Smoking

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.^23–25 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.^30–33 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 A_1c 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 A_1c <6%) without inducing significant hypoglycemia (see Chapter 28).⁵

Hypertension

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).

Dyslipidemia

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]).^44–46 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.^49–51 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).^5,55–57

Homocysteinemia

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.

Pentoxifylline

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.^79–81

Cilostazol

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.

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%.

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.^170–172 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.

Claudication

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.^176–179 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.^{178–181,183,211} 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.

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

Future Classification Systems

Although the TASC guidelines are helpful, a grading system that is based on arterial anatomy alone is inadequate to guide therapy. As a result, the SVS commissioned the lower extremity guidelines working group to create a more comprehensive classification system to serve as a more robust decision-making aid. This new classification framework, entitled the SVS Threatened Limb Classification System, incorporates three major factors that affect amputation risk and clinical management: wound, ischemia, and foot infection (WIfI).²³⁰ The intent of this new SVS WIfI classification system is for it to be applied to patients across a broad spectrum of lower extremity arterial occlusive disease of varying severity and distribution. In the SVS WIfI system, wounds are classified from grade 0 to grade 3 based on size, depth, severity, and anticipated difficulty achieving wound healing. Ischemia is classified from grade 0 to grade 4 according to ABI, ankle systolic pressure, toe systolic pressure, or transcutaneous oximetry. Infection is classified from grade 0 to grade 3 based on simple objective clinical observations. Validation efforts are currently underway to evaluate whether the SVS WIfI system accurately stratifies patients to permit more meaningful analyses of outcomes for various forms of therapy in this challenging heterogeneous population.

Medical Therapy versus Revascularization

The role of smoking cessation in treating the symptoms of claudication is unclear. Although studies have shown that smoking cessation can improve walking distance in some cases, these findings are not universal.⁵ The association between tobacco cessation and the reduction of subsequent cardiovascular events is undisputed, however. The rationale for smoking cessation is therefore based on reducing patient mortality and slowing the overall atherosclerotic disease process.

Currently available pharmacologic agents for claudication have already been discussed (see section on Phar­macologic Treatment of Claudication). The ACC/AHA guidelines recommend, in addition to routine antiplatelet therapy, a therapeutic trial of cilostazol (100 mg twice daily) as an effective method for increasing overall ambulation (class I recommendation). This agent is limited to patients with PAD and intermittent claudication and no history of congestive heart failure, because cilostazol is a phosphodiesterase-3 inhibitor capable of exacerbating ventricular dysfunction.⁷⁶ Unfortunately, adverse effects prevent the routine use of cilostazol in up to 15% of patients.^80,83 As an alternative to cilostazol, pentoxifylline (400 mg three times daily) may be of benefit in selected patients. Although this drug is well tolerated, data supporting its effectiveness are marginal.

When comparing medical to endovascular therapy, there are abundant data supporting the efficacy of medical therapy. For instance, the Edinburgh walking study consisted of a randomized trial to determine outcome differences in patients with intermittent claudication treated with angioplasty and stents versus medical management (daily low-dose aspirin, lifestyle modification) after 2 years. These investigators found no difference in maximal walking distance, treadmill distance until onset of claudication, and QoL measures between the two groups.¹²⁷ Supervised exercise therapy has also been compared with primary stenting for disabling claudication due to aortoiliac occlusive disease in the Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) trial.¹²⁸ At 6-month follow-up, they reported that change in peak walking time was greatest for supervised exercise, intermediate for stenting, and least with pharmacologic therapy (mean change versus baseline, 5.8 ± 4.6, 3.7 ± 4.9, and 1.2 ± 2.6 minutes, respectively; P < .04 for the comparison of supervised exercise versus stenting). QoL evaluation revealed significant improvements in both the supervised exercise and the stenting groups compared with pharmacologic therapy, but the benefit was greater in the stenting group than in the exercise group.

