Medical Therapy of Peripheral Arterial Occlusive Disease

LOWER EXTREMITY ARTERIAL OCCLUSIVE DISEASE

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MEDICAL THERAPY OF PERIPHERAL ARTERIAL OCCLUSIVE DISEASE John P. Cooke, MD, PhD, and Adrian O. Ma, MD

Peripheral arterial occlusive disease (PAD) is primarily a disease of the elderly population, especially those over the age of 65. The prevalence of symptomatic PAD is estimated at approximately 2% in all individuals between 40 and 60 years of age, and up to 6% in those over 70. 21 However, these figures become several-fold higher if the same population is assessed by objective noninvasive tests such as the ankle-brachial index (ABI). Based on a disease definition of ABI of 0.9 or less, the Edinburgh Artery Study reported a disease prevalence of 17% in a population aged between 55 and 74. 9 Any treatment regimen targeted for PAD should address four objectives: (1) improvement of functional capacity, that is, walking distance; (2) prevention of limb loss; (3) modification of the atherosclerotic process in the diseased vessel; and (4) reduction of cardiovascular and cerebrovascular morbidity and mortality. Selection of treatment (i.e., medical therapy alone versus a combination of medical and interventional measures) should take into account the severity of disease, the patient's life style, and the anatomic location of lesions (proximal versus distal disease). Because more than 75% of the claudicants do not experience progression in their symptoms, invasive intervention is never required for the majority of patients. However, a minority of these individuals develop ischemic rest pain or ulceration. This degree of critical limb ischemia is an indication for angiography with a view toward surgical revascularization or catheter-directed procedures. Claudication that impairs occupational performance or limits the desired life style is also a reasonable albeit subjective indication for revascularization. In this subset of patients, when the history and physical examination indicate an iliac lesion, an aggressive approach is more eaSily justified, as the long-term patency is quite good for interventional procedures directed at proximal lesions. Conversely, infrainguinal disease that does

From the Section of Vascular Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California

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not cause critical limb ischemia should be treated medically because symptoms related to infrainguinal disease respond well to exercise rehabilitation and because interventional procedures below the inguinal ligament do not have the long-term success of procedures directed at more proximal lesions. It is worth emphasizing that in trials that have directly compared the efficacy of exercise rehabilitation versus revascularization, exercise programs equal the results of surgical revascularization and exceed the gains made by catheter-directed procedures, as assessed by treadmill testing. This is not to mention the additional salutary effects that a good exercise program has on lipoprotein levels, glucose metabolism, cardiovascular conditioning, and life expectancy. In the last decade there has been a robust increase in the number of revascularization procedures performed for PAD. Despite an increase in these interventions, evidence indicates that the annual rate of lower extremity amputation has remained unchanged. 1s,20 Furthermore, these interventions do not improve survival and have a significant economic impact on health care cost. Therefore, as a rule, medical therapy is the treatment of choice for the claudicant. GENERAL MEASURES

