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052401 medical treatment of peripheral arterial disease

The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne Nevertheless, patients with peripheral arterial diseaseare undertreated with regard to the use of lipid-lower-ing and antiplatelet drugs, as compared with patients A L A S T A I R J . J . W O O D , M . D. , Editor CLINICAL MANIFESTATIONS
Approximately one third of patients with periph- ARTERIAL DISEASE AND
eral arterial disease have typical claudication (Table 1), CLAUDICATION
defined as pain in one or both legs on walking, pri-marily affecting the calves, that does not go away withcontinued walking and is relieved by rest.25 In patients with claudication, the severity of the condition increas-es slowly; 25 percent have worsening claudication, and5 percent undergo an amputation within five years.26 ERIPHERAL arterial disease, which is caused Less than 5 to 10 percent of patients have critical leg by atherosclerotic occlusion of the arteries to the ischemia (ischemic pain in the distal foot, ischemic ul- legs, is an important manifestation of systemic ceration, or gangrene), but their risk of limb loss is atherosclerosis. The age-adjusted prevalence of periph- substantial.19 More than 50 percent of patients iden- eral arterial disease is approximately 12 percent, and tified as having peripheral arterial disease on the basis the disorder affects men and women equally (Table of an abnormal ankle–brachial index value do not have 1).7,8 Patients with peripheral arterial disease, even in typical claudication or limb ischemia at rest but, in- the absence of a history of myocardial infarction or stead, have other types of leg pain on exertion, with ischemic stroke, have approximately the same relative reduced ambulatory activity and quality of life.27,28 risk of death from cardiovascular causes as do patients Thus, most patients with peripheral arterial disease with a history of coronary or cerebrovascular disease have a reduced functional capacity that limits their abil- (Table 2).12,15 In patients with peripheral arterial dis- ease, the rate of death from all causes is approximate- The goals of treatment for patients with claudica- ly equal in men and women and is elevated even in tion are to relieve their exertional symptoms, improve asymptomatic patients. The severity of peripheral ar- their walking capacity, and improve their quality of terial disease is closely associated with the risk of my- life. These goals are similar for patients with critical ocardial infarction, ischemic stroke, and death from leg ischemia, with the additional goals of relieving is- vascular causes. The lower the ankle–brachial index chemic pain at rest, healing ischemic ulceration, and (Fig. 1), the greater the risk of cardiovascular events.17,18 preventing limb loss. The overall approach to the di- Patients with critical leg ischemia (the most severe agnosis and treatment of peripheral arterial disease was clinical manifestation of peripheral arterial disease), extensively reviewed in a recent consensus publication who have the lowest ankle–brachial index values, have that provides a comprehensive discussion of the med- ical and surgical therapies for the disease.29 This review The major risk factors for peripheral arterial disease will focus on risk-factor modification and antiplatelet are older age (over 40 years), cigarette smoking, and therapies, as well as strategies for symptomatic relief in diabetes mellitus. Hyperlipidemia, hypertension, and patients with peripheral arterial disease. Diagnosis and hyperhomocysteinemia are also important risk fac- management are summarized in Figures 2 and 3.
tors.5,8,20 Because of the presence of these risk factors,the systemic nature of atherosclerosis, and the high risk MODIFICATION OF RISK FACTORS
of ischemic events, patients with peripheral arterial Smoking Cessation
disease should be considered candidates for second-ary-prevention strategies that include aggressive risk- Smoking cessation slows the progression to critical factor modification and antiplatelet-drug therapy.21,22 leg ischemia and reduces the risks of myocardial infarc-tion and death from vascular causes.30 It is not certainwhether smoking cessation reduces the severity of From the Section of Vascular Medicine, Divisions of Geriatrics and Car- claudication. The authors of a meta-analysis of pub- diology, Department of Medicine, University of Colorado School of Med- lished data concluded that smoking cessation did not icine, and the Colorado Prevention Center, Denver. Address reprint re- improve maximal treadmill walking distance.31 Smok- quests to Dr. Hiatt at the Colorado Prevention Center, 789 Sherman St.,Suite 200, Denver, CO 80203, or at will.hiatt@uchsc.edu.
ing-cessation programs, nicotine-replacement therapy, 1608 · N Engl J Med, Vol. 344, No. 21 · May 24, 2001 · www.nejm.org
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*An ankle–brachial index value of less than 0.90 was considered diagnostic of peripheral arterial disease in all the studies. Dashes indicate that no data were presented.