In summary, when deciding between medical therapy and revascularization for the treatment of intermittent claudication, the risk-to-benefit ratio favors initial medical therapy in most cases. However, medical therapy may be effective in as few as 30% of patients because of noncompliance and drug intolerance. When revascularization is chosen, modern approaches have become predominantly endovascular because of its reduced procedural risks compared with open surgery. However, an analysis of practice patterns in New England between 2003 and 2009 demonstrated that an increasing proportion of lower extremity bypass procedures were performed for claudication in recent years (19%-31%; P < .0001). In addition, the percent of patients with a history of previous endovascular intervention steadily increased (13%-23%; P = .02).¹²⁹ The authors suggested that the high rates of previous endovascular intervention seen might reflect a “treatment trap”; once the decision has been made to intervene procedurally for claudication, surgeons may feel obliged to perform an open revascularization if a previous endovascular approach failed to resolve symptoms. Clinical decision making ultimately must incorporate not only the risks and benefits of various treatment strategies, but also a discussion of realistic expectations as to the extent to which treatment will improve symptoms and improve QoL.

Endovascular Treatment versus Open Surgery

Ultimately, the selection of the best method of revascularization for an individual with claudication is based on a balance between the risks of the specific intervention and the degree and durability of improvement that can be expected from the intervention.⁵ Because the natural history of vasculogenic claudication is relatively benign, that balance usually does not favor open surgery. In contrast, its relatively low morbidity and mortality make endovascular therapy particularly attractive,⁵ and when it is anatomically feasible, endovascular therapy is generally preferred to open surgery for most cases of claudication.¹²⁷ However, it is important to note that a growing body of evidence suggests that the concept that an endovascular option “does not burn any bridges” is false.^131,132

Anatomy is a supremely important consideration when selecting the best interventional modality for patients with claudication and those with CLI. Prospective studies dating to the 1980s have characterized the arterial lesions and anatomy most conducive to long-term patency after angioplasty. Johnston et al¹³³ demonstrated, in a prospective analysis, that the arterial anatomy and clinical presentation most amenable to long-term patency and success using angioplasty were focal arterial lesions in large-diameter vessels with adequate outflow. Outcomes were more favorable in nondiabetic patients presenting with claudication than in those with CLI. Thus, the arterial segment best managed with percutaneous transluminal angioplasty is the common iliac artery, a vessel with all the favorable anatomic characteristics identified by the Johnston et al¹³³ study. Atherosclerotic lesions in this segment are usually focal and possess good outflow. Angioplasty patency rates at 5 years generally exceed 70%.¹³⁰ Conversely, long-segment arterial disease, such as a long superficial femoral artery occlusion, is probably best treated with open bypass. Diffuse multisegmental disease, more common with CLI, can present a therapeutic dilemma.

Medical Therapy versus Revascularization

The natural history of untreated CLI is poorly understood because most functional patients receive some type of revascularization. However, limb loss and cardiac death are common. One-year mortality ranges from 20% to 30%, with cardiac deaths outnumbering noncardiac deaths four to one.¹³⁸ The best information regarding the natural history of nonrevascularized limbs in patients with CLI comes from the placebo arms of pharmacotherapy trials of patients with unreconstructable vascular disease. Results suggest that this subgroup has a dismal prognosis, with nearly 40% of limbs progressing to amputation at 6 months.¹³⁹ Therefore, in functional patients, some type of revascularization is almost always preferable to medical therapy.

Medical therapy for CLI is not without some noteworthy successes, however. Wound care centers have become common adjuncts to many vascular surgical practices (see Chapter 83). Ischemic ulcer healing rates of 55% have been reported from dedicated centers using modern wound care methods, such as negative-pressure wound therapy, intense débridement, and antibiotic therapy.⁵ However, wound healing in such situations is often a slow, laborious, and unpredictable process. To date, pharmacotherapy for CLI has failed to yield any major breakthroughs. The routine use of prostanoids, vasodilators, antiplatelet agents, and even hyperbaric oxygen for the treatment of ischemic ulcers remains of unproven benefit.⁵

In summary, revascularization is an essential component in the relief of CLI. Although medical adjuncts geared at risk factor modification may be important to slow the progression of systemic atherosclerotic disease, they play a secondary role in the treatment of the severely ischemic limb. In those rare cases in which vascular disease is truly unreconstructable, a trial of intensive wound care, preferably at a dedicated wound care center, may yield satisfactory healing rates for motivated patients with superficial ulcerations, or it may avoid major limb amputation in high-risk patients who are approaching the end of life.