Regardless of the cause and severity of PAD, certain basic measures are essential in managing these patients. The patient and family should understand the rationale, goals, and expectation of the medical therapy in order to optimize compliance. Meticulous care to protect the limbs from trauma and infection is a simple but effective way of preventing limb loss, especially in the presence of diabetes mellitus. 4 Ischemia limits wound healing and response to infection, Minor trauma may progress to ulceration in the ischemic limb, In fact, about three quarters of the amputations in these patients stem from a nonhealing wound due to preventable trauma (such as poorly fitting shoes, inadvertent injury during clipping of the nails, or a puncture wound incurred while ambulating). Ambling about with bare feet is a luxury these patient can ill afford. Emollients applied twice daily after a bath or shower maintain the skin in a supple and hydrated condition to prevent drying and fissuring, which can create a portal of entry for bacteria. For the same reason, fungal infection should be recognized and treated, Toe nails should be cut straight to avoid ingrowth, In addition, lamb's wool placed between adjacent toes prevents pressure necrosis and "kissing" ulcers in patients with severe ischemia, In diabetic patients with poor vision from retinopathy and sensory loss from peripheral neuropathy, frequent foot inspection by a spouse or other family member is strongly advised, The aid of a podiatrist is often useful in providing foot care and recommending shoeware, Reducing the load that the exercising leg muscles must bear can significantly increase walking distance, The symptoms of claudication can be markedly improved in obese patients by weight loss. Elderly patients may also benefit from resistance training to improve the muscle strength of their lower extremities between exercise sessions. In some cases, modifications in the workplace may allow patients to adjust to their limitations; for example, the heavy tool belt of a maintenance worker may be replaced by a push cart. Certain medications, such as ergot preparations for migraine, should be avoided in patients with PAD, as their vasoconstrictive properties may further jeopardize the blood supply. On the other hand, several well-executed controlled studies have attested to the safety of using beta-blocking drugs in PAD, as they do not affect the walking distance in patients with intermittent claudication. In

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these patients there are often good reasons to use beta-blockers, most notably in patients with myocardial ischemia, in whom these drugs not only relieve anginal symptoms but also reduce the frequency of arrhythmias and confer increased longevity after myocardial infarction. RISK FACTOR MODIFICATION

Recent epidemiologic data suggest that PAD is a powerful predictor of risk for myocardial infarction and stroke. 3 Even in an asymptomatic patient the discovery of a reduced ABI should prompt a thorough cardiovascular risk assessment followed by aggressive modification of risk factors. PAD and coronary artery disease tend to co-exist as manifestations of the atherosclerotic process in different circulations. Therefore, it is generally assumed that the same risk factors predictive of coronary artery disease-tobacco smoking, hypercholesterolemia, hypertension, diabetes mellitus, and family history-also contribute to PAD. However, the few epidemiologic studies that specifically examined the risk factors for PAD suggest that tobacco smoking and systolic hypertension have the strongest association and are more predictive of disease progression. The use of tobacco is the most prevalent risk factor, with 80% to 90% of claudicants acknowledging a history of smoking. In the Framingham Study, heavy smokers had a twofold risk of developing claudication compared with nonsmokers with similar risk factor profiles. Numerous studies have also demonstrated the unfavorable effects of continued smoking on the patency of coronary and lower extremity saphenous venous bypass grafts and on the restenosis rate after carotid endarterectomy. The mechanisms by which tobacco accelerates atherosclerosis are poorly understood but may include enhanced cellular proliferation in the vessel wall, alterations in the release of endogenous vasoactive and cytoprotective factors, increased endothelial permeability to lipoproteins, and increased thrombogenicity. A conservative medical management strategy is successful in providing symptomatic improvement in 85% of patients who have ceased smoking, compared with only 20% of patients who continue to smoke.IS Similarly, claudicants who abstain from tobacco are much less likely to incur tissue loss. When claudication is due to Buerger's disease, approximately 50% of the patients who continue to smoke suffer tissue loss, whereas only 5% of those who desist incur this complication. 4 Although many techniques and programs such as behavior modification, hypnosis, and acupuncture are available to help patients discontinue smoking, none has been consistently shown to be superior. Patient motivation and determination are perhaps the major factors in predicting long-term success. Emphasis on the the increased risk of amputation associated with continued smoking may prove sufficient motivation for some patients with PAD. A written contract between the physician and the patient, stating that the patient will discontinue the use of tobacco before the next clinic visit, increases the number of patients who abstain. These simple counseling techniques, combined with the use of nicotine patches or gums, produce long-term abstention in 30% of patients. Relapse rate appears to be greatest approximately 3 months after smoking cessation, and therefore consistent follow-up and periodic medical evaluation are essential. The success rate can be increased to 60% long-term abstention in more intensive programs that combine patient education, nicotine substitutes, biofeedback, group therapy sessions, and frequent follow-up telephone calls by nurse practitioners.

