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randomized patients. Those who underwent surgery had a lower incidence of intermittent claudication or limb-threatening ischemia. More recently, a post-hoc analysis of the Scandinavian Simvastatin Survival Study (4S) found that treatment with 20 – 40 mg/day of simvastatin reduced the incidence of new or worsening intermittent claudication by 38% (3). No controlled trials have been conducted evaluating the effects of diabetic and antihypertensive therapy on the natural history of peripheral vascular disease. The beneficial impact of strict glycemic control upon the development of microvascular lesions observed in recent trials may, however, translate to a reduction in claudication. In addition, despite the absence of evidence relating the treatment of hypertension to a reduction in PAD progression, blood pressure should be optimized in patients with PAD to reduce morbidity from cardiovascular and cerebrovascular disease. Antiplatelet drugs, which are a cornerstone of therapy for patients with coronary or cerebrovascular atherosclerosis, were also evaluated for potential benefits in patients with intermittent claudication. In the Physicians Health Study, 325 mg of aspirin every other day did not reduce claudication, although it decreased the need for peripheral vascular surgery. In another study, combination therapy with aspirin and dipyridamole increased the pain-free walking distance and resting limb blood flow in a study of 54 patients with intermittent claudication. Ticlopidine, an adenosine diphosphate receptor antagonist that effectively inhibits platelet aggregation, modestly increased the walking distance in patients with intermittent claudication. The usual dose is 250 mg twice daily with food. Patients taking ticlopidine must be monitored closely for the development of neutropenia and thrombotic thrombocytopenic purpura. A newer adenosine diphosphate receptor antagonist, clopidogrel, was studied in the Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial where it was found more effective than aspirin in reducing cardiovascular and cerebrovascular events (4). There was no significant neutropenia compared with aspirin in the CAPRIE trial, and thus blood monitoring is not necessary with this medication. Although data is limited involving the use of clopidogrel in patients with claudication, it is likely that this agent has a similar beneficial effect.
Current and Emerging Therapies for Lower Extremity Peripheral Arterial Disease Bruce Klugherz, MD and Emile R. Mohler, III, MD, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania ower extremity peripheral arterial disease (PAD) usually results from atherosclerosis. The prevalence of this condition is approximately 20% in men and 13% in women older than 70 years (1). Intermittent claudication, the principal manifestation of PAD, is estimated to occur in 5% of men and 2.5% of women older than 60 years. Intermittent claudication, defined as reproducible discomfort of a muscle group that intensifies during walking and is relieved by rest, is the result of a mismatch between energy supply and metabolic demand in skeletal muscle perfused by atherosclerotic vasculature. The disease may progress to critical limb ischemia, defined as pain occurring at rest or the presence of ischemic ulcers that jeopardize the limbs. The 5-year amputation rate following presentation with claudication is approximately 5%. However, the 5-year mortality rate of patients with PAD approaches 30% due to cardiovascular and cerebrovascular events. The principal goals of pharmacotherapy for PAD include the following: (1) prevention of progression to critical limb ischemia and other life-threatening cardiovascular events, (2) improvement in pain-free walking distance and (3) noninvasive treatment of critical limb ischemia.
Prevention of Progression Evidence is accumulating that modification of risk factors for PAD may reduce the incidence of progression to critical limb ischemia. The principal risk factors for PAD include cigarette smoking, diabetes mellitus, hypertension and hyperlipidemia. Cessation of cigarette smoking reduces disease progression, as shown by lower amputation rates and lower incidences of rest ischemia. In one study of 343 patients with intermittent claudication, no patient who ceased smoking developed rest pain, whereas 16% of those who continued to smoke developed rest pain (2). Treatment of hyperlipidemia also retards the progression of lower limb PAD. The Cholesterol Lowering Atherosclerosis Study (CLAS) was a randomized, placebo-controlled angiographic trial testing colestipol-niacin plus diet therapy among nonsmoking men with previous coronary bypass surgery. A significant benefit of lipid reduction on angiographic progression of disease was noted in femoral arteries. The Program on Surgical Control of the Hyperlipidemias (POSCH) trial evaluated the effect of partial ileal bypass surgery on cholesterol levels among 838
Improvement in Pain-Free Walking Distance Supervised exercise is the principal nonpharmacologic intervention proven to alleviate claudication. A meta-analysis of 21 published studies found that exercise training increased the distance to onset of claudication by 179% (5). The optimal exercise program consists of more than 30 minutes of exercise per session at least 3 times per week, walking to near maximal discomfort during training, for a program duration of 6 months.