Limb Amputation versus Revascularization

For the majority of patients with CLI, revascularization is the interventional treatment of choice. However, primary limb amputation continues to be required in 10% to 40% of CLI patients because of overwhelming infection or unreconstructable vascular disease.⁵ Unreconstructable vascular disease accounts for nearly 60% of patients requiring secondary amputation.⁵ In many of these cases, revascularization has failed because of progression of disease, recurrent ischemia, or persistent infection or necrosis despite a patent revascularization.

Although counterintuitive, limb amputation and prosthetic rehabilitation can be an excellent option, offering an expedient return to a reasonable QoL in selected cases. Maintenance of ambulation can exceed 70%, and maintenance of independence can exceed 90% in young, good-risk patients after below-knee amputation.¹⁴⁰ Clearly, amputation should be considered a tool capable of extending functionality and not a failure of treatment in these cases. If there is the potential for some degree of rehabilitation, the limb amputation should be performed at the lowest possible level at which healing can be expected, because the work of walking increases dramatically as the level of amputation becomes more proximal. Typically, patients with well-controlled medical comorbidities, a palpable femoral pulse, a warm calf, and no signs of infection are likely to heal after a below-knee amputation (see Chapter 118).

The use of an immediate postoperative prosthesis (IPOP) may also aid in expediting a patient’s recovery following below-knee amputation. This technique, first described in the 1960s, gained favor after publication of the Prosthetic Research Study by Burgess et al.¹⁴¹ They reported that the use of a rigid cast placed intraoperatively facilitated faster healing and return to ambulation. Folsom et al¹⁴² studied this technique in a population where the indication for amputation was not trauma, but rather severe infection or unreconstructable PAD. Of 65 patients, 86% returned to independent ambulation, with an average time to ambulation of 15.2 days after below-knee amputation. A more recent comparative analysis of IPOP compared with traditional soft dressings demonstrated no difference in complication rates and a lower incidence of revision (soft dressings 27.6% versus IPOP 5.4%; P = .021).¹⁴³ Despite this, IPOP has not gained wide acceptance for unclear reasons.

Patients too sick or infirm to realize the benefit of limb revascularization should undergo palliative primary above-knee amputation. However, judging patients “too sick or infirm” can be difficult. Obviously, a nonambulatory, elderly, nursing-home patient with knee contractures and neuropathic heel ulcers would qualify for a palliative above-knee amputation. For patients who are minimally ambulatory, with multiple comorbidities, the decision is less clear cut. An individualized judgment is required to determine whether these patients will be better served by primary amputation or limb revascularization. In a recent single-institution study of 1000 consecutive revascularizations for CLI, preoperative functional performance status was the most important predictor of postoperative functional outcome—even more important than limb salvage itself.¹⁴⁴ This finding strongly suggests that there is a definite subset of patients who are too sick or debilitated to realize the functional benefits of revascularization. Although more work is needed to better define such patients, this cohort is likely best suited for primary amputation.

Endovascular Treatment versus Open Surgery

For many years, the classic treatment approach for CLI has been open surgery. CLI is usually associated with multilevel arterial disease that is not ideally suited to percutaneous intervention. Diffuse, extensive PAD causing CLI in both aortoiliac and femoropopliteal locations (see Figs. 109-4 and 109-5) is best treated by surgical bypass according to TASC.⁵ However, the primacy of surgical bypass for CLI management has been challenged in recent years and has become the subject of intense debate. Those who favor open surgery for the treatment of CLI often cite superior reconstruction patency and increased durability.^145–147 However, open surgery is usually associated with higher perioperative morbidity and longer hospitalization.¹⁴⁸ Also, long-term postoperative graft surveillance is necessary to maintain a patent infrainguinal bypass, as has been shown in well-performed studies from both Europe and North America, suggesting that such surveillance is economically justified by preventing vein graft occlusion and late amputation.^149,150 A re-intervention rate of 20% to 30% to treat failing grafts due to intrinsic vein graft stenoses is usually necessary to maintain the increased durability attributed to open surgery.^149,151 Last, successful surgery depends on the presence of a suitable venous conduit for bypass.^152,153 Those who favor interventional treatment cite the low morbidity and mortality associated with a procedure that is usually performed on an outpatient basis.¹⁵⁴ Although proponents acknowledge the limited reconstruction patency rates associated with endovascular treatment, especially for the high-risk lesions often encountered in CLI, they argue that restenosis rarely jeopardizes subsequent surgery.^154–156 In contrast, others have found that previous ipsilateral intervention has a negative influence on subsequent bypass. An analysis of the BASIL data by treatment received found 1-year AFS was 40% for bypass that followed a failed endovascular intervention, compared with 70% for the bypass-only group.¹³² The authors therefore do not endorse the concept of a “free shot” with an endovascular first approach. Nolan¹³¹ also found a correlation of graft failure and previous endovascular intervention; in a study of CLI patients who underwent lower extremity bypass in New England, those with a previous failed endovascular intervention had a higher incidence of major amputation (31% vs. 20%; P = .046) and graft occlusion (28% vs. 18%; P = .009) at 1 year. Although a causative relationship has not been established, the concept of “burning bridges” with an aggressive endovascular-first approach clearly deserves further study.

