Treatment of Intermittent Claudication

Overall Strategy and Basic Treatment for Intermittent Claudication

Overall Strategy
The overriding issue in the management of patients presenting with IC is that they are at significant risk of developing severe and often fatal cardiovascular complications; thus, their most serious problem is not the limitation of walking, even though that may be their only symptom. Patients with IC are at 2 to 4 times greater risk of dying from the complications of generalized atherosclerosis than similar people without claudication (see Cause of Death in Claudicants, p. 20). Therefore, the first priority in designing a treatment plan for these patients is to try to modify the known risk factors for the progression of atherosclerosis and development of atherothrombotic complications. It is important to explain to the patient the rationale for this strategy and that it is not designed to improve the claudication distance. Emphasis should be put on those risk factors whose modification has been shown to be particularly effective in decreasing morbidity and mortality, for instance, cigarette smoking. Advice regarding this, as well as some other risks such as obesity, has to be regularly reinforced. Modification of risk factors should be accompanied by the long-term prescription of antiplatelet pharmacotherapy, usually low-dose aspirin. The second step in the basic management in the newly diagnosed claudicant is the reassurance of the patient that walking into his or her claudication pain not only does no harm, but is in fact likely to gradually increase his or her pain-free walking distance. Regular walking exercise is likely to be beneficial both for the leg and for the underlying general disease, through a number of mechanisms. Risk factor modification, antiplatelet therapy, and regular exercise training are all the treatment that most patients with IC will need and is all that most should be offered in the current state of our knowledge. However, the condition of a minority of claudicants will deteriorate, and their handicap will become sufficiently severe to consider some local intervention, angioplasty or surgery, for their PAD. On rare occasions, a patients handicap may be so severe at presentation that intervention may be considered even before a full trial of basic noninterventional therapy. The decision to image the precise anatomy of the lesion depends on the decision regarding whether some form of intervention would be recommended if the morphology of the atherosclerotic lesion showed it suitable for intervention. The decision to consider a patient for interventional therapy is arrived at by the patient balancing existing disability against the procedural risk and likelihood of long-term success of an intervention. The patients disability should be assessed in terms of not only claudication distance but also the patients job and preferred everyday activities. Thus, for instance, intervention may be contemplated even in a long-distance claudicant, say, 500 meters on the flat, if this prevents a patient from pursuing his or her normal occupation in the building trade. At the other extreme, a short claudication distance might be accepted in an elderly retired person who has no particular desire to leave his of her home. On the other side of the equation is the risk of imaging and then the risk of intervention. Even if imaging is by traditional angiography, the risk is very low. In a multicenter trial of 118,591 arteriographic procedures reported by Hessel et al.,1 for example, the incidences of complications with axillary, translumbar, and femoral approaches were 3.29%, 2.89%, and 1.73% respectively; overall mortality rate was 0.025% (see Imaging Techniques, p. 73). The risks of the actual intervention have also been significantly lowered by the advent of angioplasty (PTA). Complications of PTA today are for the most part minor and typically do not require surgical treatment.2 Access-related complications range from less serious and more common (eg, groin hematoma) to the serious but rare events (eg, retroperitoneal hematoma).3 The incidence of complications at the angioplasty site, 1% to 7% in most series, is similar to that for percutaneous transluminal coronary angioplasty (PTCA) and consists principally of acute occlusion. Many of these can be managed with lytic or adjunctive mechanical therapy, including stents, so that in expert hands
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the need for emergency surgery because of a jeopardized limb is rare. The total incidence of complications countrywide is unknown, but it is probably higher than that reported from specialized centers. Distal embolization has been reported in up to 5% of cases.4 Most, however, are clinically silent,2 and even those that might be potentially problematic often can be treated successfully post-PTA by judicious use of lytic therapy. Although these complications are relatively minor, they and the significant recurrence rate after PTA must be kept in mind, and there are several randomized trials, the most recent also employing quality-of-life measures, that show no advantage of PTA over exercise training with extended follow-up (see Comparison of Therapeutic Options, p. 121). Both the risks and cost of percutaneous revascularization increase with the complexity and extent of anatomic involvement. The decision to revascularize the patient with claudication therefore must take into account both symptoms and the results of noninvasive testing (see Evaluation, p. 59). Once having clarified the anatomic basis for claudication, the recommendation to advise percutaneous revascularization is then individualized according to the two considerations just indicated. Diagnostic angiography may suggest that percutaneous revascularization has a high likelihood of technical success in one patient, suggesting that he or she may be a suitable candidate for the procedure. In other patients, certain risks and a complex of anatomic factors suggesting a low likelihood of acute or long-term success may dictate that only surgical revascularization would constitute effective therapy. In such a case, it may be appropriate to defer the risk of surgery until the patient is more severely disabled. Imaging thus may critically raise or lower the threshold for recommending that an intervention be performed. Should the patient treated by percutaneous revascularization return with clinical evidence of restenosis, repeat percutaneous intervention is probably indicated for the same reasons that led to the recommendation for the original procedure. A certain proportion of these patientsas had been clearly documented in certain patients undergoing one or more repeat coronary angioplasty procedures5 6will achieve a satisfactory long-term result after the second intervention. If the imaging indicates primary or recurrent lesions unsuitable for safe angioplasty, the possibility of surgical reconstruction has to be considered. The risks of this are significantly greater than the risks of angioplasty, in terms of not only mortality but major morbidity and delay in return to normal activities. Therefore, the assessment of the patients general condition becomes more central to deciding whether surgery is warranted. Adopting this approach with maximum concern for safety and efficacy requires coordinated input from experts in angiology, cardiology, radiology, and vascular surgery. Guidelines for appropriateness of intervention should be laid down by a team of involved specialists, but then individual patient management can be based on the guidelines as interpreted by one or two members of the team. Many centers currently perform an angiogram and then proceed immediately with percutaneous revascularization if needed. Other centers prefer to separate the diagnostic imaging from the interventional procedure. These decisions require experienced judgment, and expert advice from appropriate specialists on specific aspects should be obtained as needed. RECOMMENDATION 21: Indications for invasive therapy in intermittent claudication Before offering a patient with intermittent claudication the option of any invasive therapy, endovascular or surgical, the following considerations must be taken into account: a predicted or observed lack of adequate response to exercise therapy and risk factor modification; the patient must have a severe disability, either being unable to perform normal work or having very serious impairment of other activities important to the patient; absence of other disease that would limit exercise even if the claudication was improved (eg, angina or chronic respiratory disease); the individuals anticipated natural history and prognosis; the morphology of the lesion must be such that the appropriate intervention would have low risk and high probability of initial and long-term success.

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CRITICAL ISSUE 6: Identifying patients with intermittent claudication at higher risk of progression of peripheral arterial disease There is a need for identification of the small group of patients with intermittent claudication who, based on severity of symptoms, ankle-brachial pressure index, or anatomy of the arterial lesion, or the presence of specific risk factors, are at higher risk of progression of peripheral arterial disease.

Pharmacotherapy aimed at increasing claudication distance and improving functional status is under development (see Pharmacotherapy for Symptoms of Intermittent Claudication, p. 93). Other therapies designed to stimulate angiogenesis, improve skeletal muscle metabolism, and modulate platelet and vascular endothelial function are all under development to treat the symptoms of claudication.

Basic Treatment Risk factor modification

Modifiable atherosclerotic risk factors for PAD include smoking, diabetes mellitus, obesity, hyperlipidemia, hypertension, and homocysteine elevation. These will be considered in approximate order of importance.

Cigarette smoking.In smokers, the risk of developing PAD is increased twofold to threefold, and smoking correlates more closely with development of intermittent claudication than any other cardiovascular risk factor.7 Patients with PAD who continue to smoke have a greater likelihood of vascular disease progression, MI, stroke, and death than those who stop smoking.8 9 Smoking is also closely associated with the risk of limb loss.10 Based on these findings, smoking cessation is a critical step in the management of IC, even though the effect on the claudication symptoms may not be immediately evident.11 In a self-selected parallel group study, there was significant difference in the change in ankle pressure and treadmill walking distance between those patients who continued to smoke and those who stopped.12

RECOMMENDATION 22: Smoking cessation in peripheral arterial disease All patients with peripheral arterial disease should be strongly and repeatedly advised to stop smoking. Cessation rates are likely to be enhanced by a special program.

Obesity.The weight of the patient may be directly related to claudication distance. Overweight patients with IC
therefore directly benefit from reducing weight in terms of claudication distance. In addition, obesity is a recognized risk factor of most fatal and nonfatal cardiovascular events.

Diabetes mellitus.Diabetes mellitus is highly associated with lower-extremity arterial disease and its progression.13-16 Although glycemic control correlates well with an improvement in most diabetic complications, there is conflicting evidence about a direct correlation between glycemic control and the severity or progression of PAD.15 17-20 The United Kingdom Prospective Diabetes Study (UKPDS) provides new information on intensive glycemic control in terms of both large-vessel and small-vessel end points.21 22 Intensive glycemic control provided a significant reduction in any diabetes end point (largely microvascular) and MI. Use of metformin was also associated with a reduction in diabetes end points, all-cause mortality, and MI. However, neither intensive treatment reduced the risk of PAD. Thus, intensive glycemic control alone is insufficient to prevent the peripheral vascular complications of diabetes and underlines the importance of the control of other risk factors (smoking, hypertension, and hyperlipidemia) in these patients.
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RECOMMENDATION 23: Control of diabetes in peripheral arterial disease Patients with diabetes and peripheral arterial disease should have aggressive control and normalization of blood sugar. Fasting blood sugars should range from 80 to 120 mg/dL, and postprandial sugars should be <180 mg/dL; hemoglobin A1c should be <7.0%.

Diabetic patients are at particular risk of developing ulcers on their feet because of preexisting diabetic sensory neuropathy. Foot deformity caused by a motor neuropathy will also predispose to ulceration. It is therefore important to educate diabetic patients and their family about the importance of examining the feet regularly, wearing protective footwear at all times, avoiding abnormal pressure, and visiting a specialized diabetic foot clinic if they have any concerns.

RECOMMENDATION 24: Diabetic foot care in peripheral arterial disease All diabetic patients with peripheral arterial disease should receive special advice and regular supervision to minimize the risks of developing diabetic foot complications.

Hyperlipidemia.In PAD, the major lipid risk factors for peripheral atherosclerosis are elevated LDL cholesterol and triglyceride levels and low HDL cholesterol levels.9 15 23-25 Lp(a) is a lipoprotein fraction that is an independent risk factor for PAD.26 Unfortunately, there are no specific treatments for elevated Lp(a) levels except to aggressively treat abnormalities in other lipid fractions. Recent trials support the observation that lipid modification is associated with stabilization or regression of femoral atherosclerosis.27-31 However, this was not reproduced in the Probucol trial, in which treatment did not change the severity of femoral atherosclerosis but prevented progression.32 Neither was this reproduced in the KAPS study, in which pravastatin had no effect on the femoral artery but did reduce plaques in the carotid.33 Lipid modification in patients with CAD is associated with a reduction in the risk of vascular death. For example, simvastatin reduced cardiovascular events significantly.34 The effect of lipid-lowering therapy on the clinical progression of PAD was evaluated in a subgroup analysis of the Scandinavian simvastatin (4S) study.35 In this study, simvastatin was associated with a 38% risk reduction in the development or worsening of claudication.
Current National Cholesterol Education Program (NCEP) recommendations are to obtain a screening lipid profile in all patients with PAD.36 For patients with PAD who have elevated lipids, dietary restrictions should be the first advice.37 This may be effective in treating hypertriglyceridemia, which contributes to progression of the disease.9 The treatment goals are to achieve an LDL cholesterol less than 100 mg/dL (2.6 mmol/L), which will usually require the use of drug treatment. In addition, patients with a low HDL cholesterol level should be considered for niacin therapy. Patients with low HDL and elevated triglyceride levels in whom diet therapy fails should be placed on fibrates. On the basis of reported trials, the use of statins would result in avoiding one death per year in 640 patients treated.38 Additional studies in the PAD population are needed to assess the effects of lipid lowering on cardiovascular mortality and progression of leg arterial disease (see also Cost-effectiveness of Lipid Control in Intermittent Claudication, p. 130).

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RECOMMENDATION 25: Lipid control in peripheral arterial disease Because of the high incidence of coexistent coronary disease and similar mortality risk to coronary patients, patients with peripheral arterial disease with a low-density lipoprotein (LDL) cholesterol level greater than 125 mg/dL should be placed on therapy. In the first instance, a diet should be tried. If this fails to achieve a goal of LDL cholesterol level less than 100 mg/dL, then medications should be tried.

Hypertension.The effects of the treatment of hypertension on the natural history of peripheral atherosclerosis
have not been evaluated. In the claudicant, the goal of hypertension therapy is to reduce the risk of stroke, MI, and cardiovascular death, and this risk factor should be controlled according to the JNC guidelines.82 However, clinicians should be aware that when drug therapy results in a large decrease in systemic blood pressure, some patients may experience a slight worsening of their claudication symptoms.39 Nevertheless, it is important that such patients understand the more important risk to their life from uncontrolled hypertension, albeit asymptomatic, than from claudication. It also should be remembered that hypertension can be secondary to renal artery disease, and this is particularly likely in patients with PAD. The plasma creatinine level should therefore be monitored particularly carefully. The drug treatment of hypertension can follow the same guidelines as in patients without PAD. There is no good evidence that beta blockers adversely affect mild to moderate claudication.40 RECOMMENDATION 26: Control of hypertension in peripheral arterial disease Peripheral arterial disease patients with hypertension should have this risk factor controlled according to Joint National Committee (VI) (JNC [VI]) guidelines.

Hypercoagulable states. Hypercoagulable states should be detected and treated where needed (see Recommendation 14, p. 69 and Table XIII, p. 67). The only available treatment for these conditions is oral anticoagulation.

RECOMMENDATION 27: Hypercoagulable states in intermittent claudication Patients with intermittent claudication who have a hypercoagulable state and proven arterial or venous thrombosis should be anticoagulated with coumarins.

Homocysteine.Recently, several reports have shown a strong association between increases in plasma homocysteine concentration and PAD.41 This may be an important risk factor in patients younger than 50 years who present with claudication. A meta-analysis has clarified that at least the risk of CAD is increased with a homocysteine level above 5 mmol/L.42 In patients with CAD, elevated homocysteine levels are also independent predictors of death.43 Therapy with folic acid, vitamin B12, and vitamin B6 is effective in lowering homocysteine levels, but the effects on vascular disease severity have not been evaluated.
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CRITICAL ISSUE 7: Hyperhomocysteinemia in peripheral arterial disease There is a need for therapeutic trials to define the role of vitamin supplementation in preventing peripheral arterial disease progression and cardiovascular death. Currently there is no solid evidence to support the treatment of an elevated homocysteine level unless the symptomatic patient is known to have folic acid or vitamin B12 deficiency.

Hormone replacement therapy.The potential benefits of estrogen plus progesterone therapy in preventing
cardiovascular events in women with a history of CAD have been reported.44

Antiplatelet therapy
The Antiplatelet Trialists Collaboration reviewed 189 controlled studies involving secondary prevention of cardiovascular events in over 100,000 patients with cardiovascular symptoms. Overall, there was a 25% decrease in fatal and nonfatal MI, stroke, and vascular death. Fewer than 4,000 patients with PAD were entered (in 28 studies). They showed identical benefit to the overall group, but, because of the low numbers, this was not statistically significant.45 The benefit persisted for at least 3 years and was similar for aspirin, at dosages ranging from 75 to 350 mg/d. In the Physician's Health Study, low doses of aspirin resulted in a 54% reduction in the risk of peripheral arterial surgery as compared with placebo.46 It should be noted that higher doses of aspirin (greater than 325 mg daily) are often associated with gastrointestinal intolerance.47 Ticlopidine has been shown to reduce the risk of stroke and fatal and nonfatal MI by 29% compared with placebo.48 The most recently studied antiplatelet agent in PAD is clopidogrel, which, like ticlopidine, blocks the activation of platelets by ADP. In 19,185 study subjects enrolled with cardiovascular disease, 6,452 patients had PAD. All patients were randomized to low-dose aspirin or clopidogrel and followed up for an average of 1 to 3 years. In the PAD subgroup, clopidogrel (as compared with aspirin) resulted in a 23.8% relative risk reduction of ischemic stroke, MI, or vascular death, although the 95% confidence interval was wide (8.9%36%), and this included not only patients with IC but also those following revascularization.49 Additional studies will be necessary to define the role of these new potent (but more expensive) antiplatelet agents in the overall management of PAD50 (see also The Cost-effectiveness of Antiplatelet Therapy in Intermittent Claudication, p. 129).

RECOMMENDATION 28: Antiplatelet therapy in peripheral arterial disease All patients with peripheral arterial disease (whether symptomatic or asymptomatic) should be considered for treatment with low-dose aspirin, or other approved antiplatelet (unless contraindicated), to reduce the risk of cardiovascular morbidity and mortality.