*RR denotes relative risk, and CI confidence interval. Dashes indicate that no data were presented.
and the use of antidepressant drugs such as bupro- of atherosclerotic risk, such as serum P-selectin con- centrations.34,35 A meta-analysis was performed of ran-domized trials of lipid-lowering therapy in 698 pa- Treatment of Hyperlipidemia
tients with peripheral arterial disease who were treated Several large clinical trials have determined the ben- with a variety of therapies, including diet, cholestyr- efits of lowering cholesterol concentrations in patients amine, probucol, and nicotinic acid, for four months with coronary artery disease.33 In patients with pe- to three years.36 The total mortality was 0.7 percent ripheral arterial disease, therapy with a statin not only in the treated patients, as compared with 2.9 percent lowers serum cholesterol concentrations, but also im- in the patients given placebo — a nonsignificant dif- proves endothelial function, as well as other markers ference. This analysis also demonstrated that lipid- N Engl J Med, Vol. 344, No. 21 · May 24, 2001 · www.nejm.org · 1609
Downloaded from www.nejm.org at TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER on April 19, 2010 . Copyright 2001 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne Interpretation of ABI
Right ABI
> 1.30
Mild-to-moderate peripheral
arterial disease
Severe peripheral arterial
systolic pressure
systolic pressure
systolic pressure
systolic pressure
Figure 1. Measurement of the Ankle–Brachial Index (ABI).
Systolic blood pressure is measured by Doppler ultrasonography in each arm and in the dorsalis pedis (DP) and posterior tibial (PT)arteries in each ankle. The higher of the two arm pressures is selected, as is the higher of the two pressures in each ankle. Theright and left ankle–brachial index values are determined by dividing the higher ankle pressure in each leg by the higher arm pres-sure.16 The ranges of the ankle–brachial index values are shown, with a ratio greater than 1.30 suggesting a noncompressible, cal-cified vessel. In this condition, the true pressure at that location cannot be obtained, and additional tests are required to diagnoseperipheral arterial disease. Patients with claudication typically have ankle–brachial index values ranging from 0.41 to 0.90, and thosewith critical leg ischemia have values of 0.40 or less.
lowering therapy reduced disease progression, as meas- then randomly assigned to placebo or colestipol plus ured by angiography, and the severity of claudication.
niacin. Lipid-lowering therapy was associated with sta- Several trials have evaluated the effects of lipid-low- bilization or regression of femoral atherosclerosis.37 ering therapy on atherosclerosis in the peripheral The St. Thomas trial, in which 25 men were treated vessels. In the Cholesterol Lowering Atherosclerosis with diet, cholestyramine, nicotinic acid, or clofibrate Study, 188 men with evidence of both coronary and for an average of 19 months, demonstrated a benefi- peripheral arterial disease were treated with diet and cial effect of therapy on femoral atherosclerosis.38 In 1610 · N Engl J Med, Vol. 344, No. 21 · May 24, 2001 · www.nejm.org
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Age »70 yearsLeg pain with exertionAbnormal results on vascular Figure 2. Evaluation of Patients in Whom Peripheral Arterial Disease Is Suspected.