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Epidemiologic studies have identified hypertension (especially elevated systolic blood pressure) as the second most predictive risk factor in PAD. In the Framingham cohort, hypertension was present in about one third of claudicants and, as a risk factor, increased the incidence of claudication by 2.5- to 4-foldY Although hypertension has long been recognized to accelerate atherosclerosis in various animal studies, the precise pathophysiology is still elusive despite years of research. The concept that hypertension causes "barotrauma" has been revised in light of experimental data that hypertension is associated with specific alterations in the vessel wall, some of which precede the elevation of systemic pressure. These alterations include the induction of specific genes encoding growth factors that regulate vascular smooth muscle proliferation; activation of the tissue renin-angiotensin system; and endothelial alterations in permeability, elaboration of vasoactive factors, and interaction with circulating blood elements. 6 Whether the treatment of hypertension reverses any of these pathophysiologic processes and thereby reduces the progression of PAD remains to be determined. Given that essential hypertension is a heterogeneous disorder, the stepped-care antihypertensive regimen, once touted as a simple and efficacious approach for all patients, is no longer thought to be sufficient. Current therapeutic strategy for hypertension in these patients emphasizes not only blood pressure reduction but also consideration of concomitant risk factors. For example, in the PAD patient with diabetes mellitus or hyperlipoproteinemia, the salutary effects of beta-blockers must be carefully weighed against their tendency to aggravate carbohydrate intolerance and dyslipidemia. Finally, hypertension in a patient with claudication should always alert the physician to the possibility of renovascular disease. Diabetes mellitus confers a significantly higher risk for the development of PAD and its complications. Diabetics are 17 times more likely to develop ischemic gangrene, and the relative risk for amputation is increased five- to six-fold compared with nondiabetics.14 Diabetics are often discovered to have diffuse infrapopliteal disease, and their arteries also tend to develop medial calcinosis. Whereas intensive glycemic control has now been shown unequivocally to reduce microvascular complications (retinopathy and nephropathy) in patients with insulin-dependent diabetes, its effect on macrovascular (cardiovascular, cerebrovascular, or peripheral vascular) events remains uncertain. Nevertheless, strict glycemic control promotes wound healing and infection resistance and helps normalize elevated triglyceride concentration, which may itself be a contributing factor in the development of PAD in the diabetic population. Evidence is increasing that aggressive reduction of serum cholesterol can retard progression and even induce regression of atherosclerosis in the peripheral and coronary arteries. In the latter circulation the increment in vessel diameter is in the range of a few percent over the course of 1 to 3 years, but this is associated with a substantial reduction in the cardiovascular morbidity and mortality. This effect on the clinical course is unlikely due to the change in luminal diameter but more likely due to stabilization of the plaque and restoration of endothelial function. Because of these beneficial effects, a complete lipid profile (total cholesterol, triglyceride, high density lipoprotein [HDL] cholesterol and calculated low density lipoprotein [LDL] cholesterol) is usually obtained as part of the initial cardiovascular risk assessment of the patient. The LDL cholesterol should be reduced to 100 mg/ dL or less and the HDL increased to 45 mg/ dL or more. For the reason mentioned above, fasting serum triglyceride should be kept below 200 mg/ dL. Dietary counseling, an exercise program, weight

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control, and use of lipid-lowering drugs are all integral parts of the lipid management. Premature atherosclerosis remains the most common cause of PAD in patients under the age of 40 and is frequently associated with multiple cardiovascular risk factors, especially heavy tobacco smoking. However, in younger individuals, or in older patients without other obvious risk factors, one should consider diagnostic testing for uncommon causes of PAD such as homocystinemia, elevation of lipoprotein Lp(a), anticardiolipin antibody, necrotizing vasculitis, and Buerger's disease. EXERCISE REHABILITATION