The preceding discussion of measures to modify risk factors, including anti-platelet therapy, directed at altering natural history and reducing systemic risk is presented in algorithm form in page 90.

Exercise rehabilitation
In patients with claudication, convincing data indicate that an exercise program can produce clinically significant improvements in exercise performance and community-based walking ability. However, exercise can range from the physician recommending unsupervised walking in the community to a formal supervised exercise program on a treadmill. Several studies suggest that some level of supervision is necessary to achieve optimal results.51-53 In prospective studies of supervised exercise conducted for 3 months or longer, there are clear increases in treadmill exercise performance, and a lessening of claudication pain severity during exercise.54-66
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TABLE XV.Randomized, controlled trials evaluating the efficacy of exercise rehabilitation.

Group Larsen & Lassen,62 1966 Holm et al.,77 1973 Dahllof et al.,61 1974 Dahllof et al.,60 1976 Lundgren65 1989 Creasy et al.,58 1990 Hiatt et al.,54 1990 Mannarino et al.,66 1991 Hiatt et al.,55 1994 Regensteiner et al.,53 1997 Patterson et al.,69 1997 T C T C T C T C T1 T2 T3 T1 T2 T C T1 T2 T3 T1 T2 C T1 T2 T1 T2 n 7 7 6 6 11 23 8 10 25 25 25 13 20 9 10 10 10 10 9 8 10 10 10 19 19 Intervention Daily walks Placebo tablet Exercise Placebo tablet Exercise Placebo tablet Exercise Placebo tablet Surgery + exercise Surgery Exercise Exercise Angioplasty Supervised exercise Control Exercise + antiplatelet Exercise Antiplatelet Supervised exercise Strength training Control Supervised exercise Home exercise Supervised exercise Home exercise Duration (mo) 6 4 6 4 6 6 3 6 3 3 6 Change in ACD (%) 183* -6 133* NC 117* NC 135* 75* 263* 173* 151* 442* 57 123* 20* 105* 86* 38* 74* 36* -1 137* 5 195* 83* Functional assessment No No No No No No Improved NC No Improved NC NC Improved NC Improved Improved

Abbreviations: T, treated group; C, control group; Functional assessment, use of questionnaire to evaluate community-based functional status; NC, no change. *p < 0.05 compared with baseline. p < 0.05 difference between groups. For the Creasy study, the data given are for the 12-month follow-up point.

A recently published meta-analysis of these studies showed an average 179% increase in initial claudication distance and a 122% increase in maximal walking distance on the treadmill.67 This meta-analysis included uncontrolled observational studies as well. Table XV summarizes the results obtained in controlled trials. The predictors of response to the training program include a high level of claudication pain during the training sessions and 6 months or longer of formal training and walking exercise (vs other training modalities). Treadmill exercise also has been shown to be more effective than strength training or combinations of training modalities.55 Finally, there is virtually no morbidity or mortality from exercise rehabilitation.68 Several studies also have shown improvements in peak exercise performance and peak oxygen consumption with treadmill training. These changes are important because, as a result, patients are able to perform activities of higher intensities such as climbing stairs, gardening. and dancing, activities that were not possible before training. These studies also have shown that, at a given submaximal workload, exercise training decreased heart rate, ventilation, and oxygen consumption.54 55 These changes may contribute to the ability to sustain walking exercise for longer times before claudication pain limits the activity. In addition to evaluating changes in treadmill exercise performance, some studies used patient-based outcome assessment, SF-36 or WIQ, to determine changes in functional status and quality of life with exercise. This is important because the patient with claudication is seeking treatment for a disabling symptom that affects his or her daily activities.70 Using this approach, supervised training has been shown to improve the ability of the claudicant to walk longer distances at faster speeds, with less severe claudication pain.54 71 These studies also showed improved total caloric expenditure and physical functioning using a variety of validated questionnaires. Thus, a comprehensive approach needs to be used to assess the benefits of any claudication therapy. Exercise rehabilitation also has the potential to favorably modify other cardiovascular risk factors. Although not studied in a comprehensive fashion, initial studies have shown an improvement in glucose metabolism, a reduction in cholesterol and triglyceride concentrations (when diet therapy was also used), and enhanced smoking ces88

sation.72 73 Improvements in these cardiovascular risk factors are not typically seen with drug therapy for claudication or with bypass surgery or angioplasty. An important issue is patient acceptability and compliance with exercise training. Many patients may have contraindications for exercise (eg, severe CAD, musculoskeletal limitations, or neurological impairments). Other patients may be unwilling to participate in supervised sessions if they have long distances to travel, if an appropriate rehabilitation program is not available in their area, or if the expenses incurred are too great. In a German study of 201 patients recommended for exercise, it was found that 34% had contraindications, and 36% of the remaining patients refused to participate because of these same arguments.74 However, an American study showed that only 9% of patients referred for supervised exercise training were excluded on screening for the program.68 These exclusions were all for severe cardiac ischemia on the initial treadmill test. In patients enrolled, 73% were able to complete the program without difficulty. Thus, when offered, most patients are able to enroll and successfully complete a training program for their claudication. An important aspect of exercise is that patients need more than the simple recommendation by the physician to engage in walking exercise at home. In one study, patients with IC were randomized to a 3-month program of supervised exercise or home-based exercise. Patients exercising at home were given detailed instructions by a rehabilitation nurse at the start of the program. They were also contacted weekly by phone to assess compliance and provide encouragement. Whereas the supervised patients had the expected improvements in treadmill exercise performance and quality of life, those patients trained at home realized no benefit.53 Thus, exercise is effective primarily when performed in a supervised environment. However, unsupervised training may be more effective than no training at all.

The exercise prescription.Exercise sessions are typically held 3 times a week for approximately 1 hour each,
and 3- to 6-month periods of training are customary. During the exercise sessions, rest periods (induced by claudication) are interspersed with bouts of treadmill walking. The patient walks on the treadmill until a mild or moderate level of pain is reached (scored as 3 or 4 on a 15 scale as previously described). At that point, the patient rests until the pain abates. The initial training workload is determined from the symptom-limited maximal treadmill test on entry, such that the intensity of the treadmill exercise is set to the workload that initially brings on claudication pain in the patient. In subsequent visits, the speed or grade is increased if the patient is able to walk for 10 minutes or longer at the lower workload without reaching moderate claudication pain. Either speed or grade can be increased, but an increased grade is recommended if the patient can already walk at 2 mph (3.2 km/h). An additional goal of the program is to increase patient walking speed up to the normal 3.0 mph (4.8 km/h) from the average PAD patient walking speed of 1.5 to 2.0 mph (approximately 2.43.2 km/h). The precise mechanism behind improvement of walking ability with exercise is not established. Collateral development seems unlikely because ankle pressures and limb flow do not show any impressive increases after exercise.75 76 Even though some improvement in hemodynamic parameters are shown, they are poorly correlated to an increased walking capacity.54 Other possible explanations might be an improved metabolic capacity in the muscles and altered gait using more proximal nonischemic muscle, by analogy to amputees walking with a prosthesis.61 77 78 A further question is whether pain-developing exercise has any negative impact. It has been shown that patients with IC have an increased microalbuminuria after exercise, supporting the interpretation that an ischemia reperfusion injury takes place.79 This is also supported by the findings of thromboxane and neutrophil changes in claudicants during and after walking.80 By contrast, a recent study showed that treadmill exercise is not associated with a change in any plasma marker of endothelial damage.81
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Summary: Exercise training.Numerous trials provide evidence that the walking capacity and overall functional status are increased by exercise training in patients with disabling claudication. The most effective programs are supervised, employ walking exercise, and last 3 to 6 months. Maintenance of regular exercise, whether supervised or not, needs to be continued indefinitely or the benefit will eventually be lost.
RECOMMENDATION 29: Exercise training in intermittent claudication A program of exercise therapy (preferably supervised) should always be considered as part of the initial treatment for patients with intermittent claudication.

Treatment to Alter Natural History and reduce Systemic Risk

History and physical examination Ankle: brachial pressure index Confirm PAD with intermittent claudication Assess cardiovascular risk factors Initial evaluation: Hemoglobin Serum creatinine Smoking history Lipid profile Hypertension Diabetes

Assess disability* symptom severity Evaluate and treat intermittent Claudication as per other Algorithms See B 4.6.1 and B 4.6.2

Special investigations: Hypercoagulability screen Homocysteine level Lp(a) Other

Modify risk factors Antiplatelet therapy

Diabetes treatment HbA1C <7.0%

Hyperhomocysteinemia ?Folate of B12

Hypercoagulable and arterial thrombosis Anticoagulate

Hypertension treatment Follow JNC VI guidelines

Smoking cessation Behavior modification Nicotine replacement Bupropion SF-36 = Medical Outcomes Short Form 36 Questionnaire WIQ = Walking Impairment Questionnaire PVR = pulse volume recordong VWF = velocity waveform analysis MRA = magnetic resonance angiography JNC = Joint National Commission HbA1C = hemoglobin A1C LDL = low-density lipoprotein HDL = high-density lipoprotein *Disability as defined by the individual patient.

Lipid goals LDL cholesterol <100 mg/dL Reduce triglyceride Raise HDL cholesterol

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The association of dyslipoproteinemia with symptoms and signs of peripheral arterial disease: the lipids research clinics program prevalence study. Circulation 1986;73 (Suppl I):I-100-I-107. 24. Drexel H, Steurer J, Muntwyler J, Meienberg S, Schmid HR, Schneider E, et al. Predictors of the presence and extent of peripheral arterial occlusive disease. Circulation 1996;94[suppl I]:II-199-II-205. 25. Kannel WB, Skinner JJ Jr, Schwartz MJ, Shurtleff D. Intermittent claudication: incidence in the Framingham Study. Circulation 1970;41:875-883. 26. Valentine JR, Grayburn PA, Vega GL, Grudy M. Lp(a) lipoprotein is an independent, discriminating risk factor for premature atherosclerosis among white men. Arch Intern Med 1994;154:801-806. 27. Olsson AG, Ruhn G, Erikson U. The effect of serum lipid regulation on the development of femoral atherosclerosis in hyperlipidaemia: a non-randomized controlled study. J Intern Med 1990;227:381-390. 28. Blankenhorn DH, Azen SP, Crawford DW, Nessim SA, Sanmarco ME, Selzer RH, et al. Effects of colestipol-niacin therapy on human femoral atherosclerosis. Circulation 1991;83:438-447. 29. Duffield RGM, Lewis B, Miller NE, Jamieson CW, Brunt JN, Colchester AC. Treatment of hyperlipidaemia retards progression of symptomatic femoral atherosclerosis; a randomised controlled trial. Lancet 1983;2:639-642. 30. The Lipid Research Clinics Coronary Primary Prevention Trial Results. I: Reduction in incidence of coronary heart disease. JAMA 1984;251:351-364. 31. De Groot E, Jukema JW, van Boven AJ, Reiber JH, Zwinderman AH, Lie KI. Effect of pravastatin on progression and regression of coronary atherosclerosis and vessel wall changes in carotid and femoral arteries: a report for the Regression Growth Evaluation Statin Study. Am J Cardiol 1995;76:40C-46C. 32. Walldius G. Erikson U, Olsson AG, Bergstrand L, Hadell K, Johansson J, et al. The effect of probucol on femoral atherosclerosis: the Probucol Quantitative Regression Swedish Trial (PQRST). Am J Cardiol 1994;74:875-883. 33. Salonen R, Nyyssnen K, Porkkala E, Rummukainen J, Belder R, Park J, et al. KAPS: a population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation 1995;92:17581764. 34. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the 4S Study. Lancet 1994;344:1383-1389. 35. Pedersen TR, Kjekshus J, Pyrl K, Olsson AG, Cook TJ, Musliner TA, et al. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin survival study (4S). Am J Cardiol 1998;81:333-335.
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36. Summary of the Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. JAMA 1993;269(23):3015-3023. 37. Cooke JP Ma AO. Medical therapy of peripheral arterial occlusive disease. Surg Clin North Am 1995;75:569-579. 38. Freemantle N, Barbour R, Johnson R, Marchment M, Kennedy A. The use of statins: a case of misleading priorities? Editorial. BMJ 1997;315:826-828. 39. Solomon SA, Ramsay LE, Yeo WW, Parnell L, Morris-Jones W. b blockade and intermittent claudication: placebo controlled trial of atenolol and nifedipine and their combination. Br Med J 1991;303:1100-1104. 40. Radack K, Deck C. Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease: a meta-analysis of randomized controlled trials. Arch Intern Med 1991;151:1769-1776. 41. Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991;324:1149-1155. 42. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995;274:1049-1057. 43. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997;337:230-236. 44. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280(7):605-613. 45. Antiplatelet Trialists' Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. BMJ (Clin Res Ed) 1988;296:320-331. 46. Goldhaber SZ, Manson JE, Stampfer MJ, LaMotte F, Rosner B, Buring JE, et al. Low-dose aspirin and subsequent peripheral arterial surgery in the physicians' health study. Lancet 1992;340:143-145. 47. Krupski WC, Weiss DG, Rapp JH, Corson JD, Hobson RW. Adverse effects of aspirin in the treatment of asymptomatic carotid artery stenosis. The VA Cooperative Asymptomatic Carotid Artery Stenosis Study Group. J Vasc Surg 1992;16(4):588-597. 48. Janzon L, Bergqvist D, Boberg J, Boberg M, Eriksson I, Lindgarde F, et al. Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicenter Study. J Intern Med 1990;227:301-308. 49. CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-1339. 50. Davie AP, Love MP. CAPRIE trial. Lancet. 1997;349(9048):355. 51. Jonason T, Ringqvist I, Oman-Rydberg A. Home-training of patients with intermittent claudication. Scand J Rehabil Med 1981;13:137-141. 52. Clifford PC, Davies PW, Hayne JA, Baird RN. Intermittent claudication: is a supervised exercise class worth while? Br Med J 1980;280:1503-1505. 53. Regensteiner JG, Meyer TJ, Krupski WC, Cranford LS, Hiatt WR. Hospital vs home-based exercise rehabilitation for patients with peripheral arterial occlusive disease. Angiology 1997;48:291-300. 54. Hiatt WR, Regensteiner JG, Hargarten ME, Wolfel EE, Brass EP. Benefit of exercise conditioning for patients with peripheral arterial disease. Circulation 1990;81:602-609. 55. Hiatt WR, Wolfel EE, Meier RH, Regensteiner JG. Superiority of treadmill walking exercise vs. strength training for patients with peripheral arterial disease. Implications for the mechanism of the training response. Circulation 1994;90:1866-1874. 56. Lundgren F, Dahllof AG, Schersten T, Bylund-Fellenius AC. Muscle enzyme adaptation in patients with peripheral arterial insufficiency: spontaneous adaptation, effect of different treatments and consequences on walking performance. Clin Sci 1989;77:485-493. 57. Mannarino E, Pasqualini L, Menna M, Maragoni G, Orlandi U. Effects of physical training on peripheral vascular disease: a controlled study. Angiology 1989;40:5-10. 58. Creasy TS, McMillan PJ, Fletcher EWL, Collin J, Morris PJ. Is percutaneous transluminal angioplasty better than exercise for claudication? Preliminary results from a prospective randomized trial. Eur J Vasc Surg 1990;4:135-140. 59. Hedberg B, Langstrom M, Angquist KA, Fugl-Meyer AR. Isokinetic plantar flexor performance and fatiguability in peripheral arterial insufficiency. Acta Chir.Scand. 1988;154:363-369. 60. Dahllof A, Holm J, Schersten T, Sivertsson R. Peripheral arterial insufficiency. Effect of physical training on walking tolerance, calf blood flow, and blood flow resistance. Scand J Rehabil Med 1976;8:19-26. 61. Dahllof A, Bjorntorp P, Holm J, Schersten T. Metabolic activity of skeletal muscle in patients with peripheral arterial insufficiency. Eur J Clin Invest 1974;4:9-15. 62. Larsen OA, Lassen NA. Effect of daily muscular exercise in patients with intermittent claudication. Lancet 1966;2:1093-1096. 63. Ericsson B, Haeger K, Lindell SE. Effect of physical training on intermittent claudication. Angiology 1970;21:188-192. 64. Ernst EEW, Matrai A. Intermittent claudication, exercise, and blood rheology. Circulation 1987;76:1110-1114. 65. Lundgren F, Dahllof A, Lundholm K, Schersten T, Volkmann R. Intermittent claudication: surgical reconstruction or physical training? A prospective randomized trial of treatment efficiency. Ann Surg 1989;209:346-355. 66. Mannarino E, Pasqualini L, Innocente S, Scricciolo V, Rignanese A, Ciuffetti G. Physical training and antiplatelet treatment in stage II peripheral arterial occlusive disease: alone or combined? Angiology 1991;42:513-521. 67. Gardner AW, Poehlman ET. Exercise rehabilitation programs for the treatment of claudication pain: a meta-analysis. JAMA 1995;274:975-980. 68. Williams LR, Ekers MA, Collins PS, Lee JF. Vascular rehabilitation: benefits of a structured exercise/risk modification program. J Vasc Surg 1991;14:320-326. 69. Patterson RB, Pinto B, Marcus B, Colucci A, Braun T, Roberts M. Value of a supervised exercise program for the therapy of arterial claudication. J Vasc Surg 1997;25:312-319. 70. Hiatt WR, Hirsch AT, Regensteiner JG, Brass EP. Clinical trials for claudication: assessment of exercise performance, functional status, and clinical end points. Vascular Clinical Trialists. Circulation 1995;92:614-621. 71. Regensteiner JG, Steiner JF, Hiatt WR. Exercise training improves functional status in patients with peripheral arterial disease. J Vasc Surg 1996;23:104-115. 72. Hall JA, Barnard J. The effects of an intensive 26-day program of diet and exercise on patients with peripheral vascular dis92

