. Although the TASC II classification system can be helpful in the revascularization decision-making process (i.e., endovascular or open), atherosclerotic burden as measured by arteriography is not the sole factor upon which treatment decisions should be made. The TASC classification system lacks any features related to degree of ischemia, wounds, infection, functional status, and conduit availability, all of which are extremely important determinants of revascularization success. Clearly, angiographic anatomy alone cannot guide therapy.

Another critical element of decision making focuses on the determination of whether or not a patient will experience a meaningful benefit from a technically successful procedure. Technical success does not always equate directly with clinical success. As a result, it is important to assess baseline functional status and the burden of comorbid conditions. Patients who are either bedridden at baseline or who have prohibitive medical risks may incur significantly more benefit from a treatment that differs from the TASC II recommendations (based on lesion type alone), to more appropriately balance the chances for functional limb salvage with the risks of periprocedural morbidity. An assessment of the available conduit, if bypass is required, is included in this evaluation. The challenge of decision making in PAD is accurately assessing each of these factors and synthesizing a plan that optimizes the likelihood of a favorable outcome for each patient.

Defining Treatment Success

Optimal treatment must ultimately be tailored to each patient. The approach to decision making must involve careful discussions with the patient to identify what defines treatment “success.” This will not be the same for every patient.

Limb- and Patient-Centered Outcomes

Traditional definitions of treatment success include technical outcomes such as graft and/or stent patency. However, graft patency may not correlate well with limb preservation. Simons et al112 found that 10% of patients who underwent lower extremity bypass for CLI failed to achieve clinical improvement despite having a patent graft at 1 year postoperatively. Other outcome measures such as survival, or amputation-free survival (AFS) have also been widely used. Some have questioned the appropriateness of these endpoints. In a critique of the Bypass versus Angioplasty in Severe Ischemia of the Leg (BASIL) trial,113 Conte114 noted that lower extremity bypass was generally not offered as a life-saving therapy, and therefore, survival was not an appropriate measure for comparisons between revascularization strategies. In addition, Conte stressed the importance of limb- and patient-centered outcomes, such as freedom from re-intervention. This shift towards more patient-centered outcomes is reflected in the Society for Vascular Surgery (SVS) objective performance goals (OPGs).115 These guidelines were developed specifically for comparative evaluations of treatments for CLI,116,117 but the endpoints chosen are key components of treatment success for PAD, namely, major adverse limb events, which included both freedom from major amputation and re-intervention. This inclusion shifts the focus of outcome measures from technical success rates, such as primary and secondary patency, to one that acknowledges a burden incurred by the patient with each intervention that is required to maintain that patency (Table 109-3). Goshima et al173 attempted to quantify the efforts required, by both the patient and the physician, to achieve functional limb salvage. They used nontraditional endpoints of hospital readmission within 6 months, index limb reoperation within 3 months, and wound healing time. They found that nearly 50% of patients required both readmission and reoperation, and time to wound healing exceeded 3 months in 54%.

Table 109-3

Critical Limb Ischemia Endpoint Definitions and Event Rates*


* As reported by the Society for Vascular Surgery Working Group for the development of objective performance goals for evaluating catheter-based treatment.

Data are pooled from prospective trials of vein bypass surgery in CLI.

(From Conte MS, et al: Suggested objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia. J Vasc Surg 50:1462-1473, 2009.)