Exercise training is the most potent medical measure in the treatment of mild to moderate claudication since its introduction over 40 years ago. 17 Most patients can double their walking distance within 3 months with a daily exercise routine. More importantly, regular exercise is associated with lower incidence of overall cardiovascular events and, in the elderly population, better neuromuscular function and joint mobility. The exact mechanism responsible for the improved walking distance with exercise training remains speculative. Objective data indicate that exercise induces adaptive changes in the oxidative metabolism of skeletal muscle by induction of oxidative enzymes and by increases in tissue carnitine levels, thereby conferring more efficient oxygen extraction? Although an increase in macrovascular blood flow is probably not a dominant factor, regular exercise appears to enhance hemorrheologic properties of blood to reduce viscosity and improve local blood flow. Moreover, trained claudicants improve the biomechanical efficiency of their gait, reducing the oxygen demand for the same workload. In general, an organized, supervised program is more effective than a purely home-based program. The usual prescription for a walking program is a goal of 30 to 60 minutes, 4 to 5 days weekly, at a pace of 2 miles per hour or more. Patients should take breaks for moderately severe pain during the walks. If an indoor machine is used instead, a treadmill is preferable to the non-weightbearing stationary bicycle or rowing machine for optimal results. The positive results of an exercise program frequently reinforce the patient's compliance for other risk factor modification. Nevertheless, the majority of controlled studies on exercise training are short-term, and the few long-term studies yield conflicting data with regard to the effect of exercise on arterial disease progression. The exercise-induced gain in walking distance appears to be contingent upon continuous dynamic leg exercise. Not surprisingly, compliance with any longterm physical activity regimen can diminish significantly with time, and therefore regular feedback between patient and physician becomes an essential prerequisite for durable success. PHARMACOLOGIC TREATMENT Vasodilator Agents

A great number of drugs have been evaluated for the treatment of PAD, mostly with disappointing results. Agents from each of the major classes of vasodilators have been unsuccessfully used to relieve symptoms, including the a-adrenergic antagonists, calcium channel blockers, angiotensin-converting

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enzyme inhibitors, the serotonergic antagonist ketanserin, and hydralazine. From a pathophysiologic viewpoint, vasodilator therapy is unlikely to improve blood flow further or change the workload on skeletal muscle during exercise because the ischemic limb is already nearly maximally dilated from regional hypoxia. However, it is possible that by preferentially vasodilating collateral vessels some new agents (such as potassium channel agonists) may have efficacy.

Antiplatelet Therapy

Platelets have been implicated in the early phase of atherosclerosis as well as the late thrombotic process leading to the complete occlusion of diseased vessel. Data from clinical studies in the coronary and cerebrovascular circulation have demonstrated significant reduction of thrombotic complications in all stages of the vascular disease, from asymptomatic state to acute infarction. In addition, antiplatelet therapy reduces the acute closure of saphenous vein bypass grafts and substantially decreases the incidence of acute thrombosis after coronary angioplasty. Antiplatelet treatment also appears to reduce the progression of PAD, probably by inhibiting the accretion of thrombus. Aspirin is an irreversible cyclooxygenase inhibitor, and as such inhibits the production of thromboxane A2 (a vasoconstrictor and platelet activator) as well as prostacyclin (a vasodilator and antagonist of platelet aggregation). Its effect to inhibit thromboxane A2 production by platelets predominates over its effect to inhibit prostacyclin generated by the vessel wall, because the endothelium has the capacity to generate more cyclooxygenase, whereas the platelet (lacking a nucleus) cannot. The minimal dose of aspirin required for the optimal effect on these processes is not known, but one baby aspirin (81 mg) is probably sufficient. Indeed, the Nobel Laureate Sir John Vane (who first elucidated the arachidonic acid cascade and the role of cyclooxygenase), when asked for his opinion of the effective daily dose, is fond of stating that one need only store a single aspirin tablet in the medicine chest and lick it once daily. Cyclooxygenase is extremely sensitive to inhibition by aspirin, and this led Sir John Vane and others to investigate very low dose (30 mg) sustained-release forms of aspirin. These are absorbed slowly from the gastrointestinal tract but achieve sufficient levels in the portal circulation so as to entirely acetylate cyclooxygenase in platelets passing through the portal circulation. However, the levels of aspirin in the portal circulation are so low that, upon first-pass metabolism in the liver, the aspirin is cleared from the circulation so the systemic vasculature (and its production of prostacyclin) is unaffected. Chronic administration of aspirin to apparently healthy men was shown to reduce the need for peripheral arterial surgery.'0 Although delay in angiographic progression of PAD by aspirin has been described, more studies are needed to validate these findings. Aspirin alone appears to be as effective as a combination of aspirin and dipyridamole therapy in inhibiting platelet aggregation and vascular events? Another recently introduced class of antiplatelet agents, exemplified by ticlopidine and clopidogrel, inhibits platelet aggregation by a different mechanism than aspirin. Both of these new agents specifically antagonize ADP-dependent activation of glycoprotein IIIb/IIa receptors. Preliminary data suggest that these agents reduce cardiovascular complications in patients with claudication. These agents are more expensive than aspirin and require initial monitoring for