ease. J Cardiac Rehabil 1982;2:569-574. 73. Rosfors S, Bygdeman S, Arnetz BB, Lahnborg G, Skoldo L, Eneroth P, et al. Longterm neuroendocrine and metabolic effects of physical training in intermittent claudication. Scand J Rehabil Med 1989;21:7-11. 74. De La Haye R, Diehm C, Blume J, Breddin K, Gerlach H, Rettig K, et al. An epidemiological study of the value and limits of physical therapy/exercise therapy in Fontaine stage II arterial occlusive disease. VASA 1992;38:1-40. 75. Alpert SJ, Larsen OA, Lassen NA. Exercise and intermittent claudication: blood flow in the calf muscle during walking studied by the xenon-133 clearance method. Circulation 1969;39:353-359. 76. Johnson EC, Voyles WF, Atterbom HA, Pathak D, Sutton MF, Greene ER. Effects of exercise training on common femoral artery blood flow in patients with intermittent claudication. Circulation 1989;80(Suppl III):III-59-III-72. 77. Holm J, Dahllof AG, Bjorntorp P, Schersten T. Enzyme studies in muscles of patients with intermittent claudication: effect of training. Scand J Clin Lab Invest Suppl 1973;128:201-205. 78. Hiatt WR, Regensteiner JG, Wolfel EE, Carry MR, Brass EP. Effect of exercise training on skeletal muscle histology and metabolism in peripheral arterial disease. J Appl Physiol 1996;81(2):780-788. 79. Khaira HS, Maxwell SR, Shearman CP. Antioxidant consumption during exercise in intermittent claudication. Br J Surg 1995;82:1660-1662. 80. Khaira HS, Nash GB, Bahra PS, Sanghera K, Gosling P, Crow AJ, et al. Thromboxane and neutrophil changes following intermittent claudication suggest ischaemia-reperfusion injury. Eur J Vasc Endovasc Surg 1995;10:31-35. 81. Woodburn K, Rumley A, Hurtagh A, Lowe GDO. Acute exercise and markers of endothelial injury in peripheral arterial disease. Eur J Vasc Endovasc Surg 1997;14:140-142. 82. Prevention, detection, evaluation, and treatment of hypertension. The Sixth Report of the Joint National Committee. National Institutes of HealthNational Heart, Lung, and Blood Institute. National High Blood Pressure Education Programme. Indian Heart J 1999;51:381-396.

Pharmacotherapy for Symptoms of Intermittent Claudication

Introduction
Patients with intermittent claudication mostly receive drug treatment for coexisting disease (eg, hypertension), risk factor modification (eg, hyperlipidemia), and as prophylaxis against thrombotic events associated with atherosclerosis (eg, antiplatelet drugs). No pharmacological agent has proved efficacious enough in providing significant reduction or elimination of symptoms of claudication to gain widespread acceptance and use for improving walking. However, a number of types of drugs have been promoted for this indication, with varying evidential support, and these will be considered in this section. These drugs are frequently grouped together under the heading vasoactive agents, partly because of their multiplicity of potential mechanisms of action. Some of the drugs have been distinguished as rheologic agents, but for others such as prostanoids, the mode of action is still not well delineated. These drugs should not replace exercise programs and other lifestyle adjustments described in Basic Treatment (see p. 84). However, they have a place as adjunctive treatment where invasive therapy is not indicated, in those who cannot or will not follow exercise therapy or in those who have not sufficiently benefited from it (see Adjuvant Therapy, p. 266). Table XVI and Figure 20 show results of randomized, placebocontrolled, double-blind trials of pharmacotherapy in IC.

Established Drugs With Proven but Small Benefit in Improving Claudication Pentoxifylline
Pentoxifylline improves red cell deformability, lowers fibrinogen levels, decreases platelet aggregation, and has been shown to increase walking distance in patients with PAD. In early controlled trials, the drug produced a 22% improvement over placebo in ICD and a 12% improvement in the ACD.1 However, these percent improvements were expressed as the mean difference between week 2 and week 24. The actual improvement over placebo from entry to 6 months in ACD was 18%, but this difference was not statistically significant. A more recent study confirmed these results, with a 21% improvement over placebo (p = 0.09).2 The study showed that a subgroup of patients with symptoms for longer than a year and an ABPI < 0.80 responded better to the drug. Importantly, patient-based questionnaires to assess efficacy have not been employed in the clinical trials of pentoxifylline, so the actual clinical benefit of the drug has not been fully defined.
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TABLE XVI.Randomized, placebo-controlled, double-blind trials of pharmacotherapy in intermittent claudication.

N Cilostazol: Money et al., 199812 Dawson et al., 199813 Pentoxifylline: Lindgarde et al., 19892 (subset) Porter et al., 19821 Naftidrofuryl: Moody et al.,7 1984 Kriessmann & Neiss,6 1988 Adhoute et al.,5 1990 Trbestein et al.,8 1994 Adhoute et al.,4 1986 Buflomedil: Trbestein 19849 Diamantopoulos et al.,10 1989 Ticlopidine: Balsano et al.,17 1989 Verapamil: Bagger et al.,23 1997 Dextran: Ernst et al.,24 1990 Hexopal: Kiff,31 1988 Cinnarizine: Barber et al.,29 1980 Donald,30 1979 Staessen,28 1977 Propionyl-L-carnitine: Brevetti et al.,32 1995 Brevetti et al.,33 1996 Beraprost: Lievre et al.,34 1996 PGE1: Diehm et al.,35 1997 Belch et al.,36 1997 Dose

ACD (%) Duration (weeks) Placebo Drug

p value

WIQ/SF-36*

Comments

239 81 150 109 128 180 136 118 104 94 113 34 151 44 20 80 45 40 26

200 mg/d 200 mg/d 1.2 g/d 1.2 g/d 1.2 g/d 633 mg 633 mg 600 mg 600 mg 633 mg 600 mg 600 mg 500 mg/d 120480 mg 500 mL 4 g/d 225 mg 225 mg 200 mg

16 12 24 24 24 24 12 24 12 24 14 24 21 mo 2 6 12 16 12 16

13 10 29 30 38 25 35 46 40 28 43 9 38 -2 0 87 11 34 30

47 63 50 63 56 31 78 93 55 60 97 68 71 49 39 50 142 113 75

<0.001 <0.01 0.09 <0.05 0.19 0.045 <0.05 <0.05 NS <0.001 <0.01 0.011 <0.01 <0.001 <0.001 NS NS <0.05

Yes Yes No No No Yes No No No Yes No No No No No Yes No No Yes ICD data only ICD data only; crossover trial Phenobarbitoneplacebo Crossover trial Cross-over trial ICD data only ICD data only ICD data only

All diabetic patients

245 485 83 213 80

1-3 g/d 2 g/d 120 g/d 60 mg/d 3 doses

24 52 12 8 8

46 50 41 60 -14

73 64 91 101 53

<0.05 <0.05 NS <0.05 <0.01

No No No No Yes Optimal dose group

NOTE. DACD=% change in absolute walking distance; NS, not significant. *Functional assessment as defined by WIQ and SF-36. Percentage of patients with 50% increase in baseline ACD. Percentage of patients with 100% or greater increase in baseline ACD.

Naftidrofuryl
Naftidrofuryl has been available for treating IC for over 20 years. It is a 5HT antagonist and may improve aerobic metabolism in oxygen-depleted tissues and possibly reduce erythrocyte and platelet aggregation.3 In four placebo94

Fig. 20.Randomized placebo-controlled, double-blind trials of pharmacotherapy in intermittent claudication.

controlled studies, Naftidrofuryl was more effective than placebo in improving walking distance,4-7 and a further study showed no significant difference.8

Buflomedil
Buflomedil has an alpha-1 and -2 adrenolytic effect. It has been shown to decrease vasoconstriction. It has also been shown to have some effect on platelets, red cell deformability, and a weak calcium antagonist effect. Buflomedil has been available for the treatment of IC in some countries for over 10 years. Two relatively small studies, conducted more than 10 years ago, showed a significantly greater improvement in absolute walking distance with Buflomedil compared with placebo.9 10

Cilostazol
Cilostazol is a phosphodiesterase III inhibitor with vasodilator and antiplatelet activity.11 The first published dou95

ble-blind trial showed a 47% increase in ACD in the treatment group compared to 13% increase in the placebo group (Tab. XVI).12 This trial also showed that all subgroups of patients (age, smoking status, gender, race, and diabetes) responded equally well to cilostazol. Quality of life was assessed in this trial using the medical outcomes study SF-36 questionnaire. This showed that patients on cilostazol had significant improvement in their physical functioning relative to those on placebo. They reported improved physical performance in the community setting. Mental health scores were unaffected by treatment. Side effects included headache, diarrhea, and dizziness. Further randomized multicenter studies have been published13 14 and also show consistent improvements in ICD and ACD in the cilostazol group as compared with placebo. Subjective functional assessment was not well assessed but did suggest that there was drug effect, as noted by both patients and physicians.15

Drugs With Minimal or No Benefit in Improving Claudication Antiplatelet drugs

As discussed previously, the use of aspirin and other antiplatelet agents are important in the long-term treatment of peripheral atherosclerosis assuming a significant degree of multisystem involvement, mainly to reduce the overall incidence of cardiovascular events (see Recommendation 28, p S83). However, no studies have shown a benefit of aspirin in the treatment of claudication per se, although there is one study that presented suggestive evidence that aspirin slowed progression of atherosclerosis assessed by serial angiography.16 In contrast, ticlopidine, a potent inhibitor of platelet aggregation that also has hemorheologic effects, was shown in two randomized, placebo-controlled trials to improve claudication symptoms and exercise performance17 18 (Table XVI). However, only one of these studies, by Balsano et al., had evaluable data. In that trial, treadmill testing was performed on the flat, and therefore, the clinical benefits of the drug may have been overestimated because of the very low treadmill workload.

Vasodilators
Arteriolar vasodilators were the first class of agents used to treat claudication. Examples include drugs that inhibit the sympathetic nervous system (alpha blockers), direct-acting vasodilators (papaverine), beta2 agonists (nylidrin), calcium channel blockers (nifedipine), and angiotensin-converting enzyme inhibitors. These drugs have not been shown to have clinical efficacy in randomized, controlled trials.19-21 There are several theoretical reasons why vasodilators may not be effective. Most importantly, in the exercising claudicant, vessels in ischemic areas are already maximally dilated, so vasodilator drugs will only create a steal phenomena by dilating vessels in normally perfused tissues (primarily proximal muscles), thus shifting the distribution of blood flow away from muscles supplied by obstructed arteries.

Ketanserin
Ketanserin is a selective serotonin (S2) antagonist that lowers blood viscosity and also has vasodilator and antiplatelet properties. Controlled trials of this drug have shown it not to be effective in treating claudication.22

Verapamil
One study has looked at the possibility that the calcium antagonist verapamil may have a clinical benefit in patients with intermittent claudication. Although treatment was only for 2 weeks and the study design could be criticized, the ACD was statistically significantly greater in the treated than in the placebo group.23

Isovolemic hemodilution
Isovolemic hemodilution has been advocated for the treatment of IC even in the absence of polycythemia. No doubt, hemodilution lowers the viscosity of whole blood, but it is still uncertain whether the increase in blood flow
96

compensates for the decrease in oxygen-carrying capacity of the blood. One double-blind, placebo controlled trial of dextran hemodilution showed efficacy in selected patients.24

Aminophylline
Aminophylline inhibits adenosine receptors and thus may blunt the vasodilatation response during exercise. This effect would theoretically limit the steal of blood away from ischemic skeletal muscle. One study has shown that intravenous aminophylline improves treadmill exercise performance in patients with claudication.25

Vitamin E
Five randomized controlled trials have been published since 1953 regarding the use of vitamin E and the treatment of claudication. Although some results are encouraging, there is insufficient evidence to recommend the routine use of vitamin E in patients with IC.26

Defibrotide
Defibrotide is a polydeoxyribonucleotide drug with antithrombotic and hemorheological properties. A metaanalysis was performed in 1994 on 10 placebo-controlled trials of defibrotide in patients with PAD stage II (406 patients on defibrotide, 337 patients on placebo). The drug was used at a dose of 400 to 800 mg daily, the treatment ranging from 60 to 180 days. There was a net gain in absolute walking distance over placebo of 73 m (95% confidence interval; range, 35-111 m).27

Other vasoactive drugs

Other drugs that have been promoted include cinnarizine,28-30 cyclandelate, nicotinic acid derivatives, 31 ginkgo biloba, and Isosuprine. However, there is no consistent scientific evidence of efficacy for any of these.

RECOMMENDATION 30: Pharmacotherapy for symptoms of intermittent claudication Although some controlled clinical trials with pentoxifylline, naftidrofuryl, buflomedil, and recently cilostozol, have shown statistically significant improvement in walking distance, the average benefit was small. Greater benefit, observed in a minority of patients, may warrant a short course of therapy with continued use of such agents if sufficient benefit is observed. Recent clinical trials have shown a greater benefit of cilostazol for both walking distance and quality of life, which may warrant more widespread use. However, currently there are insufficient data to recommend the routine use of pharmacotherapy in all patients with claudication.

Incompletely Studied Drugs With Potential Benefit in Improving Claudication Carnitine

Patients with PAD not only have a limited arterial blood flow but also develop metabolic abnormalities in their skeletal muscle. An example of this is changes in carnitine metabolism. Patients with PAD have been shown to accumulate acylcarnitines (intermediates of oxidative metabolism) in their skeletal muscle.37 This abnormal accumulation of acylcarnitines is directly correlated with impaired exercise performance. It has thus been hypothesized that supplementation of patients with carnitine would improve ischemic muscle metabolism. Carnitine, and an acyl form of carnitine (propionyl-l-carnitine), are drugs that have been shown to increase exercise performance and improve claudication symptoms in small phase II trials.38 39 Larger phase II trials have also shown benefit of pro97

pionyl-L-carnitine, with the optimal dose of 2 g/d,32 33 (Tab. XVI). Three multicenter, phase III trials are evaluating the efficacy and safety of propionyl-L-carnitine in the treatment of claudication.40

Prostaglandins
Prostaglandins have been used in several studies in patients with CLI, with some success. In one open-label study of claudicants, 44 patients were treated either without an infusion (control group), with intravenous pentoxifylline, or with intravenous prostaglandin E1 (PGE1) for 4 weeks.41 All patients also underwent an exercise rehabilitation program. The exercise program alone resulted in a 99% increase in maximal walking distance; pentoxifylline, a 119% increase; and PGE1, a 371% increase. Because this trial was unblinded and not placebo controlled, and patients had a combined intervention of exercise training and drug, the results need to be confirmed with additional studies. A prodrug of PGE1 (AS-013) was studied in a randomized, controlled, prospective study of 80 patients with IC, comparing placebo with three dosage regimens of the drug given intravenously for 5 days per week over 8 weeks. There was a significantly greater increase (p < 0.01) in maximum walking distance in the combined active treatment group (53%) compared with the placebo group (-14%). There was also a dose-related improvement in the response to a quality-of-life questionnaire.36 In another recent study, intravenous PGE1 given for 5 days per week over 4 weeks and twice weekly per week for a further 4 weeks was compared with placebo in 213 claudicants. At the end of the 8 weeks of treatment, pain-free walking distance increased by 60% in the placebo group compared with 101% in the treated group (p < 0.05). These improvements remained virtually unchanged over 3 months follow-up without treatment.35 Intravenous administration may not be the most practical preparation. The recent development of an oral preparation may be more suitable in patients with IC. The experience with orally active prostaglandins in claudication is more limited, with only two published reports for evaluation. Beraprost is a PGI2 analog that is orally active. A single phase II dose-ranging study has been published in which 164 patients were randomized to placebo or three doses of drug.40 The improvement in absolute claudication distance over placebo was as follows: 60 g/d produced a 48% increase, 120 g/d a 51% increase, and 180 g/d a 31% increase (Tab. XVI). None of these changes was statistically significant. A concern was that at the highest dose, 62% of the patients reported side effects of headache, flushing, and gastrointestinal intolerance. Several phase III trials are evaluating the effectiveness of these drugs in claudication, and it is hoped that these studies will clarify the utility of this class of drug.