Functional Outcome

It has been recognized that traditional clinical measures of success—namely, reconstruction patency, limb salvage, and mortality—do not fully address the functional concerns of most patients who present with lower extremity PAD. Bypass patency after revascularization matters little to the patient or the patient’s family if progressive disability, limb loss, or death occurs over the ensuing months. A better understanding of such patient-oriented measures of success will have a profound impact on decision making for the treatment of lower extremity PAD.169 This departure from the traditional construct, which makes the implicit assumption that technical success, low morbidity and mortality, and anatomic patency are the criteria by which we should judge treatment effectiveness highlights a significant unmet need in PAD research. Considering procedurally oriented endpoints only, reconstruction patency rates of 60% to 80% and limb salvage rates of 70% to 90% have consistently been reported after the treatment of CLI, implying that with appropriate treatment methods, the problem of lower extremity PAD has largely been solved.5 However, in the late 1990s, the vascular surgery group from the Oregon Health Sciences Center published a series of studies that examined outcomes after lower extremity revascularization from the patient’s perspective. They concluded that superior results in terms of graft patency and limb salvage only partially defined success, and more often than not, patient function was not improved.170172 Patients who present with CLI are often consumed by their disease and are condemned to a course of prolonged recovery with multiple re-operations and hospital admissions.173 The Oregon group reported that only 14% of patients who underwent revascularization had uncomplicated operations, symptom relief, wound healing, and no reoperation, and maintained their original level of function. In contrast, the remaining 86% required ongoing treatment in some fashion for the remainder of their lives. Based on such observations, it is apparent that clinically oriented endpoints, such as bypass graft patency and limb salvage, fail to accurately represent successful outcome after revascularization for CLI. However, the benefits of graft patency in terms of QoL, wound healing, and relief of chronic ischemic pain should not be discounted.


Similarly for patients with claudication, surgeon-defined procedural endpoints may not accurately capture all relevant outcomes. Some have challenged the traditional approach to patients with claudication.174,175 Given the more benign natural history with respect to limb loss, nonoperative therapy is traditionally recommended as the first-line treatment; limb loss is therefore not a logical measure of treatment success. Kalbaugh et al,136 using the Short Form (36) Health Survey (SF-36), found that reassurances about the benign natural history of their condition did little to alleviate patients’ symptoms. Conversely, intervention for claudication improved QoL scores considerably. Improvements were similar to those found after coronary artery bypass surgery for angina and were half as beneficial as hip replacement surgery. In a more recent series, Taylor et al130 reported significant symptomatic improvement after intervention for claudication in nearly 80% of treated patients. Revascularization in this series was exceedingly safe, with no early amputations and a 99% limb salvage rate at 5 years.

Although it is accepted that revascularization is not appropriate in every case, there is clear evidence that QoL is improved by revascularization in most instances.176179 The recent focus on patient-oriented endpoints has stimulated new research in the objective measurement of QoL for patients undergoing lower extremity revascularization. Various questionnaires have emerged as tools to measure QoL. Unfortunately, there is no consensus on the ideal questionnaire to use for the evaluation of patients with CLI. The two most commonly used surveys are the SF-36 and the Nottingham Health Profile.180,181 These questionnaires assess overall QoL and sometimes fail to consider disease-specific issues. Morgan et al182 developed the Vascular QoL Questionnaire as a disease-specific survey capable of assessing QoL in patients with CLI. To date, the largest study performed assessing QoL in patients with CLI is the Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT III) trial, which used the Vascular QoL Questionnaire to study QoL as a secondary endpoint in 1404 patients who underwent infrainguinal bypass.183 This study and others demonstrated significant improvement in QoL after bypass and also found that QoL correlated directly with bypass graft patency.178181,183,211 In addition, prolonged patency is required in many patients to eventually achieve healing. A significant number of patients with CLI take longer than 6 months to heal175; nevertheless, they have their limbs and are at home, wound care is simplified, and ischemic pain is relieved. In addition, severe ischemia and extensive infection or soft tissue necrosis can be major factors in selecting tibial or pedal bypass over percutaneous transluminal angioplasty for patients with TASC type C and D disease (see Chapter 113); such patients are likely to require maximal and durable foot perfusion to achieve and maintain a healed foot.172,175,181