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neutropenia. However, they are excellent alternatives for those who cannot tolerate aspirin. Hemorrheologic Therapy

Tissue ischemia, hypoxia, and reduced intracellular adenosine triphosphate render red cells and platelets less deformable. The increased membrane rigidity and loss of flexibility increase the viscosity of circulating blood and promote the microcirculatory disturbance. Thus, the rationale for using hemorrheologic agents in occlusive peripheral arterial disease is to restore blood fluidity in the microcirculation and hence improve oxygen delivery to the ischemic tissue. Pentoxifylline is the only oral hemorrheologic agent currently approved by the US Food and Drug Administration for the treatment of intermittent claudication. In addition to its ability to reduce red cell rigidity and aggregation, it lowers fibrinogen concentration and thereby causes a decrease in whole blood viscosity. Some studies have also suggested that the drug stimulates prostacyclin elaboration by the endothelium and reduces leukocyte vessel wall interaction. In the first major double-blind, placebo-controlled study conducted in the United States, the drug increased the duration of treadmill exercise time by 45%, compared with a 23% improvement in placebo-treated controls at 24 weeks' follow-up.16 Much of the improvement (as demonstrated in the placebo group) may have been a training effect, as the patient adapted to walking on a treadmill. This "training effect" is more commonly observed when using constant-load treadmill protocols, as in this study, and is less of an obfuscating factor when a graded-load protocol is employed. In addition, it appears that this small drugrelated gain in walking distance infrequently translates into subjective improvement. In the authors' experience, only a minority of patients gain any relief with pentoxifylline. Because of its salutary effects on the microcirculation, this drug may have greater utility in patients with ischemic or venous stasis ulcers, in which a disorder of the microcirculation predominates and is characterized by platelet aggregation, leukocyte adherence, and increased viscosity. For claudication the recommended dose of pentoxifylline is 400 mg orally three times a day, preferably taken with meals to minimize its gastrointestinal side effects. In light of the data from the clinical studies, a course of pentoxifylline should be offered for 8 to 12 weeks and its effect re-evaluated by the clinician. If there has been no improvement by this time, the drug should be discontinued. Ketanserin, a selective antagonist of serotonin receptors (5HT2) has been assessed as therapy for intermittent claudication. In addition to its inhibitory action on serotonin-induced platelet aggregation, ketanserin improves hemorrheologic properties, particularly red cell deformability. However, no consistent benefit for symptoms has been observed with this agent. Antioxidant Therapy