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Pentoxifylline (Trental) and cilostazol (Pletal) are the only two Food and Drug Administration–approved pharmaceuticals for the treatment of claudication. The mechanism of symptom relief with pentoxifylline remains poorly understood. Pentoxifylline improves red blood cell deformity and reduces fibrinogen concentration, platelet adhesiveness and whole blood viscosity, any of which effects may be responsible. The usual dose is 400 mg 3 times daily with meals. Studies on the efficacy of pentoxifylline, however, have yielded conflicting results. A meta-analysis found that pentoxifylline improved walking distance by 29 meters over placebo. The improvement was approximately 50% compared with baseline in the placebo group, whereas pentoxifylline provided an additional 30% improvement. Cilostazol is a recently approved agent whose mechanisms of action include inhibition of platelet aggregation and vasodilation through phosphodiesterase III inhibition. The standard dose is 100 mg twice daily ingested on an empty stomach, although 50 mg twice daily should be considered when coadministered with drugs such as ketoconazole, erythromycin, diltiazem or omeprazole. Cilostazol is also contraindicated in patients with congestive heart failure of any severity. In one study of 81 patients with moderately severe claudication treated for 12 weeks, cilostazol increased initial claudication distance and maximum distance walked by 35% and 41%, respectively (6). A second, 16-week randomized trial of 239 patients found that cilostazol increased the maximum distance walked by 41%, compared with a 15% increase with placebo (7). A number of investigational agents are being examined for potential benefit in alleviating claudication. Naftidrofuryl, for example, is a 5-hydroxytryptamine-2 receptor antagonist currently available only in Europe. A meta-analysis of four studies using this agent showed an increase in treadmill tolerance over a 3- to 6-month period (8). Propionyl-Lcarnitine is another investigational agent that is believed to improve energy metabolism in ischemic muscle. A single randomized study demonstrated a 73% improvement in maximal walking distance among patients taking this drug, compared with a 46% improvement for placebo (9). Finally, prostaglandin E1, a vasodilator and inhibitor of platelet aggregation, has been evaluated experimentally. A recent study involving intravenous administration of prostaglandin E1 to 80 patients with intermittent claudication demonstrated a dose-related improvement in walking distance and quality of life at 4 and 8 weeks (10). Because of their short half-life, however, parenterally administered prostanoids may find their greatest use in patients with more severe, limb-threatening PAD.
didates for revascularization is associated with a perioperative mortality exceeding 5% for below-the-knee amputation and 15% for above-the-knee amputation. Full mobility is achieved less than half the time, and 2-year mortality following successful amputation is approximately 40%. Aside from amputation, nonpharmacologic treatment of critical leg ischemia consists primarily of revascularization by percutaneous interventional or surgical reconstructive techniques. Prostanoids have emerged as a promising alternative to invasive management of critical leg ischemia. These agents exhibit several attractive pharmacologic properties, including inhibition of activation, adhesion and aggregation of platelets, vasodilation, vascular endothelial cytoprotection, inhibition of leukocyte activation and antithrombotic and profibrinolytic properties. A meta-analysis of seven trials of prostanoids among patients with critical leg ischemia who were ineligible for revascularization demonstrated improved pain relief and reduced ulcer size in treated patients (11). A recent multicenter randomized open-label study evaluated the safety and efficacy of prostaglandin E1 alprostadil-alphacyclodextrine, administered as a daily IV infusion, among 1,560 inpatients with critical leg ischemia. Treated patients had a modestly lower frequency of the combined end point (death, myocardial infarction, stroke, major amputation or persistence of critical leg ischemia) both at hospital discharge and during 6 months of follow-up, although the difference at the latter end point was not statistically significant (12). Other prostacylclin analogues are also currently undergoing evaluation in patients with severe PAD. At present, there are no approved prostanoids for treatment of PAD in the United States. Gene therapy using DNA encoding angiogenic factors is another avenue of ongoing investigation. The administration of gene encoding vascular endothelial growth factor demonstrated marked increased collateral formation as assessed by contrast arteriography and magnetic resonance angiography, as well as clinical improvement in the majority of patients in an uncontrolled study (13). Larger controlled studies will be necessary to confirm these preliminary observations before intramuscular gene transfer achieves widespread acceptance. Conclusion The new millenium holds promise for patients suffering with claudication and critical leg ischemia. Current therapy with antiplatelet agents and cholesterol lowering drugs reduces risk of amputation and cardiovascular events in patients with PAD. A treatment program consisting of supervised exercise and phrarmacologic therapy will improve pain-free walking distance in most patients with intermittent claudication. As novel strategies emerge for the treatment of PAD, it is hoped that these patients will experience further improvements in quality of life and prolonged survival.
Noninvasive Treatment of Critical Leg Ischemia The prognosis for patients with critical leg ischemia is dismal. Limb amputation among patients not considered can-
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claudication: A retrospective analysis. J Cardiovasc Pharmacol 1994; 23(Suppl 3):S48 –52.
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9. Brevetti G, Perna S, Sabba C, Martone VD, Condorelli M. Propionyl-Lcarnitine in intermittent claudication: Double-blind, placebo-controlled, dose titration, multicenter study. J Am Coll Cardiol 1995;26:1411– 6. 10. Belch JJ, Bell PR, Creissen D, et al. Randomized, double-blind, placebocontrolled study evaluating the efficacy and safety of AS-013, a prostaglandin E1 prodrug, in patients with intermittent claudication. Circulation 1997;95:2298 –302. 11. Loosemore TM, Chalmers TC, Dormandy JA. A meta-analysis of randomized placebo control trials in Fontaine stages III and IV peripheral occlusive arterial disease. Int Angiology 1994;13:133– 42. 12. ICAI Study Group. Prostanoids for chronic critical leg ischemia. A randomized, controlled, open-label trial with prostaglandin E1. Ann Intern Med 1999;130:412–21. 13. Baumgartner I, Pieczek A, Manor O, et al. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 1998;97: 1114 –23.
Address correspondence and reprint requests to Emile R. Mohler, III, MD, University of Pennsylvania Health System, 432, Philadelphia Heart Institute, 51 North 39th Street, Philadelphia, PA 19104.
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