Patients should be evaluated for peripheral arterial disease if they are at increased risk because of their age or the presence ofatherosclerotic risk factors, have leg pain on exertion, or have distal limb ulceration for which the history and examination do notprovide an obvious explanation. Additional vascular studies can be performed in patients with an ankle–brachial index value above1.30, including pulse-volume recording, measurement of pressure in the first toe, or duplex ultrasonographic imaging of the pe-ripheral vessels, to determine whether peripheral arterial disease is present. Patients with leg pain on exertion who have ankle–brachial index values of 0.91 to 1.30 should be considered for an exercise test. An ankle–brachial index value that is over 0.90 atrest but decreases by 20 percent after exercise is diagnostic of peripheral arterial disease.16 If the initial ankle–brachial index valueis 0.90 or less at rest, the patient probably has peripheral arterial disease, and no additional tests are necessary.
contrast, the Probucol Quantitative Regression Swed- duction in serum Lp(a) lipoprotein concentrations ish Trial evaluated 303 patients with peripheral arterial in patients receiving combined therapy, as compared disease who were treated with diet and cholestyramine with a 15 percent increase in patients receiving simva- and then randomly assigned to receive probucol or statin alone (P<0.001). Peripheral arterial end points placebo for three years.39 This study found no ben- were assessed with duplex ultrasonographic imaging eficial effect of probucol (a drug that lowers serum of the femoral and tibial vessels. At the end of the low-density lipoprotein [LDL] and high-density lip- study, the number of patients in the simvastatin-only oprotein [HDL] cholesterol concentrations and has group with hemodynamically important new stenoses antioxidant properties) on femoral atherosclerosis or in their peripheral vessels had increased from 6 to 13, as compared with a decrease from 9 to 7 patients In a recent study of plasma apheresis to reduce se- in the simvastatin-plus-apheresis group (P=0.002).
rum Lp(a) lipoprotein concentrations, 42 patients Although apheresis is not a practical means of treat- with coronary artery disease were randomly assigned ing hyperlipidemia, this study suggests that high se- to simvastatin plus apheresis or simvastatin alone and rum Lp(a) lipoprotein concentrations are important followed for two years.40 There was a 19 percent re- in the development of peripheral arterial disease.
N Engl J Med, Vol. 344, No. 21 · May 24, 2001 · www.nejm.org · 1611
Downloaded from www.nejm.org at TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER on April 19, 2010 . Copyright 2001 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne Treadmill MWD and PFWDSF-36 and WIQ questionnaires Glycosylated hemoglobin <7.0%Blood pressure <130/85 mm HgAngiotensin-converting– Hemodynamic localizationDuplex ultrasonographyMagnetic resonance angiographyConventional angiography Figure 3. Evaluation and Treatment of Patients with Proved Peripheral Arterial Disease.
All patients with peripheral arterial disease, regardless of the severity of symptoms, should undergo risk-factor modification toachieve the listed treatment goals and should receive antiplatelet therapy with aspirin or clopidogrel. Angiotensin-converting–enzyme inhibitors may be considered because of the potential for prevention of ischemic events that is independent of blood-pres-sure lowering.
A treadmill test to define the maximal walking distance (MWD) and the pain-free walking distance (PFWD) can provide an objectiveassessment of the severity of claudication and the response to therapy. The functional limitations of claudication and response totherapy can also be quantified by the physical-function scales of the non–disease-specific Medical Outcomes Short Form 36 ques-tionnaire (SF-36) and the disease-specific Walking Impairment Questionnaire (WIQ). Treatment of claudication should begin withexercise therapy or drugs such as cilostazol. In patients whose condition does not improve and who remain disabled, or who haveworsening symptoms, the location of the occlusive lesions should be determined to plan endovascular or surgical intervention.
Noninvasive localization can be performed with hemodynamic tests, such as segmental-limb-pressure and pulse-volume recording.
Duplex ultrasonographic imaging and magnetic resonance angiography both have high sensitivity and specificity for the localiza-tion of lesions (with magnetic resonance angiography having the higher sensitivity), but conventional angiography is still requiredin most patients before surgery or angioplasty. Patients with critical leg ischemia typically have ankle–brachial index values of lessthan 0.40 and should initially be considered for localization of their occlusive disease in anticipation of the need for revasculariza-tion. LDL denotes low-density lipoprotein.