CRITICAL ISSUE 8: Use of prostanoids for symptoms of intermittent claudication There is a need to investigate the possibly greater efficacy of prostanoids in patients with intermittent claudication, because most randomized, open, or double-blind trials with intraarterial or intravenous prostanoids have been performed in patients with end-stage critical limb ischemia. Predictors to select the most suitable patients for prostanoid treatment need to be determined.

Vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are mitogenic agents for the development of new collateral channels in models of peripheral ischemia. VEGF has been shown to augment collateral vessel development and increase capillary density in skeletal muscle in a rabbit model.41 This effect has been observed when the VEGF protein is administered by intraarterial infusion and when the DNA encoding for VEGF is given by intramuscular injection.42 Early phase I and phase II trials are now in progress to determine whether this novel therapy has a clinical application in patients with claudication and severe leg ischemia.

Other new agents

98

L-arginine is an amino acid that has been shown to improve nitric oxide formation and endothelial-dependent vasodilatation in patients with atherosclerosis. A few small studies have been performed with this compound in patients with claudication.43 44 These studies have shown improvements in pain-free and maximal walking distance, but larger studies are necessary to determine the benefit of this treatment. Another new class of agent is drugs that open potassium channels in vascular smooth muscle. In animal studies, this unique vasodilating drug improves muscle blood flow and energy metabolism in experimental models of vascular disease.45 Other metabolic factors that may be addressed in PAD include modification of the balance between fatty acids versus carbohydrates as substrates for ischemic skeletal muscle. Although fatty acids are a plentiful source of energy, they require relatively more oxygen than carbohydrates for complete oxidation. The adenosine triphosphate (ATP)/oxygen ratio is 5.7 for fatty acids and 6.3 for glucose. Thus, when oxygen is limited, as during claudication, a shift toward carbohydrate metabolism would be favorable in terms of ATP production. Several agents are now under investigation that address these concepts.

Summary: Pharmacotherapy for Symptoms of Intermittent Claudication

In summary, patients with IC have cardiovascular risk factors that are critical to identify and modify to decrease the mortality risk of coronary and cerebrovascular disease. The pharmacological treatment of claudication itself is limited to a few drugs of uncertain efficacy. However, several new drugs are under investigation and may show marked benefit in the direct treatment of claudication symptoms.

CRITICAL ISSUE 9: New pharmacological agents for symptoms of intermittent claudication There is a need for extensive clinical trials to identify the place, if any, of emerging pharmacological agents in the treatment of symptoms of intermittent claudication. Such pharmacological agents may fill the need for an additional effective therapy besides exercise training and intervention.

References
1. Porter JM, Cutler BS, Lee BY, Reich T, Reichle FA, Scogin JT. Pentoxifylline efficacy in the treatment of intermittent claudication: Multicenter controlled double-blind trial with objective assessment of chronic occlusive arterial disease patients. Am Heart J 1982;104:66-72. 2. Lindgarde F, Jelnes R, Bjorkman H, Adielsson G, Kjellstrom T, Palmquist I, et al. Conservative drug treatment in patients with moderately severe chronic occlusive peripheral arterial disease. Circulation 1989;80:1549-1556. 3. Waters KJ, Craxford AD, Chamberlain J. The effect of naftidrofuryl (Praxilene) on intermittent claudication. Br J Surg 1980;67:349-351. 4. Adhoute G, Bacourt F, Barral M, Cardon JM, Chevalier JM, Cuny A, et al. Naftidrofuryl in chronic arterial disease: results of a six month controlled multicenter study using Naftidrofuryl tablets 200 mg. Angiology March 1986;37(3):160-169. 5. Adhoute G, Andreassian B, Boccalon H, Cloarec M, di Maria G, Lefebvre O, et al. Treatment of stage II chronic arterial disease of the lower limbs with the serotonergic antagonist naftidrofuryl: results after 6 months of a controlled, multicenter study. J Cardiovasc Pharmacol 1990;16(Suppl 3):S75-S80. 6. Kriessmann A, Neiss A. Demonstration of the clinical effectiveness of naftidrofuryl in intermittent claudication. VASA 1988;24:2732. 7. Moody AP, Al-Khaffaf HS, Lehert P, Harris PL, Charlesworth D. An evaluation of patients with severe intermittent claudication and the effect of treatment with Naftidrofuryl. J Cardiovasc Pharmacol 1984;23(Suppl 3):S44-S47. 8. Trbestein G, Bohme H, Heidrich H, Klken N, Muller-Weifel H, Unkel B, et al. Naftidrofuryl in chronic arterial disease: results of a controlled multicenter study. Angiology 1994;35(11):701-708. 9. Trbestein G, Balzer K, Bisler H. Buflomedil in arterial occlusive disease: results of a controlled multicentre study. Angiology 1984;35:500-505. 10. Diamantopoulos E, Grammoustianos GS, Stavreas NP. Controlled trial of Buflomedil in diabetic peripheral occlusive disease. International Symposium on Ischemic Disease and the Microcirculation. Frankfurt, Zuckschwerdt 1989:80-84. 11. Okuda Y, Kimura Y, Yamashita K: Cilostazol. Cardiovasc Drug Rev 1993;11:451-465. 12. Money SR, Herd JA, Isaacsohn JL, Davidson M, Cutler B, Heckman J, et al. Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease. J Vasc Surg 1998;27:267-275. 13. Dawson DL, Cutler BS, Meissner MH, Strandness DE. Cilostazol has beneficial effects in treatment of intermittent claudication Circulation 1998;98:678-686. 14. Beebe HG, Dawson DL, Cutler BS, Herd JA, Strandness DE Jr., Bortey EB, Forbes WP. A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial. Arch Intern Med 1999;159:2041-2050. 15. Dawson DL, Beebe HG, Davidson MH, et al. Cilostazol or pentoxifylline for claudication? Circulation 1998;98:5012.
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16. Hess H, Mietaschk A, Deichsel G. Drug-induced inhibition of platelet function delays progression of PAD: a prospective double-blind arteriographically controlled trial. Lancet 1985;1:415-419. 17. Balsano F, Coccheri S, Libretti A, Nenci GG, Catalano M, Fortunato G, et al. Ticlopidine in the treatment of intermittent claudication: A 21-month double-blind trial. J Lab Clin Med 1989;114:84-91. 18. Arcan JC, Blanchard J, Boissel JP, Destors JM, Panak E: Multicenter double-blind study of ticlopidine in the treatment of intermittent claudication and the prevention of its complications. Angiology 1988;39:802-811. 19. Solomon SA, Ramsay LE, Yeo WW, Parnell L, Morris-Jones W: b blockade and intermittent claudication: placebo controlled trial of atenolol and nifedipine and their combination. Br.Med.J 1991;303:1100-1104. 20. Coffman JD: Vasodilator drugs in peripheral vascular disease. N Engl J Med 1979;300:713-717. 21. Spence JD, Arnold JMO, Munoz CE, Viswanatha A, Huff M, Derose G, et al. Angiotensin-converting enzyme inhibition with cilazapril does not improve blood flow, walking time, or plasma lipids in patients with intermittent claudication. J Vasc Med Biol 1993;4:23-28. 22. PACK Claudication Substudy Investigators. Randomized placebo-controlled, double-blind trial of ketanserin in claudicants: changes in claudication distance and ankle systolic pressure. Circulation 1989;80:1544-1548. 23. Bagger JP, Helligsoe P, Randsbaek F. Effect of verapamil in intermittent claudication. Circulation 1997;95:411-414. 24. Ernst E, Kollar L, Matrai A. A double-blind trial of Dextran-haemodilution versus placebo in claudicants. J Int Med 1990;227:1924. 25. Picano E, Testa R, Pogliani M, Lattanzi F, Gaudio V, L'Abbate A. Increase of walking capacity after acute aminophylline administration in intermittent claudication. Angiology 1989;40:1035-1039. 26. Kleijnen J, Mackerras D. Vitamin E for the treatment of intermittent claudication. ACP Journal Club. 1998 (Sept):37. 27. Ferrari PA. Defibrotide versus placebo in the treatment of intermittent claudication:.a meta-analysis. Drug Invest 1994;7:157160. 28. Staessen AJ. Treatment of peripheral circulatory disturbances with Cinnarizine: a multi-centre, double-blind, placebo-controlled evaluation. Proc R Soc Med 1977;70(Suppl 8):S17-S20. 29. Barber JH, Reuter CA, Jageneau AHM, Loots W. Intermittent claudication: a controlled study in parallel time of the short-term and long-term effects of cinnarizine. Pharmatherapeutica 1980;2(6):400-407. 30. Donald JF. A multicentre general practice study of Cinnarizine in the treatment of peripheral vascular disease. J Int Med Res 1979;7:502-506. 31. Kiff RS, Quick CRG. Does inositol nicotinate (Hexopal) influence intermittent claudication? a controlled trial. Br J Clin Pract 1988;42(4):141-145. 32. Brevetti G, Perna S, Sabba C, Martone VD, Condorelli M. Propionyl-L-carnitine in intermittent claudication: double-blind, placebo-controlled, dose titration, multicenter study. J Am Coll Cardiol 1995;26:1411-1416. 33. Brevetti G, Diehm C, Lambert D. European multicenter study on Propionyl-l-carnitine in intermittent claudication. J Am Coll Cardiol 1999;34:1618-1624. 34. Lievre M, Azoulay S, Lion L, Mornd S, Girre JP, Boissel JP. A dose-effect study of beraprost sodium in intermittent claudication. J Cardiovasc Pharmacol 1996;27:788-793. 35. Diehm C, Balzer K, Bisler H, Bulling B, Camci M, Creutzig A, et al. Efficacy of a new prostaglandin E1 regimen in outpatients with severe intermittent claudication: results of a multicenter placebo-controlled double-blind trial. J Vasc Surg 1997;25:537544. 36. Belch JJF, Bell PRF, Creissen D, et al. Randomised, placebo-controlled, double-blind study evaluating the efficacy and safety of AS-013, a prostaglandin E1 prodrug, in patients with intermittent claudication. Circulation 1997;95:2298-2302. 37. Hiatt WR, Wolfel EE, Regensteiner JG, Brass EP: Skeletal muscle carnitine metabolism in patients with unilateral peripheral arterial disease. J Appl Physiol 1992;73:346-353. 38. Brevetti G, Chiariello M, Ferulano G, Policiccio A, Nevola E, Rossini A, et al. Increases in walking distance in patients with peripheral vascular disease treated with L-carnitine: a double-blind, cross-over study. Circulation 1988;77:767-773. 39. Brevetti G, Perna S, Sabba C, Martone VD, Condorelli M. Superiority of L-propionyl carnitine vs L-carnitine in improving walking capacity in patients with peripheral vascular disease: an acute, intravenous, double-blind, cross-over study. Eur Heart J 1992;13:251-255. 40. Hiatt WR. Current and future drug therapies for claudication. Vasc Med 1997;2(3):257-262.. 41. Scheffler P, de la Hamette D, Gross J, Mueller H, Schieffer H: Intensive vascular training in stage IIb of peripheral arterial occlusive disease: the additive effects of intravenous prostaglandin E1 or intravenous pentoxifylline during training. Circulation 1994;90:818-822. 42. Tsurumi Y, Takeshita S, Chen D, Kearney M, Rossow ST, Passeri J, et al. Direct intramuscular gene transfer of naked DNA endoding vascular endothelial growth factor augments collateral development and tissue perfusion. Circulation 1996;94:32813290. 43. Maxwell AJ, Anderson B. Improvement in walking distance and quality of life in peripheral arterial disease by a nutritional product designed to enhance nitric oxide activity. JACC 1999;33:277a.
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44. Boger RH, Bode-Boger SM, Thiele W, Creutzig A, Alexander K, Frolich JC. Restoring vascular nitric oxide formation by Larginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. J Am Coll Cardiol 1998;32:1336-1344. 45. Cook NS, Rudin M, Pally C, Blarer S, Quast U. Effects of the potassium channel openers SDZ-PCO 400 and cromakalim in an in vivo rat model of occlusive arterial disease assessed by 31P-NMR spectroscopy. J Vasc Med Biol 1993;4:14-22.

Endovascular Procedures for Intermittent Claudication

General Concepts Regarding Catheter Intervention in PAD
Intervention by endovascular procedure or surgery is only indicated in selected patients with IC in whom exercise treatment has failed. Imaging-guided catheter intervention for PAD was first described by Dotter and Judkins1 in 1964. Since that original report of PTA in femoropopliteal arteries using coaxial catheter techniques, more than 30 years have passed. The materials and methods have now been refined, practitioners have been and continue to be trained, and the application of percutaneous transluminal balloon angioplasty (PTA) and now stenting in PAD has become more widespread. Endovascular interventions other than balloon and stent procedures may have a limited application in selected patients and are therefore not emphasized here. The following section considers the role of PTA and stenting in PAD patients with IC and aortoiliac disease, femoropopliteal disease, or both. Most trials cited were on claudicants only. Thrombolytic therapy has a role in some new claudicants and in previously stable claudicants whose symptoms worsen because of thrombosis superimposed on atherosclerotic stenosis (particularly those with thrombusdominant rather than plaque-dominant occlusions). However, the topic of thrombolytic therapy in PAD has been treated in another consensus document and will be discussed in Acute and Critical Limb Ischemia (sections C and D).2 Although the degree of disability is obviously a prime consideration, anticipated short- and long-term clinical benefit is the major determinant of the role of catheter techniques in the management of claudication. Metallic stents are surely the latest major technical/methodological development to impact endovascular treatment of PAD, and stented endografts may soon follow. However, to appreciate their currently understood role in the treatment of patients with IC, it is first necessary to know the indications and results of PTA above and below the inguinal ligament and their relationship to lesion characterization. It is also necessary to appreciate the problems and limitations of both the disease/treatment and the evidence in the literature. The issue of the preferred interventional technique for particular types of lesions needs to be addressed. However, it is difficult to be categorical about such recommendations, because the management of an individual lesion in a particular patient depends on a large number of factors. Management will vary according to local circumstances. Furthermore, with the rapid development of new interventional techniques, the optimal treatment for a particular patient will vary not only from place to place but also within the same institution as new expertise is developed. It has therefore been decided to define types of lesions for interventions and then place them in four groups, each group usually being treated in a similar way. The two extremes are type A lesions, in which endovascular approach is the treatment of choice, and type D lesions, in which surgery is the treatment of choice. Between these two groups are types B and C lesions, in which no firm recommendations can be made about the preferred interventional option. At present, endovascular treatment is more commonly used in type B lesions, and surgical treatment is more commonly used in type C lesions. It should be emphasized that there is insufficient solid evidence to make any firm recommendations, particularly in the case of types B and C. This proposed classification of types of lesions may have the advantage of encouraging the standardization of description of lesions and promoting the reporting of results in such a way that in the future it will be possible to make firmer recommendations about the optimal treatment for particular types of lesion. This system of presentation is used throughout the document to categorize types of lesions and their preferred treatment. This system was devised in a similar structure to the AHA classification, but differs significantly in content.
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Aortoiliac PTA
PTA is generally applied to more focal disease, for instance, of the distal abdominal aorta, common iliac arteries, and external iliac arteries. For diffuse, extensive, complex, multilevel, multifocal, or totally occluded atherosclerotic segments of the infrarenal abdominal aorta and iliac arteries, the procedure of choice is surgery.

RECOMMENDATION 31: Morphological stratification of iliac lesions TASC type A iliac lesions: 1. Single stenosis <3 cm of the CIA or EIA (unilateral/bilateral). TASC type B iliac lesions: 2. Single stenosis 310 cm in length, not extending into the common femoral artery (CFA). 3. Total of two stenosis <5 cm long in the CIA and/or EIA and not extending into the CFA. 4. Unilateral CIA occlusion. TASC type C iliac lesions: 5. Bilateral 510-cm-long stenosis of the CIA and/or EIA, not extending into the CFA. 6. Unilateral EIA occlusion not extending into the CFA. 7. Unilateral EIA stenosis extending into the CFA. 8. Bilateral CIA occlusion. TASC type D iliac lesions: 9. Diffuse, multiple unilateral stenoses involving the CIA, EIA, and CFA (usually >10 cm). 10. Unilateral occlusion involving both the CIA and EIA. 11. Bilateral EIA occlusions. 12. Diffuse disease involving the aorta and both iliac arteries. 13. Iliac stenoses in a patient with an abdominal aortic aneurysm or other lesion requiring aortic or iliac surgery. Abbreviations: CIA, common iliac artery; EIA, external iliac artery; CFA, common femoral artery.

RECOMMENDATION 32: Treatment of choice for TASC type A and D aortoiliac lesions Endovascular procedure is the treatment of choice for type A lesions, and surgery is the procedure of choice for type D lesions.