Oxidative modification of LDL cholesterol plays an important role in the development of atherosclerosis. The endogenous antioxidant system that protects against naturally occurring free radicals consists of enzymes (glutathione reductase) and nonenzymatic antioxidant free radical scavengers (vitamins E, C, and ~-carotene). These enzymes and natural antioxidants form a synergistic, multilevel defense system against free radical injury to the endothelial cells. Accumulating data from animal experiments, epidemiologic studies, several

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large prospective cohort studies, and a few clinical trials suggest that the antioxidant vitamins E, C, and Jj-carotene, consumed either in foods or in supplements, may retard atherosclerosis and reduce the risk of cardiovascular disease. ls In patients with PAD, we employ supplements of vitamin E (400 IU) and vitamin C (1000 mg) daily. Currently, the National Heart, Lung and Blood Institute is sponsoring a large-scale study of the effect of antioxidants in patients with peripheral arterial disease. MEDICAL TREATMENT OF CRITICAL ISCHEMIA

Limb-threatening ischemia manifested as rest pain or an ischemic ulceration occurs when resting blood flow is insufficient to satisfy basic maintenance metabolic requirements for nonexercising tissue and is an absolute indication for arteriography. Several objective parameters obtained by noninvasive study may help make the decision regarding early intervention, including amputation. These include an ABI of 0.40 or less or a toe systolic pressure of less than 20 mm Hg. Although the prognosis is generally poor in patients in whom revascularization is either not feasible or contraindicated, about 30% of ischemic ulcers eventually heal with vigorous medical therapy. Local therapy to debride the thick necrotic eschar (wet-to-dry soaks or mechanical debridement) is necessary to allow re-epithelialization. Rest, pain control, protection of the ischemic limb, and intravenous antibiotic treatment of infection, if present, should be instituted without delay. Systemic anticoagulation may retard thrombosis in the stagnant circulation of the ischemic tissue and prevent further decreases in blood flow. Dextran expands plasma volume and purportedly enhances microcirculatory blood flow but is infrequently used. Despite anecdotal reports of benefit in the treatment of severe limb ischemia, no valid studies have been performed to demonstrate the efficacy of dextran. Other hemorrheologic agents such as pentoxifylline and ancrod have also not yielded consistent results. Topical epidermal growth factors have been reported to benefit venous stasis ulcers, but it is unlikely that they will be successfully applied to ischemic ulceration. Considerable interest has been generated in using prostaglandin (PG) derivatives for treatment of critical ischemia. s These agents possess platelet-antiaggregatory and cytoprotective effects that may improve the microcirculatory disturbance in these patients. Earlier preparations of prostanoids, PGE I and PGI2 , are extremely short-lived, unstable, and difficult to administer. More stable analogues of prostacyclin and PGEI can be given intravenously with beneficial effects upon critical limb ischemia. When administered as an intermittent infusion for 4 weeks, these agents reduce rest pain and improve ulcer healing in 40% to 60% of patients with critical leg ischemia and delay amputation in the majority of responding individuals during 6 to 12 months of follow-upY Similar efficacy of PGE I and PGI2 analogues is seen in patients with ulcers due to thromboangiitis obliterans and Raynaud's phenomenon. More studies are under way to better define patient selection and dose regimen. Oral forms are being developed as an alternative to intravenous therapy. FUTURE THERAPEUTIC STRATEGIES

Several new drugs are on the horizon for the symptoms of claudication, some of these with novel mechanisms of action. These include agents that