Two studies evaluated the effects of lipid-lowering control group. In a subgroup of patients treated with therapy on clinical end points in the leg. The Program simvastatin in the Scandinavian Simvastatin Survival on the Surgical Control of the Hyperlipidemias was Study, the relative risk of new claudication or worsen- a randomized trial of ileal-bypass surgery for the treat- ing of preexisting claudication was 0.6 (95 percent ment of hyperlipidemia in 838 patients.41 After five confidence interval, 0.4 to 0.9; absolute risk reduction, years, the relative risk of an abnormal ankle–brachial 1.3 percentage points), as compared with patients ran- index value was 0.6 (95 percent confidence interval, 0.4 to 0.9; absolute risk reduction, 15 percentage In summary, lipid-lowering therapy has benefit in points; P<0.01), and the relative risk of claudication patients with peripheral arterial disease, who often or limb-threatening ischemia was 0.7 (95 percent con- have coexisting coronary and cerebral arterial disease.
fidence interval, 0.2 to 0.9; absolute risk reduction, The current recommendation for patients with periph- 7 percentage points; P<0.01), as compared with the eral arterial disease is to achieve a serum LDL cho- 1612 · N Engl J Med, Vol. 344, No. 21 · May 24, 2001 · www.nejm.org
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lesterol concentration of less than 100 mg per deci- The use of angiotensin-converting–enzyme inhib- liter (2.6 mmol per liter) and a serum triglyceride itors in patients with peripheral arterial disease may concentration of less than 150 mg per deciliter (1.7 confer protection against cardiovascular events beyond mmol per liter).43 A statin should be given as initial that expected from blood-pressure lowering. In the therapy, but niacin is an important drug because it Heart Outcomes Prevention Evaluation Study, 4051 increases serum HDL concentrations and lowers se- of the 9297 patients (44 percent) had evidence of rum triglyceride concentrations without worsening peripheral arterial disease (ankle–brachial index val- ues of <0.90).52 In the entire study population, theprimary end point of death from vascular causes, Treatment of Diabetes Mellitus
nonfatal myocardial infarction, or stroke occurred in Intensive control of blood glucose prevents the mi- 17.7 percent of the placebo group, as compared with crovascular complications of diabetes, but its effect on 14.1 percent of the ramipril group. The efficacy of macrovascular complications is less certain. The Di- ramipril did not differ significantly between patients abetes Control and Complications Trial compared in- with peripheral arterial disease and those without it tensive and conventional insulin therapy in 1441 pa- (Fig. 4). This study not only underscores the impor- tients with type 1 diabetes. Intensive therapy was tance of including patients with peripheral arterial associated with a trend toward a reduction in cardio- disease in trials of the secondary prevention of car- vascular events (P=0.08) but had no effect on the diovascular disease, but also suggests that angioten- risk of peripheral arterial disease.45 The results were sin-converting–enzyme inhibitors reduce the risk of similar in 3867 patients with type 2 diabetes in the United Kingdom Prospective Diabetes Study, whichcompared intensive drug treatment using sulfonylu- Additional Approaches to Risk Modification
rea or insulin with dietary therapy. Intensive drug ther- A high serum homocysteine concentration is an apy was associated with a trend toward a reduction independent risk factor for peripheral arterial disease in myocardial infarction (P=0.05) but had no effect and also increases the risk of death from cardiovas- on the risk of death or amputation due to peripheral cular causes.20 Homocysteine facilitates the oxidation arterial disease (relative risk 0.6; 95 percent confidence of LDL cholesterol. Furthermore, by causing the for- interval, 0.4 to 1.2).46 These data suggest that inten- mation of reactive oxygen species, homocysteine can sive blood glucose control in patients with either promote endothelial dysfunction and the proliferation type 1 or type 2 diabetes may not favorably affect of vascular smooth-muscle cells, leading to accelera- tion of atherosclerosis.53 The causes of high serum ho-mocysteine concentrations include genetic defects in Treatment of Hypertension
homocysteine metabolism, alterations in vitamin B12 Hypertension is a major risk factor for peripheral metabolism, and dietary folate deficiency. Supplement- arterial disease (as recognized by the Joint National ing the diet with B vitamins and fortification of food Committee22), but data are not available to clarify with folate lower serum homocysteine concentra- whether treatment will alter the progression of the dis- tions.54 Despite the ease of therapy with vitamin sup- plements, there are no clinical trials demonstrating Beta-adrenergic–antagonist drugs have been that reducing serum homocysteine concentration is thought to have unfavorable effects on symptoms in beneficial in patients with peripheral arterial disease.