CRITICAL ISSUE 10: Treatment of TASC type B and C lesions More evidence is needed to make any firm recommendations about the best treatment for type B and C lesions.* *CIRSE dissenting opinion: Currently endovascular treatment is more commonly used for type B and C lesions, but more evidence is needed to make any firm recommendatioins about best treatment. Reason for dissenting opinion: Due to technical developments, type C lesions of iliac and femoral arteries can be treated by endovascular means with a resonable technical success rate (for references, see p. 101). Therefore, CIRSE believes that in clinical practice these lesions are more commonly treated by endovascular techniques, although scientific evidence of any superiority over vascular surgery is lacking. The technical and initial clinical success of PTA of iliac stenoses (Fig. 21) in all series exceeds 90% and for focal iliac stenosis approaches 100%. The technical success rate of recanalization of segmental (external or common) iliac occlusions is 80% to 85% with or without additional fibrinolysis. Only a few studies have carefully documented clinical results over a long period of follow-up using standard life-table methods and more exclusively in

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Fig. 21.Summary of preferred options in interventional management of iliac lesions.

claudicants. These are listed in Tables XVII and XVIII. Long-term patency rates in patients with IC are close to 80% at 1 year and 60% at 5 years (Tab. XVII, XVIII).3-10 Once an iliac artery occlusion has been recanalized successfully, the patency rate does not differ from that for patencies after PTA of stenoses. However, complications are higher after recanalization of occlusions (6.0%) than after standard PTA of stenoses (3.6%). Factors affecting patency have been identified (see Patency, p. 42). Better results can be expected in common versus. external iliac stenoses, short segmental versus long diffuse stenoses, patients with good versus poor runoff, and patients
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TABLE XVII. Patency rates for PTA of iliac artery stenoses (patency based on ABPI).
Patients (limbs)
Tegtmeyer et al.,3 1991 Jeans et al.,4 1990 Jorgensen et al.,5 1992 Johnston,6 1993 Weighted average 200 (263) 180 (243) 150 (174) (584) (1,264)

Study design
R P R R

Claudicants (%)
59 73 71 91 77

Technical success (%)

93 88 93 99 95

Primary patency rate (%)* 1y

92 67 79 77 78

3y
82 60 68 61 66

5y
78 57 63 54 61

Complication (%)
4.4

Comments
85% 5yr secondary patency 62% 5yr primary

patency in claudicants 2.3 81% 5yr secondary patency 3.6 68% 3yr CIA patency 51% 3yr EIA patency 3.6

Abbreviations: R, retrospective; P, prospective. *Including technical failures. Including major or significant complications, as far as distinguished in the text. Adjusted for inclusion of technical failures. Modified from Bosch JL, Hunink MGM.18

TABLE XVIII.Patency rates for PTA of iliac artery occlusions (patency based on ABPI).
Patients (limbs)
Colapinto et al.,7 1985 Hausegger et al.,8 1991 (64) 42 (42)

Study design
R R

Claudicants (%)
88 81

Technical success (%)

78 83

Primary patency rate (%)* 1y

68 67

3y
61

5y

Complication (%)
3.1 5

Comments
f/up by ABPI f/up by ABPI; additional fibrinolysis in 36 patients; sesecondary stent placement in 16 patients 59% 3-year patency excluding recanalization failures; 66% 3year success rate after Cox regression estimate f/up by Duplex; fibrinolysis in all cases; secondary stents in 18 patients f/up by ABPI; 61% 3-year secondary patency

Johnston,6 1993

(82)

91

82

60

48

4.8

Blum et al.,9 1993

47 (47)

64

98

94

85

10.6

Gupta et al.,10 1993

50 (56)

77

79

59

56

56

8.0

Weighted average

(291)

82

83

68

60

6.0

Study design: R= retrospective. P=prospective. f/up=follow-up. *Including technical failures. Including major or significant complications, as far as distinguished from the text. Adjusted for inclusion of technical failures.

with IC versus limb salvage patients. The use of PTA in the aortoiliac segment produces better results than when used in the femoropopliteal region. In an analysis of long-term results in the literature, Rutherford and Durham11 produced composite patency curves for iliac and femoropopliteal PTA. Femoropopliteal PTA had twice the initial and early (1-year) failure rate (16% vs 8% and 20% per year vs 10% per year, respectively) but shared the same late failure rate (3%/y) as iliac PTA. The 5-year patencies were 52% and 70%, respectively. Becker et al.12 found a similar 5-year patency rate (72%) in an analysis of 2,697 cases from the literature, noting that this was 79% in claudicants. Patency rates at 3 years are approximately 80% when performed for stenosis of the iliac artery and 60% when performed for occlusion. An approximately 20% difference also is found between common iliac and external iliac stenoses. Thus, it is clear
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TABLE XIX.Stents in iliac arteries-stenoses.

Patients (limbs)
Palmaz et al.,18 1992 Strecker et al.,19 1993 Wolf et al.,20 1993 Long et al.,21 1995 Henry et al.,22 1995 486 (567) 116 (116) 37 (56) 61 (64) 184 (184)

Study design
P R R P P

Claudicants (%)
68 66 86 91 93

Technical success (%)

99 100 100 97 99

Primary patency rate (%)* 1y

91 95 94 84 94

3y
69 95 41 86

5y

Complication (%)
6.4 10.8 3.3 1.0

Comments
patency rate based on clinical stage f/up based on ABPI f/up based on ABPI f/up based on Duplex f/up by Duplex; major complications from both iliac and

fempop stents; 94% 3yr secondary patency Martin et al.,23 1995 Vorwerk et al.,24 199628 (163) 109 (118) P R SE3% 77 97 97 100 81 97 86 72 4.3 3.4

f/up by Duplex and/or DSA; 91% 3yr secondary patency SE3% f/up by Duplex; part of randomized study

Murphy et al.,29 Tetteroo et al., 21 1998 Weighted average

66 (99) 143(149) 1,365 (1,430)

52 100 78

91 99 99

78 89 90

53 74

72

7.6 0 6.3

Abbreviations: R, retrospective; P, prospective; f/up,follow-up. *Including technical failures. Including major or significant complications, as far as can be distinguished from the text. Modified from Bosch JL, Hunink MGM.18

Table XX.Stents in iliac arteries-occlusions.

n (limbs)
Hausegger et al.,8 1991 Blum et al.,9 1993 16 (16) 18 (18)

Study design
P P

Claudicants (%)
81 64

Technical Primary patency rate (%)* success (%) 1y 3y 5y

94 98 94 89 78

Complication (%)
5 10.6

Comments
F/up based on ABPI F/up based on Duplex; primary fibrinolysis F/up based on duplex or DSA; 69% 3-year secondary patency; 3%SE

Vorwerk et al.,11 1995

127 (127)

91

80

68

62

35

5.8

Weighted average

187

86

82

72

64

5.6

NOTE. Study design: R, retrospective; P, prospective. *Including technical failures. Including major or significant complications as far as can be distinguished from the text. Adjusted for inclusion of technical failures.

that lesion location and morphology greatly affect PTA results and that the selective application of PTA for claudicants should be aimed at favorable lesions. Selective stenting may improve these results, but the use of stenting to extend PTA to more extensive (less favorable) lesions has not been proved to be more efficacious and is more costly (see also Endovascular Procedures, p. 101).13 14

Aortoiliac Stents
The availability of stents for use in aortoiliac PTA has improved the immediate hemodynamic results of iliac PTA and effectively managed recoil and PTA-related flow-limiting dissections (Tab. XIX). Another application of
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iliac stenting is for treatment of chronic iliac artery occlusions. PTA alone often fails in cases of iliac occlusion because of dissection and marked elastic recoil with re-obstruction of the lumen and a residual pressure gradient. Thus, before 1989, the available literature was more critical to the use of PTA for iliac artery occlusions. This has changed since large series have demonstrated a 1-year and 3-years patency rate after successful recanalization of 90% and 80%, respectively (Tab. XX).8 9 15 Thus, the indications for iliac artery stenting, which are generally accepted in clinical practice, are as follows: insufficient hemodynamic result of PTA due to elastic recoil based on residual pressure gradient; massive, lumen-obstructing dissection; treatment of chronic occlusions; iliac artery ulceration associated with symptoms; restenoses after previously performed PTA; complex lesions for which primary stenting may give more satisfactory results. The value of hemodynamic measurements in addition to angiography to assess the result of PTA and stent placement has been accepted. However, resting mean and systolic pressure gradients were used as well as pressure gradients after vasodilatation. Objective thresholds of pressure gradients for a hemodynamic significant stenosis do not exist. However, a resting mean pressure gradient of more than 5 to 7 mm Hg and a postvasodilatation mean pressure gradient of more than 10 to 15 mm Hg are thresholds commonly used to define a hemodynamically significant lesion16 (see Critical Issue 32, p. 224). However, more recent data have shown that iliac artery stenting probably provides a more durable result than PTA alone for both stenoses and occlusions on an intention-to-treat basis. One obvious reason is that stenting provides a better early result, which raises the starting point of the life-table curve.17

CRITICAL ISSUE 11: Use of pressure gradients to assess hemodynamic significance of stenoses Pressure gradient criteria with or without vasodilators for assessing hemodynamic significance in iliac lesions remain to be established.

CRITICAL ISSUE 12: Multiple stents The usefulness and cost-effectiveness of multiple stents have yet to be established.

A recent meta-analysis by Bosch and Hunink18 comparing the results of aortoiliac PTA versus. aortoiliac stenting used a Medlars search of the post-1989 literature and yielded only six articles (including 2,116 patients) with sufficient detail to allow stratification over subgroups with various risk levels for long-term patency. Technical success was higher for stenting, whereas complication rates and 30-day mortality rates did not differ significantly. In patients with intermittent claudication, the severity-adjusted 4-year primary patency rates (95% confidence intervals) after excluding technical failures, for PTA and stenting, were: 68% (65-71%) and 77% (7281%), respectively. Including technical failures, the 4-year primary patency rates are 65% (PTA) versus 77% (stent) for stenosis and 54% (PTA) versus 61% (stent) for occlusion. The relative risk of long-term failure was reduced by 39% after stent placement compared with PTA. In a re-analysis of the Palmaz multicenter iliac data, Laborde et al.19 determined the influence of anatomic distribution of atherosclerosis (ie, disease severity) on the outcome of revascularization by stenting. They divided the 455 patients of the study population into three groups according to the Brewster classification of disease patterns20 and then used a statistical analysis to determine differences in outcome between groups. Brewster pattern type I includes only those patients with focal aortoiliac disease or common iliac disease (39.6% of the study group); Brewster pattern type II includes external iliac artery lesions (12.8% of the study group); Brewster pattern type III or multilevel disease involving the infrainguinal vessels was seen in 47.7% of study patients. Complete relief of symptoms occurred in 88.3% and 85.4% of Brewster pattern type I and II patients, respectively, whereas only
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60.1% of those with Brewster pattern type III experienced complete relief (p < 0.05). Persistent clinical benefit at 36 months was seen in 91.6% and 97.9% of patients with Brewster pattern type I and type II disease, respectively, as compared with 60.8% in type III (p = 0.006 for type II vs type III and p = 0.001 for type I vs type III, Wilcoxon test). Multivariate logistic regression showed that pattern type III was the most powerful indicator of unsatisfactory early outcome in iliac stenting (p < 0.001). Female gender also predicted unsatisfactory clinical outcome (p < 0.01) and higher periprocedural complications (p < 0.001). The Dutch Iliac Stent Trial compared primary stent placement versus primary angioplasty followed by selective stent placement in patients with claudication caused by iliac-artery obstructive disease.17 In the PTA group, selective stent placement was performed in 59 of 136 (43%) with a residual mean pressure gradient greater than 10 mm Hg after balloon angioplasty. A primary technical success was achieved in 279 of 286 patients (97.5%). A hemodynamic success was achieved in 97% of the successfully recanalized iliac arteries. At 2 years, the clinical success rates were 78% versus 76%, the hemodynamic success rates as assessed by ABPI measurements were 85% versus 85%, and the patency rates as measured by color Duplex were 71% versus 70% in the stent versus PTA plus stent groups, respectively. It should, however, be remembered that most patients in this study had IC with mild lesions, and the results cannot be extrapolated to patients with more severe lesions. Thus, selective stenting yields equivalent effectiveness and is less costly than primary stenting in the treatment of claudication due to iliac artery stenoses.18 21 Furthermore, selective stenting compared with PTA alone yields an increase in effectiveness that justifies the additional costs in these cases. (see Tab. XIX).22-29 To summarize, stents have influenced modern aortoiliac PTA by providing a means to oppose elastic recoil, treat PTA-related dissections, and improve the long-term clinical results. In addition to these benefits, stents have provided a method to effectively treat TASC types C and D aortoiliac bifurcation disease in selected patients. The short- and long-term clinical benefits of iliac stenting are influenced by anatomic distribution of disease. Benefit is less variable and complications and mortality are higher in patients with Brewster type III diseases than in those with Brewster types I and II.

RECOMMENDATION 33: Role of stenting for residual pressure gradient, dissection, or elastic recoil Stenting improves the technical and initial clinical success in cases of residual pressure gradient or dissection after angioplasty, or in cases of elastic recoil.

CRITICAL ISSUE 13: Role of primary stenting of iliac occlusions Primary stenting is widely used to optimize procedural results in iliac artery occlusions. This practice needs to be subjected to rigorous clinical evaluation.

Femoropopliteal PTA
Selected PAD patients with claudication may be considered for femoropopliteal PTA. There are, however, additional considerations. Patients with isolated aortoiliac disease tend to be younger and have a low likelihood of coronary heart disease comorbidity, whereas those with femoropopliteal disease, infragenicular disease, or multilevel disease tend to have the lowest ABPI and the highest likelihood of coronary heart disease comorbidity.30 31 32 33 34 35 36 Preservation of the saphenous veins for coronary bypass grafting is a potential advantage in such patients, in whom the benefit/risk ratios of surgery, PTA, and conservative therapy must be weighed. Some highrisk patients may be offered PTA for their claudication; however, for such patients, for example, those with diabetes mellitus, surgical bypass is usually reserved for severe leg ischemia. As with aortoiliac disease, femoropopliteal lesions have been categorized in morphological terms, with preferred therapeutic options as follows:
107

RECOMMENDATION 34: Morphological stratification of femoropopliteal lesions TASC type A iliac lesions: 1. Single stenosis <3 cm of the CIA or EIA (unilateral/bilateral) TASC type B iliac lesions: 2. Single stenosis 3-10 cm in length, not involving the distal popliteal artery* 3. Heavily calcified stenoses up to 3 cm in length 4. Multiple lesions, each less than 3 cm (stenoses or occlusions) 5. Single or multiple lesions in the absence of continuous tibial runoff to improve inflow for distal surgical bypass TASC type C femoropopliteal lesions: 6. Single stenosis or occlusion longer than 5 cm* 7. Multiple stenoses or occlusions, each 3-5 cm, with or without heavy calcification TASC type D femoropopliteal lesions: 8. Complete common femoral artery or superficial femoral artery occlusions or complete popliteal and proximal trifurcation occlusions. *CIRSE agrees except for the following changes: Type B femoropopliteal lesions: 2. Single stenosis or occlusions 3-10 cm long, not involoving the distal popliteal artery Type C femoropopliteal lesions: 6. Single stenosis or oclusion >10 cm long Reason for dissenting opinion: The lower long-term clinical success rate of long stenoses and occlusions in earlier studies was due to a low technical rate. However, developments of catheters and wires have improved the technical success rate, to be followed by higher patency rates.35 36 Studies comparing PTA with bypass surgery in femoropopliteal lesions 4-10 cm long do not exist.

RECOMMENDATION 35: Treatment of choice for TASC type A and D femoropopliteal lesions Endovascular procedure is the treatment of choice for type A lesions, and surgery is the procedure of choice for type D lesions.

CRITICAL ISSUE 14: Treatment of TASC type B and C femoropopliteal lesions More evidence is needed to make and firm recommendations about the best treatment for types B and C lesions.

Several important studies of femoropopliteal PTA have appeared in the literature in recent years (Figure 22).4 37-40 The primary success rates and the long-term patency rates of the successfully dilated arteries are listed in Table XXI. In only one study were all patients claudicants. Table XXII shows estimated patency by length of lesion. These results are also discussed in Critical Limb Ischemia (see Infrainguinal Disease - Endovascular Treatment, p. 242). Factors predicting outcome of PTA were evaluated in three studies37-39 using a Cox stepwise multiple regression model. Factors predictive for a favorable outcome are claudication as an indication, nondiabetic patients, proximally located short lesions, stenoses, good distal run-off, and lack of a residual stenosis on the post-PTA angiogram. However, it also has been claimed that once an occlusion has been recanalized, the long-term patency does not differ in comparison with stenoses.19 The technical success rate in stenoses is greater than 90%; in occlu108

TABLE XXI.PTA of femoropopliteal arteriesstenoses and occlusions.