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enhance skeletal muscle oxidative metabolism, improve collateral flow, or reverse the microcirculatory derangements in patients with peripheral arterial disease. Drugs such as L-carnitine have theoretical appeal in the treatment of claudication because they favorably alter the metabolism of ischemic muscle, allowing a higher level of energy expenditure before claudication develops. L-Carnitine is a necessary factor for fatty acyl transport and metabolism by the mitochondria. In skeletal muscle ischemia, tissue levels of carnitine fall, interfering with mitochondrial metabolism of fatty acids and the subsequent generation of high-energy phosphate groups. Recent studies show significant increases in walking distance after intravenous carnitine compared with the placebo group. Currently, clinical studies on L-propionylcarnitine, an oral derivative of carnitine, are actively under way. Another investigational drug that alters the oxidative metabolism of exercising muscle is ranolazine. Ranolazine may reduce exerciseinduced skeletal muscle ischemia in patients with PAD. This effect is not due to any hemodynamic alterations induced by ranolazine but rather is thought to be due to an enhancement of oxidative metabolism, possibly by increasing the activity of pyruvate dehydrogenase. Agents that activate the potassium channels of vascular smooth muscle induce vasodilation by causing hyperpolarization of the vessel wall. Some agents of this class are under investigation as preferential vasodilators of collateral vessels. Another novel class of vasodilators are agents that enhance the activity of cGMP phosphodiesterase, which induce vasodilation by virtue of their ability to increase intracellular levels of cGMP, the intracellular second messenger for nitroglycerin and other nitrovasodilators, including endothelium-derived nitric oxide. Both classes are under clinical investigation in claudication. Intravenous administration of analogues of prostacyclin and prostaglandin El has been shown to accelerate the healing of ischemic ulcers. Oral forms are now under investigation. Because the atherosclerotic vessel makes less endogenous prostacyclin (thereby favoring vasoconstriction, platelet aggregation, and leukocyte adherence), restoration of vasodilator prostanoid levels with oral therapy has theoretical appeal. For similar reasons, therapies aimed at restoring endogenous levels of nitric oxide (NO) will likely be beneficial for patients with atherosclerotic arterial occlusive disease. Like prostacyclin, NO is a potent vasodilator, inhibits the adherence of platelets and leukocytes to the vessel wall, and decreases vascular smooth muscle proliferation. 5 In animal models, NO prevents restenosis. Indeed, the NO donor molsidomine had a modest effect on restenosis in patients undergoing coronary angioplasty in the ACCORD triaP We and others have shown that intravenous administration of the NO precursor L-arginine restores endogenous NO production and NO-dependent vasodilation in hypercholesterolemic animals and humans. More recently we have shown that by augmenting NO release chronically, oral arginine administration inhibits monocyte-endothelial interaction and prevents atherogenesis in animal models. Based on these data, human trials of arginine therapy are now under way at Stanford. The application of molecular biologic strategies to atherosclerosis has suggested novel strategies for PAD. The concept of therapeutic angiogenesis has been realized in animal models and is under investigation in patients with PAD. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. In an animal model of limb ischemia, intra-arterial injection of VEGF augmented the development of significant collateral vessels as demonstrated by angiography and histology, in association with significant hemodynamic improvement. 19 Potentially, VEGF (or other angiogenic factors) could be delivered intra-arterially as peptides. Alternatively, plasmid constructs containing the gene encoding

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these factors could be introduced into the vessel wall. The latter approach of gene transfer is appealing because a single intraluminal application could allow sustained and local generation of a therapeutic factor or inhibition of endogenous growth factors or cytokines required for the progression of vascular disease. In animal models, oligonucleotides that interfere with the production of factors required for vascular smooth muscle proliferation have been locally delivered by intraluminal administration and effectively block restenosis after balloon angioplasty. More recently, transfer of the gene encoding NO synthase has been shown to restore vascular NO production and inhibit restenosis after balloon angioplasty in an animal model. 22 The application of these molecular strategies to human disease is under intense investigation and promises to open up an exciting new chapter in vascular medicine. To conclude, although "stop smoking and keep walking"12 continues to be the cornerstone of medical treatment, the past decade has witnessed the emergence of a new paradigm for the treatment of patients with claudication. Specifically, therapies aimed at preventing the progression and complications of the disease (Le., antiplatelet, antioxidant, and aggressive antilipid therapy) have received experimental support and are achieving widespread application. Novel therapies for claudication are under development that will not only treat symptoms but will modify the disease process. Furthermore, it can be anticipated that the rate of this progress will accelerate in the next 10 years as the insights gleaned from vascular biology are translated into clinical practice.