patients with peripheral arterial disease.22 This con- Estrogen therapy reduces several cardiovascular risk cern arose from several early case reports of worsen- factors in postmenopausal women. In a population- ing claudication and decreases in blood flow in the based study of 2196 women who had undergone nat- legs in patients taking these drugs.47 In one study, ural menopause, estrogen treatment for one year or either atenolol or the calcium-channel–blocking drug more was associated with a decrease in the incidence nifedipine, given alone, did not adversely affect skin of peripheral arterial disease, defined by an ankle–bra- temperature in the extremities or maximal treadmill chial index value of <0.90 (odds ratio, 0.5; 95 per- walking distance, but the combination of the two cent confidence interval, 0.2 to 0.8).55 The Heart and drugs reduced maximal treadmill walking distance by Estrogen/Progestin Replacement Study evaluated the 9 percent.48 In other studies, both selective and non- effects of estrogen therapy in 2763 postmenopausal selective beta-adrenergic–antagonist drugs had no ad- women with coronary artery disease.56 The incidence verse effects on the peripheral circulation in patients of peripheral arterial events (defined as aortic or ca- with peripheral arterial disease.49 A meta-analysis rotid surgery or revascularization or amputation of the and a critical review of these studies concluded that foot or leg) was unaffected by therapy. In addition, beta-adrenergic antagonists are safe in patients with estrogen therapy has been associated with reduced peripheral arterial disease, except in the most severe- graft patency in women undergoing femoropopliteal ly affected patients, in whom the drugs should be bypass surgery, possibly as a result of the prothrom- botic effects of the therapy.57 Thus, at present, estro- N Engl J Med, Vol. 344, No. 21 · May 24, 2001 · www.nejm.org · 1613
Downloaded from www.nejm.org at TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER on April 19, 2010 . Copyright 2001 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne Figure 4. Results of Ramipril Therapy in Patients with and Patients without Peripheral Arterial Disease from the Heart
Outcomes Prevention Evaluation Study.
The rate of the composite outcome of death from vascular causes, nonfatal myocardial infarction, and stroke was re-duced in patients treated with ramipril; the outcomes did not differ significantly between patients with and patientswithout peripheral arterial disease.52 Horizontal bars denote 95 percent confidence intervals. In the graph, values belowunity favor ramipril treatment.
gen has no role in the treatment of peripheral arte- who had received peripheral arterial grafts or had rial disease in postmenopausal women; however, the undergone peripheral angioplasty. The interpretation presence of peripheral arterial disease is not a con- of these results has varied. The American College of traindication to estrogen therapy in women with in- Chest Physicians recommends aspirin at doses of 81 to 325 mg per day for patients with peripheral arte-rial disease.59 In contrast, a Food and Drug Admin- Antiplatelet-Drug Therapy
istration (FDA) expert panel found insufficient evi- In patients with cardiovascular disease, antiplatelet dence to approve the labeling of aspirin as indicated drugs reduce the risks of nonfatal myocardial infarc- for patients with peripheral arterial disease.60 tion, ischemic stroke, and death from vascular causes.