Patients (limbs)
Gallino et al.,41 1984 280 (329)

Study design
R

Claudicants (%)
61

Technical success (%)

87

Primary patency rate (%)* 1y

62

3y
60

5y
58

Complication (%)
2.5

Comments
F/up based on ABPI; 74% 2-y primary patency in stenoses, <3 cm occlusions in claudicants 38 by coaxial Dotter

Krepel et al.,42 1985

129 (164)

90

84

68

Jeans et al.,4 1990

190 (190)

51

82

50

Capek et al., 37 1991 Johnston,38 1992

152 (217) 236 (254)

R R

74 80

90 96

71 63

Hunink et al.,43 1993

106(131)

58

95

57

Matsi et al.,39 1994

106 (140)

100

89

47

Murray et al.,40 1995

42 (44)

89

93

86

Weighted average

1,241 (1,469)

72

90

61

6.0 set; 88% technical success in 126 balloon cases 45 41 F/up based on ABPI; 5-y patencies 61% (stenoses) 31% (occlusions) 51 48 5.5 F/up based on ABPI 51 38 6.3 F/up based on ABPI; stenoses/occlusions 10 cm 45 45 2.4 F/up based on ABPI; 55% 5-y patency for stenoses+occlusions 42 4.0 F/up based on ABPI; 59% 3-y secondary patency 53 5.0 F/up based on duplex; >10-cm lesions only; 24-mo patency, SE 26% 51 48 4.3

57

57

Abbreviations: R, retrospective; P, prospective. *Including technical failures. Including major or "significant" complications, as far as can be distinguished from the text. Adjusted for inclusion of technical failures.

sions, 80% to 85%. The studies listed in Table XXI illustrate several interesting findings on the issue of transluminal treatment of stenoses versus occlusions. Studies approximately 15 years old, such as those of Gallino et al.41 and Krepel et al.,42 tended to show a greater impact of occlusion length on initial technical success rates (33% and 26%, respectively, for occlusions larger than 3 cm) compared with more recent studies. For example, in Matsis 1994 study, the technical success for occlusions 2 to 15 cm in length was 83%. This compared to 91% for 125 stenoses.39 In Murray et als.40 study, the authors remarked that earlier results of angioplasty bore little relevance to the results that could now be achieved. Once a lesion is crossed and dilated, it has the same anticipated long-term success as a stenosis treated by PTA.37 Therefore, the principal reason that clinical success rates reported in the past were lower for PTA of femoropopliteal occlusions than for stenoses is that with lower initial technical successes the curves for occlusion started off lower. The life-table patency and cumulative clinical success curves are, in fact, essentially parallel. Johnstons38 report seems to show dramatically better results for PTA of femoropopliteal stenoses than occlusions. However, this was a re-analysis of an old PTA series and was therefore subject to the same problems and limitations mentioned previously for older PTA series. The most important factor that emerged from Johnstons study, as well as others, is that patients with poor (0- to 1-vessel) runoff consistently show poorer long-term outcomes than those with 2-3-vessel runoff. 38-42 A summary of these observations is that (1) older femoropopliteal PTA studies describe lower technical success with femoropopliteal occlusion than do newer studies; (2) because of arbitrary limits placed on the transluminal technique and imposed on a generation of interventionists, long-segment occlusions have not commonly been attempted; (3) in the older literature, the apparently lower long-term clinical success of PTA for femoropopliteal occlusions compared with stenoses was attributable in large part to
109

Fig. 22.Summary of preferred options for interventional treatment of femoropopliteal lesions.

lower technical success (lesion crossing) and a resultant lower starting point on an otherwise identical life-table curve (lower, but parallel); (4) by far the most consistent, important determinant of long-term clinical success versus failure among the studies listed in Table XXI is not occlusion versus stenosis at all, but rather the status of the runoff circulation below the knee. An important study in this area is a decision and cost-effectiveness analysis of revascularization procedures for femoropopliteal disease by Hunink et al (Tab. XXIII; Fig. 23).45 The authors used a literature review of mortality, morbidity, patency, and cost data as a source. They included only procedures performed after 1985. There were 4,800 PTA and 4,511 bypass operations. They developed a decision analytic model to examine the choice between bypass surgery and PTA for lesions amenable to either procedure. These patencies were offered to guide initial strategy in patients with disabling claudication and femoropopliteal lesions.

Femoropopliteal Stents
110

TABLE XXII.Estimated patency by length of lesion.

Reference Jeans et al.,4 1990 Length of lesion <1 cm Patency (%) Stenoses @5 y; <1 cm = 76 >1 cm = 50; p < 0.05 longest lesion length implied > 5 cm primary patency stenoses @5 y; <2 cm = 77 >2 cm = 54 longest lesion length not stated primary vs secondary patency not stated occlusions @1 y; <3 cm = 93 >3 cm = 50 longest lesion length not stated primary vs secondary patency not stated @2 y; stenoses/occlusions < 3 cm with 23 vessel runoff = 71 occlusions with 01 vessel run-off = 37 @6 mo; <5 cm = 59 >5 cm = 4 stenoses @ 6 mo; <7 cm = 81 >7 cm = 23 longest lesion length not stated, implied > 10 cm. Secondary patency but <5% redilated Inclusion of technical failures technical failures included in life table Indication CLI with ABPI <0.5

Krepel et al.,38 1985

<2 cm

technical failures excluded from results

90% claudication

Krepel et al.38 1985

<3 cm

technical failures excluded from results

90% claudication

Gallino et al.,37 1984

<3 cm

primary patency

claudication + CLI

Currie et al.,44 1994 Murray et al.,36 1995

<5 cm <7 cm

technical failures excluded from results immediate failures excluded

CLI predominant claudication 66% rest pain 34%

TABLE XXIII.Outcome of PTA and bypass of femoropopliteal obstructionsclaudication (modified from Hunink et al.45).
Indication PTAstenosis68 PTAocclusion Femoropopliteal bypassvein Femoropopliteal bypassPTFE AK Femoropopliteal bypassPTFE BK Patency modeled on 5 years (%)

35 80 75 65

The most troublesome lesions for femoropopliteal PTA include eccentric stenoses, long-segment stenoses and occlusions, and stenoses due to intimal hyperplasia at graft anastomoses. Balloon dilatation of these lesions can fail because of elastic recoil. It also may fail because of obstructing intimal flaps caused by extensive dissection. Stents have been applied as a potential solution. In general, the immediate and early results have been excellent, and many cases of angioplasty failure have been converted to early successes because of the impact of stents. However, restenosis caused by intimal hyperplasia in the stented segment is quite common in the first 3 to 9 months after treatment. Preliminary studies using a variety of stents show less than promising results because of intimal hyperplasia and occlusion (Tab. XXIV).26 27 46 48-51 There is some reference to an increased risk of compression of balloon-expandable stents in femoropopliteal arteries. This may be caused by external trauma or muscle compression within the adductors canal. Therefore, the use of self expandable stents seems advisable.52

111

Fig. 23.Average results for endovascular treatment.

RECOMMENDATION 36: Femoropopliteal stenting in PAD Femoropopliteal stenting as a primary approach to the interventional treatment of intermittent claudication or CLI is not indicated. However, stents may have a limited role in salvage of acute PTA failures or complications. In general, it may be stated that the experience with infrainguinal stenting for femoropopliteal disease has been limited. Stents appear indicated only for salvage of failed PTA attributable to dissection or marked recoil. Finally, covered stents may have a role in limiting or preventing restenosis caused by intimal hyperplasia. This concept is in trials now, but has not yet been proved. Cejna et al.56 performed a multicenter, randomized trial. PTA was compared with Palmaz stent implantation in femoropopliteal artery obstructions in 142 patients (154 lesions). In 10 of 77 patients randomized to balloon angioplasty, primary PTA failed (12.9%) as compared with one primary stent failure (1.3%). Cumulative primary angiographic patency rates for PTA were 79%, 64%, and 53% at 6, 12, and 24 months, respectively. Primary patency rates for stent placement were 86%, 63%, and 58% at 6, 12, and 24 months, respectively. Thus, despite better short-term and midterm results, primary stenting does not improve long-term success rates as compared with PTA alone. Table XXV summarizes the weighted-average primary patency rates for iliac and femoropopliteal procedures.

CRITICAL ISSUE 15: Infrapopliteal percutaneous transluminal angioplasty in intermittent claudication The role of infrapopliteal percutaneous transluminal angioplasty to improve run-off in intermittent claudication remains to be established.
112

TABLE XXIV.Stents in femoropopliteal arteriesstenoses and occlusions.

Patients (limbs) Rousseau et al.,46 1989 36 (40) Study design P Claudicants (%) 78 Technical success (%) 100 Primary patency rate (%)* 1y 76 3y 5y Complication (%) 0

Comments f/up based on DSA; 25% lesions >7 cm length; 30% total occlusions f/up based on ABPI and angiography; 80% occlusions with average length 13.5 cm f/up based on ABPI and duplex; 100% occlusions; 69% secondary patency at 1 y f/up based on duplex and angiography; 82% occlusions; 67% secondary patency at 1 y f/up based on ABPI F/up based on duplex; major complications from both iliac and femoropopliteal arteries; 31% occlusions; 96% secondary patency at 1 y, 1.8% SE f/up based on ABPI; 84% secondary patency at 1 y F/up based on Doppler; 47% occlusions; 93% secondary patency at 1 y f/up based on Duplex; 61% occlusions; 82% secondary patency at 1 y f/up based on ABPI; 59% occlusions f/up based on Duplex; 89% occlusions with av. length 16.5 cm; 46% secondary patency at 1 y

Zollikofer et al.,47 1991

13 (15)

76

93

55

18

6.6

Do et al.,48 1992

26 (26)

85

100

59

Sapoval et al.,49 1992

21 (22)

86

95

49

49

4.5

Liermann et al.,50 1992 Henry et al.,26 1995

48 (48) 126 (126)

R P

65 93

94 99

71 81

72

65

4 1

Martin et al.,27 1995 White et al.,53 1995

96 (96) 32(32)

P P

77 94

100

61 75

17

Bray et al.,54 1995

(57)

NA

100

79

Strecker et al.,51 1997 Gray & Olin,55 1997

80 (80) 50(58)

P P

82 50

98 100

76 22

48

8.8 12.0

Weighted average

585 (600)

80

98

67

58

7.3

Abbreviations: R, retrospective; P, prospective; f/up, follow-up. *Including technical failures. Including major or "significant" complications, as far as can be distinguished from the text.

Infrapopliteal PTA
Unlike the aortoiliac and femoropopliteal segments, the infrapopliteal vessels are usually not treated unless there is critical acute or chronic limb ischemia. Therefore, most of the experience in infrapopliteal endovascula recanalization has come from patients with limb-threatening ischemia. However, more recent reports of PTA of tib ial arteries have also included patients with severe claudication.57-60 The primary goal of infrapopliteal PTA in patients with IC is improvement of the outflow after femoropopliteal PTA, stent placement, or bypass. The ratio nale for this is the fact that the distal runoff has a significant influence on the long-term patency rates afte femoropopliteal PTA and bypass surgery.37 38 61 Dotter and Judkins1 and others first described infrapopliteal PTA

113

TABLE XXV.Weighted-average primary patency rate in patients with intermittent claudication, including technical failures. Patency rates excluding technical failures are shown in parentheses.
Technical success (%) PTA iliac stenoses PTA iliac occlusions Stents iliac stenoses Stents iliac occlusions PTA femoropopliteal Stents femoropopliteal 95 83 99 82 90 98 1y 78 (83) 68 (85) 90 (91) 75 (90) 61 (71) 67 (69) Primary patency rate (%) 3y 66 (71) 60 (77) 74 (75) 64 (82) 51 (61) 5y 61 (66) 72 (73) 48 (58)

TABLE XXVI.Summary of aggregate complication rates for endovascular procedures.

Source Aortoiliac interventions; PTA of a stenosis PTA of an occlusion PTA all lesions Stents all lesions Femoropopliteal interventions; PTA Stents Weighted average complication rate (range)

Table XVII Table XVIII Bosch & Hunink,18 1997 Bosch & Hunink,18 1997 Table XXI Table XXIV

3.6% (2.34.4%) 6% (3.110.6%) 4.3% 5.2% 4.3% (2.46.3%) 7.3% (017%)

however, results were mixed.1 62 63 The efficacy of infrapopliteal PTA has been substantially improved by technical developments, such as DSA with road mapping, steerable guidewires, and low-profile balloons. Indications for treatment are categorized by symptomatology, anatomic localization, and clinical outcome (see also Endovascular Procedures for Acute Limb Ischemia, p. 161; Aortoiliac DiseaseEndovascular Treatment, p. 230; Infrapopliteal Angioplasty, p. 245). In summary, experience is accumulating that demonstrates the effectiveness and safety of infrapopliteal artery PTA. However, it is still debatable whether infrapopliteal PTA should be performed in patients with IC for improvement of outflow and for an increased patency of proximal dilatation sites.

Complications of Endovascular Procedures

Complications of percutaneous treatments of PAD include the risks of the diagnostic study with the increased risks of all the therapeutic modalities employed: lysis, PTA, stents. Interventional morbidity increases because of larger vascular access that often is needed for treatment and the use of anticoagulation, and also because of the additional catheterguidewire manipulations needed for therapy. Published complication rates vary considerably. As with efficacy, reporting of complications is not standardized. Some series have included complications with no clinical sequelae or have classified technical failure as a complication.64 Many older reports included as complications events that currently could be managed by either percutaneous techniques applied during the ongoing procedure (eg, lysis for distal embolic events) or noninvasive maneuvers (eg, ultrasound-guided compression for femoral pseudoaneurysms). Furthermore, it is difficult to derive a single value for complication rates in claudicants or CLI patients alone, because most reported series comprise both claudicators and limb salvage patients. Complications can be classified as major (resulting in unplanned increase in the level of care, prolonged hospitalization, permanent adverse sequelae or death) or as minor. Becker et al.65 reviewed complications of 4,662 published PTA procedures. Major complications were observed in 5.6%. In 2.5%, surgery was required; limb loss was observed in 0.2%, and another 0.2% died. Minor complications were observed in 4.6%. In a prospective series accumulated after the period covered by Beckers review, Matsi and Manninen66 noted a similar complication rate of 10.5%, with 2% requiring operative repair. As with Becker et al., these authors noted that major complications constitute approximately half of the total (major plus minor) complications. When percutaneous or interventional therapy is applied to treat complications associated with PTA, it can be expected to be successful in 75% of
114

patients.66 The most common complications are thromboembolic vessel occlusions and puncture site injury such as a hematoma or false aneurysm. Less commonly, complications occur at the PTA site itself, including thrombosis, dissection, perforation, and occlusion. Endovascular Procedures (see p. 101) and Incidence and Management of Complications (see p. 262), give aggregate complication rates for specific procedures, which are also summarized in Table XXVI. Gardiner et al.67 reviewed the complications of PTA and reported a rate of major complications of 3% for iliac PTA and 3% for femoropopliteal PTA. Hence, there may be no difference in complication rate between iliac and femoropopliteal PTA. In studies of stent placement, higher complication rates were reported, which might be explained by the learning curve of the investigators. Martin et al.27 noted that femoropopliteal stent placement engendered higher complication rates than iliac stent placement because of bleeding related to the antegrade approach; the more frequent use of anticoagulation during and after stent placement in the infrainguinal vessels (when compared with the iliac arteries) is probably another factor. Recanalization of iliac artery occlusions has an increased level of complications (mostly thromboembolic events) of 6% to 16%,6-9 15 26 especially when the occlusions are longer than 2 cm.66 Complex lesions associated with long procedure times and multiple catheter manipulations and exchanges probably predispose to higher complication rates. Patient factors such as obesity can increase puncture site complications. Cardiac and renal comorbidities frequently found in this group also contribute to increased risk. The 30day mortality rate of patients undergoing PTA was 4% in one recent study; the claudicators in this group had a 0.5% 30-day mortality rate, whereas the limb salvage patients endured a 10% 30-day mortality rate.66 Thus, the complexity of limb salvage patients apparently places them at higher risk than the aggregate population of treated patients as a whole, but this must be weighed against higher potential surgical morbidity. Management strategies specific for PTA and stent placement that may reduce the incidence of potential complications include the use of low-profile devices as well as use of the contralateral approach in obese patients or in easily accessible lesions.68 Familiarity with ultrasound compression for puncture-site pseudoaneurysms, lysis for distal embolization, and stent placement for occluding dissections will all increase effectiveness and decrease morbidity from these procedures.