References 1. ACCORD Study Investigators: Nitric oxide donor reduces restenosis after coronary angioplasty: The ACCORD study [abstract]. J Am Coll Cardiol59A: 1994 2. Antiplatelet Trialists' Collaboration: Secondary prevention of vascular disease by prolonged antiplatelet treatment. BMJ 296:320-331, 1988 3. Applegate W: Ankle/arm blood pressure index: A useful test for clinical practice? JAMA 270:497-498, 1993 4. Cooke J: Medical management of chronic arterial disease. In Cooke JP, Frohlich ED (eds): Current Management of Hypertensive and Vascular Diseases. St. Louis, MosbyYear Book, 1992 5. Cooke J, Tsao P: Cytoprotective effects of nitric oxide. Circulation 88:2451-2454, 1993 6. Dzau VI, Gibbons GH, Cooke JP, et al: Vascular biology and medicine in the 1990's: Scope, concepts, potentials, and perspectives. Circulation 87:705-719, 1993 7. Ernst E, Flalka V: A review of the clinical effectiveness of exercise therapy for intermittent claudication. Arch Intern Med 153:2357-2360, 1993 8. European Working Group on Critical Leg Ischemia: Second European consensus document on chronic critical leg ischemia. Circulation 84(Suppl IV):IV-I-IV-26, 1991 9. Fowkes E, Housley E, Prescott R: Edinburgh artery study. Prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Int J Epidemiol 20:384--392, 1991 10. Goldhaber S, Manson J, Hennekens C, et al: Low-dose aspirin and subsequent peripheral arterial surgery in the Physician's Health Study. Lancet 340:143-145, 1992 11. Grant S, Goa K: Iloprost: A review. Drugs 43:890-923,1992 12. Housley E: Treating claudication in five words. BMJ 296:1483-1484, 1988 13. Kannel W, McGee D: Update on some epidemiologic features of intermittent claudication: The Framingham study. J Am Geriatr Soc 33:13-18, 1985 14. Orchard T, Strandness D, et al: Assessment of peripheral vascular disease in diabetics: Report and recommendations of an international workshop. Circulation 88:819-828, 1993 15. Pentecost M, Criqui M, Dorros G, et al: Guidelines for peripheral percutaneous translu-

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minal angioplasty of the abdominal aorta and lower extremity vessels. Circulation 89:511-531, 1994 Porter J, Cutler B, Lee B, et al: Pentoxifylline efficacy in the treabnent of intermittent claudication: Multicenter controlled double-blind trial with objective assessment of chronic occlusive arterial disease patients. Am Heart J 104:66-72, 1982 Radack K, Wyderski R: Conservative management of intermittent claudication. Ann Intern Med 113:135-146, 1990 Rimm E, Stampfer M, Ascherio A, et al: Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 328:1450-1456, 1994 Takeshita S, Zheng L, Isner J: Therapeutic angiogenesis: A single intra-arterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J Clin Invest 93:662-670, 1994 Tunis S, Bass E, Steinberg E: The use of angioplasty, bypass surgery and amputation in the management of peripheral vascular disease. N Engl J Med 325:556-562, 1991 Vogt M, Wolfson S, Kuller L: Lower extremity arterial disease and the aging process: A review. J Clin EpidemioI45:529-542, 1992 Von der Leyen H, Gibbons GH, Morishita R, et al: Gene therapy inhibiting neointimal vascular lesion: In vivo transfer of ec-nitric oxide synthase gene. Proc Natl Acad Sci USA, in press

Address reprint requests to John P. Cooke, MD, PhD Section of Vascular Medicine Division of Cardiovascular Medicine Stanford University School of Medicine Stanford, CA 94305