Fibroblast Growth Factor

The Therapeutic Angiogenesis with Recombinant Fibroblast Growth Factor-2 for Intermittent Claudication (TRAFFIC) study was the first randomized clinical trial to show a positive effect of growth factor therapy in limb ischemia.¹²¹ In this study, patients with intermittent claudication were treated with 30 µg/kg of recombinant FGF-2 via bilateral femoral artery infusions; both maximal walking time and ABI increased at 90 days. Unfortunately, these encouraging results were offset by the adverse effects of proteinuria and lower extremity edema.

The Therapeutic Angiogenesis Leg Ischemia Study for the Management of Arteriopathy and Nonhealing Ulcer (TALISMAN) trial was a placebo-controlled randomized, prospective multicenter trial that demonstrated that intramuscular injection of FGF-1 resulted in a twofold decrease in major amputation compared with placebo.¹²² There was no difference in hemodynamics or wound healing between the groups. However, the phase 3 study that followed TALISMAN (TAMARIS)¹⁹⁵ failed to show a significant difference at 1 year for the primary endpoint of time to major amputation or death (hazard ratio, 1.11, 95% CI, 0.83-1.49; P = 0.48).

Hepatocyte Growth Factor

The Study to Assess the Safety of Intramuscular Injection of Hepatocyte Growth Factor Plasmid to Improve Limb Perfusion in Patients with Critical Limb Ischemia (HGF-STAT) was a placebo-controlled randomized, prospective multicenter trial that demonstrated a doubling of the transcutaneous oxygen tension (tcPO₂) from baseline in the HGF gene therapy group compared with the placebo group.¹²³ In that trial, 80% of the gene therapy patients had a tcPO₂ greater than 30 mm Hg at the 6-month endpoint, compared with 39% of the placebo-treated patients. However, there was no difference between groups for several clinical endpoints, including pain relief, wound healing, and major amputation. In a follow-up study, Powell¹⁹⁸ evaluated the safety and efficacy of modified HGF gene delivery in CLI patients using endpoints of change in toe-brachial indices, pain at rest, wound healing, amputation, and death at 3 and 6 months. Complete ulcer healing at 12 months occurred in 31% of the HGF group and 0% of the placebo group (P = .28). There was no difference in major amputation of the treated limb (HGF 29% vs. placebo 33%) or mortality at 12 months (HGF 19% vs. placebo 17%) between groups.

Shigematsu et al¹⁹⁶ performed a phase 3 randomized controlled trial of intramuscular HGF plasmid in patients with CLI. They found a significant improvement for the primary endpoint of resolution of rest pain and reduction of ulcer size at 12 weeks (70.4% in the treatment group vs. 30.8% in the placebo group; P = 0.014). They also demonstrated significant improvements on QoL measures among the treatment group, with no major adverse events recorded in 12 weeks of study.

Gene therapy to achieve therapeutic angiogenesis has now been investigated long enough that studies evaluating longer term outcomes are being reported. Makino et al¹⁹⁷ reported 2-year outcomes for patients with CLI who were treated with HGF plasmid. Reduction in pain at rest was observed in 9 of 9 patients (100%) at 2 years; 9 of 10 patients (90%) experienced reduction in the size of ischemic ulcers by >25%. The authors noted some temporal trends: improvements in ABI and maximum walking distance peaked at approximately 3 to 6 months and then decreased slightly, whereas pain at rest and ulcer size improved continuously until 2 years after gene therapy. Tests of significance could not be conducted on any of these findings due to small sample size. This study was not randomized, and did not contain a control group.