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Femoropopliteal angioplasty in patients with claudication: primary and secondary patency in 140 limbs with 1-3 year follow-up. Radiology 1994;191:727-733. 40. Murray JG, Apthorp LA, Wilkins RA. Long-segment (>10 cm) femoropopliteal angioplasty: improved technical success and long-term patency. Radiology 1995;195:158-162. 41. Gallino A, Mahler F, Probst P, Nachbur B. Percutaneous transluminal angioplasty of the arteries of the lower limbs: a 5 year follow-up. Circulation 1984;70(4):619-623. 42. Krepel VM, van Andel GJ, van Erp WF, Breslau PJ. Percutaneous transluminal angioplasty of the femoropopliteal artery: initial and long term results. Radiology 1985;156(2):325-328. 43. Hunink MG, Donaldson MC, Meyerovitz MF, Polak JF, Whittemore AD, Kandarpa K, et al. Risks and benefits of femoropopliteal percutaneous balloon angioplasty. J Vasc Surg 1993;17(1):183-192. 44. Currie IC, Wakeley CJ, Cole SE, Wyatt MG, Scott DJ, Baird RN, et al. Femoropopliteal angioplasty for severe limb ischemia. Br J Surg 1994;81:191-193. 45. Hunink MGM, Wong JB, Donaldson MC, Meyerovitz MF, de Vries J, Harrington DP. Revascularization for femoropopliteal disease: a decision and cost-effectiveness analysis. JAMA 1995;274:165-171. 46. Rousseau HP, Raillat CR, Joffre FG, Knight CJ, Ginestet MC, et al. Treatment of femoropopliteal stenoses by means of selfexpandable endoprostheses: midterm results. Radiology 1989;172:961-964. 47. Zollikofer CL, Antonucci F, Pfyffer M, Redha F, Salomonowitz E, Stuckmann G, et al. Arterial stent placement with use of the Wallstent: midterm results of clinical experience. Radiology 1991;179:449-456. 48. Do-dai-Do, Triller J, Walpoth BH, Stirnemann P, Mahler F. A comparison study of self-expandable stents vs balloon angioplasty alone in femoropopliteal artery occlusions. Cardiovasc Intervent Radiol 1992;15:306-312. 49. Sapoval MR, Long AL, Raynaud AC, Beysson BM, Fiessinger JN, Gauz JC, et al. Femoropopliteal stent placement: longterm results. Radiology 1992;184:8334-839. 50. Liermann D, Strecker EP, Peters J. The Strecker stent: indications and results in iliac and femoropopliteal arteries. Cardiovasc Intervent Radiol 1992;15:298-305. 51. Strecker EP, Boos IB, Gottmann D. Femoropopliteal artery stent placement: evaluation of long-term success. Radiology 1997;205(2):375-383. 52. Rosenfield K, Schainfeld R, Pieczek A, Haley L, Isner JM. Restenosis of endovascular stents from stent compression. J Am Coll Cardiol 1997;29:328-338. 53. White GH, Liew SC, Waugh RC, Stephen MS, Harris JP, Kidd J, et al. Early outcome and intermediate follow-up of vascular
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stents in the femoral and popliteal arteries without long-term anticoagulation. J Vasc Surg 1995;21(2):270-279. 54. Bray AE, Liu WG, Lewis WA, Harrison C, Maullin A. Strecker stents in the femoropopliteal arteries: value of duplex ultrasonography in restenosis assessment. J Endovasc Surg 1995;2(2):150-160. 55. Gray BH, Olin JW. Limitations of percutaneous transluminal angioplasty with stenting for femoropopliteal arterial occlusive disease. Semin Vasc Surg 1997;10(1):8-16. 56. Cejna M, Illiasch H, Waldenberg P, Horvath W, Thurnber SA, Lammer J. PTA vs Palmaz stent in femoropopliteal obstructions: a prospective randomised triallong term results. Radiology 1998;209:492. 57. Horvath W, Oertl M, Haidinger D. Percutanoues transluminal angioplasty of crural arteries. Radiology 1990;177: 565-569. 58. Flueckiger F, Lammer J, Klein GE, Hausegger K, Pilger E, Waltner F, et al. Percutanous transluminal angioplasty of crural arteries. Acta Radiol 1992;3:152-155. 59. Bull PG, Mendel H, Hold M, Schlegl A, Denck H, et al. Distal popliteal and tibioperoneal transluminal angioplasty: long-term follow up. JVIR 1992;3:45-53. 60. Wagner HJ, Starck EE, McDermott JC. Infrapopliteal percutanous transluminal revascularization: results of a prospective study on 148 patients. J Intervent Radiol 1993;8:81-90. 61. Pilger E, Lammer J, Bertuch H, Stark G, Decrinis M, Pfeiffer KP, et al. ND:YAG laser with sapphire tip combined with balloon angioplasty in peripheral arterial occlusions: long term results. Circulation 1991;83:141-147. 62. Starck EE, McDermott J, Crummy AB, et al. Angioplasty of the popliteal and tibial arteries. Semin Intervent Radiol 1984;4:269277. 63. Tamura S, Sniderman KW, Beinart C, Sos TA. Percutaneous transluminal angioplasty of the popliteal arteries and its branches. Radiology 1982;143:645-648. 64. Ballard JL, Sparks SR, Talor FC, Bergan JJ, Smith DC, Bunt TJ, et al. Complicatoins of iliac artery stent deployment. J Vasc Surg 1996;24:545-555. 65. Becker GJ, Katzen BT, Dake MD. Noncoronary angioplasty. Radiology 1989;170:921-940. 66. Matsi PJ, Manninen HI. Complications of lower-limb percutaneous transluminal angioplasty: a prospective analysis of 410 procedures on 295 consecutive patients. Cardiovasc Int Radiol 1998;21:361-366. 67. Gardiner GA Jr, Meyerovitz MF, Stokes KR, Clouse ME, Harrington DP, Bettmann MA. Complications of transluminal angioplasty. Radiology 1986;159:201-208. 68. Kashdan BJ, Trost DW, Jagust MB, Rackson ME, Sos TA, et al. Retrograde approach for contralateral iliac and infrainguinal percutaneous transluminal angioplasty: experience in 100 patients. JVIR 1992;3:515-521.

Surgery for Intermittent Claudication

Introduction
The most compelling indication for an open surgical revascularization procedure on the lower limb is critical limb ischemia (rest pain, tissue loss). Therefore, surgical procedures are discussed in greater breadth and depth in the section of the document dealing with CLI (see Treatment of Critical Limb Ischemia, p. 208). The following section addresses only the limited application of surgical procedures appropriate to the treatment of patients with IC. Surgery is rarely necessary in patients with IC; in fact, surgery should be avoided initially and other options pursued in most patients. The generalized disease process present in patients with atherosclerotic occlusive disease is not benefited by limb revascularization, other than the relatively minor considerations that increasing exercise capacity may improve conditioning and allow exercise therapy for angina. The overriding consideration is that, in the claudicant, the threat to life of generalized atherosclerosis takes priority over the limited threat to limb of the peripheral lesions. In a nonlimb-threatening situation, conservative treatment will provide sufficient improvement in most, so the risk of both early and late complications associated with bypass grafting cannot be justified. However, exceptional circumstances do exist, and these deserve discussion, for in practice, valid exceptions to the general reservation against surgical revascularization may occur. Ordinarily, if exercise therapy fails or is rejected by the patient for other reasons, these patients may try pharmacotherapy or be referred for imaging to evaluate the possibility of balloon angioplasty. If these options are not possible, or fail, surgery may be considered. The decision to involves an individualized risk:benefit analysis, balancing the benefit of relieving that particular patients disability against the immediate risks (morbidity/mortality/technical failure) and the risk of late failure of the proposed surgical procedure. This weighing of risk and benefit must be settled in the patients favor.

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Surgical Procedures General considerations

Surgical procedures are discussed separately in terms of the results of their application to proximal or distal disease, the common femoral artery being the boundary. This is because not only is the patency durability better for proximal disease but one often can treat both legs with the same procedure. Even if a single-leg bypass does not fail, claudication may return because of progression of like lesions in the contralateral extremity. The latter is not gauged by standard outcome measures. Continuing this comparison, distal procedures usually can be performed with a lower general and systemic, but not local, morbidity rate than proximal procedures performed through abdominal incisions. The use of prophylactic antibiotics has reduced the risk of graft infections to a rare but disastrous occurrence, whose risk is increased if there is a groin incision.1 Finally, although the overall cardiac mortality/morbidity risk would seem intrinsically greater for those proximal reconstructions involving aortic exposure and clamping, this is balanced by the fact that those with distal disease, specifically diabetic patients, generally have a higher prevalence of atherosclerotic involvement of cardiac, renal, and other visceral circulations. Their perioperative risk is as high and their survival worse than proximal reconstructions.2 3 Although these overall observations do not apply specifically to patients with IC, a peripheral/distal procedure cannot be assumed to be inherently less risky than a proximal one and thus easier to justify in a claudicant. The patency rate for operations to treat inflow disease (aortoiliac occlusive disease) is also better than that of femoropopliteal bypass. There are few direct comparative data in equivalent cases indicating which type of bypass graft (extraanatomic vs anatomic, unilateral vs bilateral, and bypass assisted by PTA) is the most appropriate in the patient suffering from IC.4 5 The choice is generally based on arteriographic findings and patient risk, but most patients with IC who would be accepted for bypass would be good risk with single-level disease. Given that, current feeling is to perform the lesser operative procedure capable of producing high and durable patency.

Proximal disease
With disease confined to the aortoiliac segments, the preferred operation is an aortofemoral (usually bilateral) bypass or an extended endarterectomy.6 7 The results of these procedures are reasonably good, with an operative mortality rate of 1% to 4% and a 5-year patency of 85% to 90%, with the results for patients with IC being on the better side of these ranges.8 9 Modern perioperative care has further improved the results and safety of the reference operation aortobifemoral bypass, which allows treatment of both legs with a single operation and provides the best durability. In a meta-analysis, De Vries and Hunink8 reviewed 8,123 operations with an operative mortality of 3.3%, and the patency rates for that subset of patients with claudication were as shown (Tab. XXVII). This mortality rate applies to reported series dating back to 1975. It can be presumed that the current mortality rate for claudicants undergoing proximal bypass is closer to 1% than 2%. Sexual dysfunction has been a concern in the operative treatment of proximal disease in sexually active men, but by avoidance of the hypogastric plexus and selection of bypass based on careful preoperative study of the arteriogram,11 this type of complication can be minimized and sexual function improved after proximal bypass. Improved results with respect to erectile dysfunction have also been reported after endarterectomy.12 13 Axillobifemoral bypass is an extra-anatomic bypass that reduces the risk of proximal reconstruction by avoiding an abdominal incision with aortic dissection and clamping. However, its primary patency is inferior to aortobifemoral bypass and, in spite of improving results, it is still not recommended for the treatment of IC. In the case of unilateral iliac artery occlusion or extensive disease within one iliac artery not amenable to PTA and stenting, there is a role for limited procedures such as iliofemoral or crossover femorofemoral bypass grafts, the latter even in combination with donor iliac artery dilatation, because they lessen operative morbidity while yielding acceptable results.14-16 In fact, in the absence of distal, that is, superficial femoral artery occlusion, which is the case with most patients with IC, femorofemoral bypass carries a similar patency to aortobifemoral bypass.17
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TABLE XXVII.Patency at 5 and 10 years after aortobifemoral bypass.

Patency (range in sensitivity) 5y Limb-based claudication Patient-based claudication 91.0 (90-94) 85.8 (85-89) 10 y 86.8 (85-92) 79.4 (78-83)

In summary, proximal bypasses in patients with IC offer primary patency rates in the 80% to 90% range, and, if the appropriate patient and bypass are matched, reasonable morbidity and mortality rates (close to 1%). Their greater durability and degree of symptom relief may be a reasonable trade-off for the immediate morbidity in active good-risk patients with IC whose aortoiliac lesions are not suitable for PTA and stent.

Distal disease
Extensive infrainguinal occlusive disease requiring bypass to infrapopliteal arteries, or to a popliteal artery with significant runoff disease but causing only claudication, very rarely justifies surgical intervention. In rare patients with extensive disease and severe claudication, there have been reports of successful tibial bypass.18 19 If the disease is confined to the superficial femoral artery and the distal vessels are relatively disease free, bypass may be justified in selected patients, following previously stated principles and strategies. Controversy remains about the use of autogenous vein versus prosthesis in above-knee bypass. The ar-guments are summarized in Table XXVIII. Those favoring above-knee prosthetic bypass point out that (1) patency is close enough to autogenous vein that most series fail to show statistically significant difference and (2) it preserves vein for other, later uses. The opposing point of view insists that autogenous vein is better and should be used first and that other or later need for the vein is only 5% to 10%.20 Because below-knee patency is better than above-knee patency for autogenous femoropopliteal bypass,21 this would favor bypass to the below-knee popliteal segment.19 However, although the available data do not allow absolute recommendations, most surgeons either would withhold surgery for such claudicators or use above-knee prosthetic bypass. The evaluation of results for different grafts in patients with IC is complicated by the fact that most authors report success rates for a given operation with no substratification for indications for operation. The combinations of procedures and variability of graft material inhibit the interpretation of patency data. For reconstruction of the aortoiliac segment, prosthetic material (Dacron or expanded polytetrafluorethylene [ePTFE]) with or without external support is used without clear preference. For infrainguinal reconstruction, possible graft materials include ePTFE, glutaraldehyde-treated human umbilical vein [HUV], Dacron, and autologous vein (Tab. XXVIII).22-24 Further discussion of these details is undertaken in Treatment of Critical Limb Ischemia (see p S192), but some comparative data are available for claudicants. The best patency data available come from the meta-analysis by Hunink et al.,22 the data for IC being as shown (Tab. XXIX). CRITICAL ISSUE 16: Conduit for femoropopliteal bypass There is a need for further studies to resolve the debate regarding the most appropriate conduit for an above-knee femoral popliteal bypass.

Summary: Surgery for Intermittent Claudication

To benefit from surgery, it is not only important that the patencies be high, but rather that mortality and morbidity rates be kept low. Although it is generally accepted that surgical mortality should be less than 5% when dealing with both patients with IC and those with severe ischemia, this should be significantly lower before considering surgery for claudication. One must take into account that the expected 5-year survival rate for claudicants treated without surgery is as high as 87%, an estimated risk of limb loss of only 1% per year, and a required intervention rate of 6% per year for limb salvage.23 From the Swedish Vascular Registry, it has recently been calcu119

TABLE XXVIII.Benefits of vein versus prosthetic grafts for above-knee femoropopliteal bypass.
In favor of vein Better long-term patency rates Avoidance of "staged" approach to femoral popliteal reconstruction (ie, best operation first time) Other graft material (ie, internal mammary arteries) are available for those patients requiring coronary artery bypass. Need for other use overestimated. Lower risk of graft infection In favor of prosthesis Close to equivalent long-term patency rates Better combined patency rates with prosthesis first, vein second if the need for secondary reconstructions is considered Fewer wound complications Vein available for secondary or coronary bypass Shorter operative time

TABLE XXIX.Patency data for bypass grafts in patients with intermittent claudication22.
5-year primary patency Baseline Vein bypass PTFE (above knee) PTFE (below knee) 80 (2) 75 (3) 65 (6) Sensitivity analysis 7887 6783 5676

lated that during the 10-year period 1987 to 1996, the combined mortality and amputation rate was 2.2% for aortofemoral reconstruction, 1.4% for femoropopliteal reconstruction, and 2.0% for distal reconstructions, so results are improving.24 This and patency rates that are predictably 20% or more above those of PTA and stents for a given lesion will preserve a role for surgical bypass in claudicants, albeit a very selective one. RECOMMENDATION 37: Surgery for intermittent claudication Surgery should be offered to treat severe symptoms only after other forms of medical therapy have been recommended and have either failed or been rejected for good reason. If used, surgery for IC should employ the procedure offering extended clinical benefit, ie, one with a high benefit-to-risk ratio. If necessary, surgery is the treatment of choice of type D lesions but may be used also in type B and C lesions (see Recommendation 32, p. 102, and Critical Issue 10, p. 102).