Critical Limb Ischemia

Taylor et al211 recently studied 331 consecutive patients treated for Rutherford class 5 and 6 ischemia (tissue loss). A bypass was deemed clinically successful if all four outcome criteria were met: (1) bypass patency until wound healing occurred; (2) limb salvage for at least 1 year; (3) maintenance of ambulatory status for at least 1 year; and (4) survival for at least 6 months. The authors found acceptable results when examining these components separately, including a graft patency rate of 72% and a limb salvage rate of 73% at 36 months. However, the clinical success rate, defined as the achievement of all four criteria, was only 44%. Furthermore, patients who presented with impaired ambulatory status, end-stage renal disease, gangrene, and infrainguinal disease (each independent statistical predictors) were especially prone to failure (Table 109-4).211 Prospects for a successful outcome became progressively dismal as the number of independent negative predictors increased. Patients harboring two of these independent predictors of failure experienced roughly a 33% probability of success; those with three predictors, a 10% probability of success; and those with all four independent predictors of failure, less than a 5% probability of success. Similar studies using consensus definitions of success are needed to help guide decision making regarding who should receive intervention and who should not.

Table 109-4

Probability of Failure after Bypass* When the Clinical Condition Is Present at Presentation

Predictor Variable Probability of Failure (%) Odds Ratio (95% CI)
Impaired ambulation 58 6.4 (2.9-14.4)
Infrainguinal disease 46 3.9 (1.6-9.8)
ESRD 35 2.5 (1.2-5.4)
Gangrene 34 2.4 (1.5-4.0)
Hyperlipidemia 11 0.6 (0.34-0.93)

* Defined as patent bypass until healed, limb salvage for 1 year, maintenance of ambulation for 1 year, and survival for 6 months.

CI, Confidence interval; ESRD, end-stage renal disease.

(From Taylor SM, et al: Critical analysis of clinical success after surgical bypass for lower extremity ischemic tissue loss using a standardized definition combining multiple parameters: a new paradigm of outcome assessment. J Am Coll Surg 204:831-839, 2007.)

Treatment Guidelines According to Anatomic Disease Classification

Several classification systems have been developed that characterize PAD on the basis of anatomic descriptions of lesion type and location. The major goals included standardization of reporting disease burden, development of methods to correlate disease burden with clinical severity, and development of recommendations for method of intervention. Although these classification schemes provide some value, they notably fail to capture all the factors that determine the success of intervention.

Bollinger Classification

The Bollinger score, which was used by the BASIL trial, utilizes a scoring system to classify angiographic lesions in terms of pattern and severity.212 There is then an additive component that categorizes severity of lesions into four classes: plaques, stenoses <25%, stenoses <50%, stenoses >50%, or occlusions. The primary goal of this scoring system is to provide a semiquantitative method of evaluating atherosclerotic burden to facilitate comparisons either between patients or between time points (e.g., postinterventions) for the same patient.

Graziani Classification

The Graziani scoring system proposed a new morphologic categorization for disease severity among diabetic patients with CLI.213 Unlike the Bollinger score, this system described the frequency of various patterns of disease, and correlated angiographic findings with transcutaneous oxygen tension values.

Trans Atlantic Inter Society Consensus Classification

In January 2000, the TASC for the Management of Peripheral Arterial Disease published a document authored by a working group of representatives from 14 surgical vascular, cardiovascular, and radiologic societies.109 An updated document (TASC II) was published in January 2007.5 These important works went a step beyond the Bollinger and Graziani scoring systems, by not only classifying the lesions, but also by providing treatment recommendations according to lesion type. The authors compiled and interpreted evidence-based data concerning the treatment of lower extremity PAD and offered a series of treatment recommendations based on presentation.

Recognizing the importance of the pathologic anatomy for decision making, the TASC working group has classified anatomic patterns of disease involvement (types A through D) for both the aortoiliac (Fig. 109-4) and femoropopliteal (Fig. 109-5) segments, based on recommended treatment (endovascular versus open surgery). The TASC working group advocated endovascular treatment for TASC type A lesions and open surgical treatment for TASC type D lesions. For TASC type B and C lesions, the authors concluded that there was insufficient evidence to definitively recommend one modality over the other.5