Pooled Result Analysis

De Haro et al¹⁹⁹ carried out a meta-analysis on the data presented in several of these studies; they applied a pooled analytic approach to evaluate the efficacy and safety of gene and cell angiogenic therapies. They found a significant improvement compared with placebo (odds ratio, 1.437, 95% CI, 1.03-2.0; P = .033) for all patients. Subgroup analysis did not show a significant difference in response rate among claudicants receiving gene therapy compared with placebo, but did find significant improvement in the CLI population. They also reported a significant difference for potential nonserious adverse events, with higher rates among the treatment group (edema, hypotension, proteinuria); there were no differences in mortality, malignancy, or retinopathy.

Because of the heterogeneous nature of the CLI population, these trials have demonstrated the necessity of incorporating a placebo control arm into the clinical trial design. These trials have also demonstrated that angiogenic gene therapy can improve perfusion in ischemic limbs; the extent to which there is clinical benefit has varied. Thus far, angiogenic gene therapy has proved to be safe. Potential side effects of gene therapy, such as the progression of diabetic retinopathy or the development of malignancy, have not been observed. There are currently several larger pivotal trials under way to assess the efficacy of angiogenic gene therapy on the clinically relevant endpoint of AFS.

Autologous Cells

Autologous stem cell therapies have used bone marrow mononuclear cells or endothelial progenitor cells obtained from bone marrow harvest or, less frequently, from circulating peripheral blood stem cells. Endothelial progenitor cells can be identified by cell sorting for CD34-positive, VEGF receptor-2–positive cells. Once concentrated, the cells can be injected into the ischemic limb to induce angiogenesis.²⁰⁰ The mechanisms by which stem cell therapy induces angiogenesis are unclear. Tateishi-Yuyama et al,¹²⁴ in a randomized prospective trial, showed that injection of bone marrow–derived mononuclear cell injections resulted in a significant increase in ABI and tcPO₂ compared with controls. Other phase 2 trials of bone marrow–derived stem cells (derived from concentrated bone marrow aspirate) have also demonstrated significant benefits on clinical endpoints, including major amputation.^201,202 The Use of Tissue Repair Cells (TRCs-Autologous Bone Marrow Cells) in Patients with Peripheral Arterial Disease to Treat Critical Limb Ischemia (RESTORE-CLI) trial also used bone marrow–derived stem cells, but utilized a technique of culturing and expanding the cells.²⁰³ They found a significant difference for the composite endpoint of death, major amputation, doubling of wound size, or new-onset gangrene (treatment group, 40% compared with placebo group, 67%) at 1 year (P = .003). A phase 3 trial was underway (REVIVE, NCT01483898, http://clinicaltrials.gov), but was halted due to low enrollment.

Major differences between the two techniques that utilize bone marrow–derived stem cells relate to the logistics of performing the therapy. The concentrated marrow technique requires removal of large quantities of bone marrow, but the treatment can be performed in that same setting. In contrast, the expansion technique involves harvest of a much smaller quantity of bone marrow, but requires a 2-week wait time before therapeutic injection can occur.²⁰⁴

Allogenic Cells

Allogenic stem cell therapies are also being studied. Placental stem cells are considered immune-privileged, and therefore, offer the advantage of off-the-shelf availability.²⁰⁴ Prather et al²⁰⁵ reported the use of placental-derived adherent stromal cells in a mouse model of hind-limb ischemia. They demonstrated significantly improved blood flow (P = .0008), increased capillary density (P = .021), reduced oxidative stress (P = 0.034), and reduced endothelial damage (P = 0.004) compared with placebo.

It is too early to determine what role, if any, therapeutic angiogenesis will have in the future care of patients with vascular disease. Early results from clinical trials are encouraging, but much work needs to be done to determine whether this will prove effective as a stand-alone therapy for patients with ischemic vascular disease, or will serve as an adjuvant treatment to current forms of revascularization.