Lumbar sympathectomy
No objective evidence supports the use of lumbar sympathectomy in the treatment of IC.25 Neither resting nor exercise blood flow is increased by the performance of a sympathectomy.26

References
1. Allen BT, Reilly JM, Rubin BG, et al. Femoropopliteal bypass for claudication: Vein vs. PTFE. Ann Vasc Surg 1996;10:178185. 2. Krupski WC, Layug EL, Reilly LM, Rapp JH, Mangano DT. Study of Perioperative Ischemia (SPI) Research Group. Comparison of cardiac morbidity between aortic and infrainguinal operations. J Vasc Surg 1992;15:354-365. 3. Krupski WC, Layug EL, Reilly LM, Rapp JH, Mangano DT. Study of Perioperative Ischemia Research Group. Comparison of cardiac morbidity rates between aortic and infrainguinal operations: two-year follow-up. J Vasc Surg 1993;18(4):609-617. 4. van den Akker PJ, van Schilfgaarde R, Brand R, Van Bockel JH, Terpstra JL. Long term success of aortoiliac operation for arteriosclerotic obstructive disease. Surg Gynecol Obstet 1992;174:485-496. 5. Brewster DC. Clinical and anatomical considerations for surgery in aortoiliac disease and results of surgical treatment. Circulation 1991;83(suppl I):I42-I52. 6. Szilagyi DE, Elliott JP, Smith RF, Reddy DJ, McPharlin M. A thirty-year survey of the reconstructive treatment of aortoiliac occlusive disease. J Vasc Surg 1986;3:421-436. 7. Inahara T. Evaluation of endarterectomy for aortoiliac and aortoilio-femoral occlusive disease. Arch Surg 1975;110:14581464. 8. De Vries SO, Hunink MGM. Results of aortic bifurcation grafts for aortoiliac occlusive disease: a meta-analysis. J Vasc Surg
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1997;26:558-569. 9. Brewster DC. Current controversies in the management of aortoiliac occlusive disease. J Vasc Surg 1997;25:365-379. 10. Weinstein MH, Machleder HI. Sexual function after aortoiliac surgery. Ann Surg 1975;181:787-790. 11. Flanigan DP, Schuler JJ, Keifer T. Elimination of iatrogenic impotence and improvement of sexual function after aortoiliac revascularization. Arch Surg 1982;117:544-550. 12. Nevelsteen A, Beyens G, Duchateau J, Suy R. Aorto-femoral reconstruction and sexual function: a prospective study. Eur J Vasc Surg 1990;4:247-251. 13. Cormio L, Edgren J, Lepntalo M, Lindfors O, Nisn H, Saarinen O, et al. Aortofemoral surgery and sexual function. Eur J Vasc Endovasc Surg 1996;11:453-457. 14. Hanafy M, McLoughlin GA. Comparison of iliofemoral and femoro-femoral crossover bypass in the treatment of unilateral iliac arterial occlusive disease. Br J Surg 1991;78:1001-1002. 15. Brewster DC, Cambria RP, Darling RC, et al. Long-term results of combined iliac balloon angioplasty and distal revascularization. Ann Surg 1989;210:324-331. 16. Kalman PG, Hosang M, Johnston KW, Walker PM. Unilateral iliac disease: The role of iliofemoral bypass. J Vasc Surg 1987;6:139-143. 17. Piotrowski, JJ, Pearce WH, Jones DN, Whitehall T, Bell R, Patt A, et al. Aortobifemoral bypass: the operation of choice for unilateral iliac occlusion? J Vasc Surg 1988;8:211-218. 18. Byrne J, Darling RC, Chang BB, et al. Infrainguinal arterial reconstruction for claudication: is it worth the risk? an analysis of 409 procedures. J Vasc Surg 1999;29(2):259-267. 19. Conte MS, Belkin M, Donaldson MC, Baum P, Mannick JA, Whittemore AD. Femorotibial bypass for claudication: do results justify an aggressive approach? J Vasc Surg 1995;21(6):873-880. 20. Michaels JA. Choice of material for above-knee femoropopliteal bypass graft. Br J Surg 1989;76:7-14. 21. Veith FJ, Gupta SK, Ascer E, White-Flores S, Samson RH, Scher LA, et al. Six-year prospective multicenter randomized comparison of autologous saphenous vein and expanded polytetrafluoroethylene grafts in infrainguinal arterial reconstructions. J Vasc Surg 1986;3:104-114. 22. Hunink MGM, Wong JB, Donaldson MC, Meyerovitz MF, Harrington DP. Patency results of percutaneous and surgical revascularization for femoropopliteal arterial disease. Med Decis Making 1994;14:71-81. 23. Reunanen A, Takkunen H, Aromaa A. Prevalence of intermittent claudication and its effect on mortality. Acta Med Scand 1982;211:249-256. 24. Bergqvist D, Troeng T, Elfstrom J, et al. Auditing surgical outcome. Ten years with the Swedish Vascular Registry (SWEDVASC). Eur J Vasc Surg 1998;164(suppl 581):23. 25. Strandness DE, Bell JW. Critical evaluation of the results of lumbar sympathectomy. Ann Surg 1964;160:1021. 26. Rutherford RB, Valenta J. Extremity blood flow and distribution: the effects of arterial occlusion sympathectomy and exercise. Surgery 1971;69:332-344.

Comparison of Therapeutic Options for Intermittent Claudication

There is overwhelming evidence that walking capacity is increased by exercise. The timing and type of exercise has been extensively studied, and supervised frequent exercise sessions offer significant benefit in increasing claudication distance (see Basic Treatment, p. 84).1 The question as to whether exercise is superior to limited interventions such as balloon angioplasty (PTA) is more controversial. In a study from the United Kingdom, in which patients were followed-up for 6 years, ABPI increased during the first 15 months after PTA; however, more significant changes in walking distances were seen in the exercise group. At 6 years follow-up, there were no differences between groups2 (see also Recommendation 29, p. 90). The loss of the initial advantage of PTA was attributable to restenosis of the dilated segment, whereas those treated conservatively had a steadily increasing benefit of exercise. The later loss of advantage of exercise was probably due to lack of adherence to the exercise program. The best effect of exercise was found in patients with disease confined to the superficial femoral artery, in contrast to PTA, which has the best effect in iliac lesions. In a second British study screening 600 patients with IC during follow-up of 6 months, PTA patients benefited more in walking distance and ABPI than those randomized to exercise.3 The report on quality of life recorded a better response after PTA than after exercise. However, when the same group reported their results after 2 years follow-up, there were no significant differences in patient-reported walking distances, exercise treadmill distances (to onset of pain or maximal distance), ABPI, or quality of life.4 Only the number of patent arteries favored PTA. Thus, two randomized trials with extended follow-up showed no advantage to PTA. However, in these two trials, the predominant lesions were in the femoropopliteal segment, not the iliac arteries, where PTA results are much better (over 20% better patency). Another study has shown that unsupervised exercise programs are unlikely to significantly improve the patients quality of life compared with interventional treatment.5 Using the McMaster Health Index Questionnaire, an Italian
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study showed that the quality of life was impaired in patients suffering from IC; however, this impairment correlated poorly to the reduced exercise capacity.6 A randomized study compared percutaneous transluminal angioplasty (n = 20) with a supervised program of dynamic leg exercises (n = 16).7 Constant-load treadmill testing was performed at 3, 6, 9, and 12 months to evaluate change in pain-free and maximal walking distances. It was found that, after angioplasty, mean ABPI were significantly improved, but only at the 3-month point was maximum walking distance improved over baseline. In contrast, in the exercise group, despite no improvement in the ABPI, maximal and pain-free walking distances were progressively increased at each follow-up, with significant increases at 6, 9, and 12 months. For example, pain-free walking distance increased by 296% and maximum walking distance by 442% at the 12-month point in the exercise-trained group. Care must be taken when reviewing reports of comparative trials of PTA. Many studies report the results of the treatment of the most favorable lesions, and these may not always be extrapolated to all lesions in a similar area. The breadth of vascular disease frequently makes comparative study groups less than equal. The results of PTA are frequently reported for claudicators, whereas surgical results often include patients with CLI. These facts must be remembered when reviewing the literature and choosing the best treatment for an individual patient. Calls for appropriate long-term randomized control trials have been made.8 Such studies should include assessment of both walking distance and quality of life. A further question is whether there is a functional benefit of surgery in patients with IC. In a study presented in 1993, it was found that after 6 weeks there was an improvement in resting ABPI, as well as of treadmill walking time and of self-reported community-based walking ability.9 Another study evaluating functional outcome included 68% inflow procedures, with the remaining being infrainguinal operations, of which 93% were femoropopliteal bypass grafts. It was found that the procedure gave optimal results if restricted to patients younger than 70 years, who were nondiabetic patients, and in those in whom a normalization of the ankle pressure could be anticipated.10 Interestingly, when functional status was assessed postrevascularization, this study showed that 17% of patients were dissatisfied with their outcome. Of these, approximately 50% had a normal postoperative ABPI. This implies that surgical morbidity, even without complications, is important in patient satisfactionindependent of the success of the revascularization. Lundgren et al.11 conducted a randomized, controlled trial comparing the effects of (1) peripheral bypass surgery alone; (2) surgery followed by 6 months of supervised exercise training with dynamic leg exercises; and (3) 6 months of supervised exercise training alone in 75 patients with claudication. Constant-load treadmill testing was used in this study. At 13 months after randomization, walking ability was improved in all three groups. In this study, the most effective treatment for improving functional status was exercise training plus surgery. The changes in maximal walking distance were 173% for the operated group, 263% for the group that received both therapies, and 151% for the exercise-trained group. The authors found that although all surgically treated patients increased their walking distance more than patients who received only exercise training, they also had a greater rate of complications than the exercise group. In another study, surgery was compared with PTA.12 This study included not only patients with IC, but also a small proportion of patients with severe ischemia. This randomized, controlled trial was not able to show a significant difference between bypass surgery and angioplasty, but, given the sample size, it has only a power of 0.21 to detect a difference of 50%. For detecting differences in subgroups, the power was even lower. Furthermore, only patients who were considered to have lesions appropriate for PTA were entered in this trial. Today, these cases would not be considered candidates for surgery but rather would be referred for PTA. The 1-year result of PTA versus surgery was also evaluated in 102 patients over a 6-year period.13 It was found that only 5% of the patients screened for the study were suitable for both kinds of treatments and could therefore be included. Thus, these were almost all patients that today would be considered for PTA as primary invasive treatment. The success and complication rates were the same in both groups, but the hospital stay was significantly shorter for the PTA patients. This points out the difficulties in conducting a randomized control trial comparing two modalities that are suited for quite different lesions. The most important femoropopliteal study is a decision and cost-effectiveness analysis of revascularization procedures for femoropopliteal disease by Hunink and colleagues.14 The authors used a literature review of mor122

tality, morbidity, patency, and cost data as a source. There were 4,800 PTAs and 4,511 bypass operations. They developed a decision analytic model to examine the choice between bypass surgery and PTA for lesions amenable to either procedure. Outcomes measured included 5-year patency, QALY, lifetime costs, and incremental costeffectiveness ratios. Six treatment strategies were analyzed: (1) no treatment; (2) initial PTA with no further revascularization; (3) initial PTA with subsequent PTA; (4) initial PTA with subsequent bypass surgery; (5) bypass surgery followed by no further therapy; (6) bypass surgery followed by graft revision. The results showed that for a 65year-old man with disabling claudication and a femoropopliteal stenosis or occlusion, the initial PTA strategy increased QALY by 2 to 13 months and resulted in decreased lifetime expenditures as compared with bypass surgery. Sensitivity analysis showed that when the 5-year patency of PTA exceeds 30%, PTA is the preferred initial invasive strategy. The authors concluded that PTA is the preferred initial strategy in patients with disabling claudication and femoropopliteal stenosis or occlusion. To evaluate the results of the various procedures, reporting standards are important, including operative morbidity, mortality, and patency figures that do not exclude initial failures and identify reintervention as secondary patency.15 The interpretation of results of reconstruction is complicated by the mixture of patients included in the series, which included not only claudication as an indication, but more frequently combinations series of severe ischemia and IC. Furthermore, in the comparison of various treatment modalities, combinations of proximal and distal reconstruction are described. Descriptive series of infrainguinal bypass for claudication with a distal anastomosis above the knee, but including all kinds of autologous or synthetic materials, claim a 5-year patency of 60% to 70%.16 17 It therefore could be assumed that a synthetic graft (ePTFE or glutaraldehyde-treated HUV) perform equally well as the autologous vein. This has lead to the conclusion that one could advocate a prosthetic conduit, specifically PTFE, for an AK reconstruction.18 This is not supported by other studies, however.19 If the procedure has to be extended below the knee, the use of autologous vein is strongly recommended.20 It is unfortunate that surgical studies reviewed did not include exercise therapy as one of the treatment options. However, the meta-analysis cited will be helpful in choosing between different forms of interventional therapy. Although not a comparative study, the meta-analysis by Hunink et al.21 at least yields patency data for the procedures performed to relieve IC caused by atherosclerosis in the femoropopliteal region (for further results, see Endovascular Procedures, p. 101). Applied across the board, this treatment strategy of initial PTA provides quality-of-life and lifetime expenditure advantages over a strategy of initial bypass surgery (see also Recommendation 31, p. 102; Recommendation 34, p. 108).

References
1. Gardner AW, Phoehlman ET. Exercise rehabilitation programs for the treatment of claudication pain. JAMA 1995;274:975980. 2. Perkins JMT, Collin J, Creasy TS, Fletcher EWL, Morris PJ. Exercise training versus angioplasty for stable claudication: long and medium term results of a prospective, randomized trial. Eur J Vasc Endovasc Surg 1996;11:409-413. 3. Whyman MR, Fowkes FGR, Kerracher EMG, Ruckley CV. Randomized controlled trial of percutaneous transluminal angioplasty for intermittent claudication. Eur J Vasc Endovasc Surg 1996;12:167-172. 4. Whyman MR, Fowkes FGR, Kerracher EMG. Is intermittent claudication improved by percutaneous transluminal angioplasty? J Vasc Surg 1997;26:551-557. 5. Currie IC, Wilson YG, Baird RN, Lamont PM. Treatment of intermittent claudication: the impact on quality of life. Eur J Vasc Endovasc Surg 1995;10:356-361. 6. Barletta G, Perna S, Sabba C, Catalano A, O'Boyle C, Brevetti G. Quality of life in patients with intermittent claudication: relationship with laboratory exercise performance. Vasc Med 1996;1:3-7. 7. Creasy TS, McMillam PJ, Fletcher EWL, Collin J, Morris PJ. Is percutaneous transluminal angioplasty better than exercise for claudication? Preliminary results from a prospective randomized . Eur J Vasc Surg 1990;4:135-140. 8. Bradbury AW, Ruckley CV. Angioplasty for lower-limb ischemia: time for randomized control trials. Lancet 1996;347:277-278. 9. Regensteiner JG, Hargarten ME, Rutherford RB, Hiatt WR. Functional benefits of peripheral vascular bypass surgery for patients with intermittent claudication. Angiology 1993;44:1-10. 10. Zannetti S, L'Italien GJ, Cambria RP. Functional outcome after surgical treatment for intermittent claudication. J Vasc Surg 1996;24:65-73. 11. Lundgren F, Dahllof A, Lundholm K, Schersten T, Volkman R. Intermittent claudication: surgical reconstruction or physical training? A prospective randomized trial of treatment efficiency. Ann Surg 1989;209:346-355. 12. Wilson SE, Wolf GL, Cross AP. Percutaneous transluminal angioplasty versus operation for peripheral arteriosclerosis: report of a prospective randomized trial in a selected group of patients. J Vasc Surg 1989;9:1-9. 13. Holm J, Arfvidsson B, Jivegard L, Lundgren F, Lundholm K, Schersten T, et al. Chronic lower limb Ischemia: a prospective randomized controlled study comparing the 1-year results of vascular surgery and percutaneous transluminal angioplasty
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(PTA). Eur J Vasc Surg 1991;5:517-522. 14. Hunink MGM, Wong JB, Donaldson MC, Meyerovitz MF, de Vries J, Harrington DP. Revascularization for femoropopliteal disease: a decision and cost-effectiveness analysis. JAMA 1995;274:165-171. 15. The Ad Hoc Committee On Reporting Standards. Society for Vascular Surgery/North American Chapter. International Society for Cardio-vascular Surgery: suggested standards for reports dealing with lower extremity ischemia. J Vasc Surg 1986;4:8094. 16. Dalman RL, Taylor LM Jr, Moneta GL, Yeager RA, Porter JM. Simultaneous operative repair of multilevel lower extremity occlusive disease. J Vasc Surg 1991;13:211-221. 17. Dalman RL, Taylor LM Jr. Basic data related to infrainguinal revascula-rization procedures. Ann Vasc Surg 1990;4:309-312. 18. Quinones-Baldrich WJ, Busuttil RW, Baker JD, Baker JD, Vescera CL, Ahn SS, et al. Is the preferential use of poly-tetrafluoroethylene grafts for femoropopliteal bypass justified? J Vasc Surg 1988;8:219-228. 19. Londrey GL, Ramsey DE, Hodgson KJ, Barkmeier LD, Sumner DS. Infrapopliteal bypass for severe ischemia: comparison of autogenous vein, composite, and prosthetic grafts. J Vasc Surg 1991;13:631-636. 20. Veith FJ, Gupta SK, Ascer E, White-Flores S, Samson RH, Scher LA, et al. Six-year prospective multicenter randomized comparison of autologous saphenous vein and expanded polytetrafluoroethylene grafts in infrainguinal arterial reconstructions. J Vasc Surg 1986;3:104-114. 21. Hunink MGM, Wong JB, Donaldson MC, Meyerovitz MF, Harrington DP. Patency results of percutaneous and surgical revascularization for femoropopliteal arterial disease. Med Decis Making 1994;14:71-81.

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Management Algorithm for Intermittent Claudication

Basic Strategy Algorithm for Intermittent Claudication

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Complete Management Algorithm for Intermittent Claudication

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