Despite the lack of a statistically significant effect These conclusions are based primarily on meta-analy- of aspirin in reducing the overall risk of ischemic ses of studies of antiplatelet-drug therapy (primarily events in patients with peripheral arterial disease, as- aspirin) conducted by the Antiplatelet Trialists’ Col- pirin may favorably affect the peripheral circulation.
laboration, which included 102,459 patients who had For example, in the Physicians’ Health Study, a pri- clinical evidence of cardiovascular disease (acute or mary-prevention trial, aspirin reduced the subsequent prior myocardial infarction, ischemic stroke, or other need for peripheral arterial surgery.61 The Antiplate- vascular diseases, including peripheral arterial dis- let Trialists’ Collaboration found that aspirin therapy ease).58 The principal conclusion was that antiplate- significantly improved vascular-graft patency in 3226 let-drug therapy reduced the risk of fatal or nonfatal patients with peripheral arterial disease who were treat- cardiovascular events from 11.9 percent in the con- ed with bypass surgery (with a saphenous-vein or pros- trol group to 9.5 percent in the treatment group.
thetic graft) or peripheral angioplasty and followed Thus, aspirin is recommended for secondary disease for an average of 19 months.62 Overall, there was a prevention in patients with cardiovascular disease. The 43 percent reduction in the rate of vascular-graft oc- data supporting the use of antiplatelet drugs in pa- clusion: 25 percent in the control group as compared tients with peripheral arterial disease are described with 16 percent in the aspirin group. All the anti- platelet regimens contained aspirin. Aspirin alone wasas effective as the combination of aspirin and dipy- Aspirin
ridamole, sulfinpyrazone, or ticlopidine in preventing The analysis by the Antiplatelet Trialists’ Collabo- graft occlusion, and high-dose aspirin (600 to 1500 ration included a subgroup of 3295 patients with mg per day) was as effective as low-dose aspirin (75 to claudication. In these patients, the risk of myocardial infarction, stroke, or death from vascular causes aftera mean of 27 months of follow-up was 9.7 percent Ticlopidine
in patients who received antiplatelet therapy, as com- Ticlopidine is a thienopyridine drug that inhibits pared with 11.8 percent in control patients — a re- platelet activation by blocking platelet adenosine di- duction of 18 percent. However, the reduction was phosphate receptors. In patients with peripheral arteri- not statistically significant. Similar nonsignificant re- al disease, ticlopidine was more effective than placebo sults were obtained in a subgroup of 1928 patients in reducing the risk of fatal or nonfatal myocardial 1614 · N Engl J Med, Vol. 344, No. 21 · May 24, 2001 · www.nejm.org
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infarction or stroke.63 Ticlopidine may reduce the se- there was a nonsignificant 19 percent reduction in fa- verity of claudication and the need for vascular sur- tal and nonfatal ischemic events in the picotamide gery.64,65 However, enthusiasm for this drug is tem- group, as compared with the placebo group.69 No pered by the substantial risk of thrombocytopenia, further studies have been performed with this drug.
neutropenia (which occurs in 2.3 percent of treated Ketanserin is an antagonist of S serotonin receptors patients), and thrombotic thrombocytopenic purpu- that has antiplatelet effects. In a large trial of ketanserin ra (which occurs in 1 in 2000 to 4000 patients), in 3899 patients with peripheral arterial disease, the for which extensive hematologic monitoring is re- mortality rate was slightly, but not significantly, high- quired.66,67 This concern has led to the development er in the ketanserin group (perhaps in relation to pro- of other drugs in the thienopyridine class.
longation of the QT interval), and the drug did notrelieve claudication.70,71 Clopidogrel
In summary, patients with peripheral arterial dis- Clopidogrel is a thienopyridine drug that has few- ease have systemic atherosclerosis and are at high risk er hematologic side effects than ticlopidine. The pri- for cardiovascular disease and death. Although the mary data that support the use of clopidogrel were data are not conclusive, aspirin should be considered derived from the Clopidogrel versus Aspirin in Pa- the primary antiplatelet drug for preventing ischemic tients at Risk of Ischaemic Events (CAPRIE) trial.
events in patients with peripheral arterial disease. As- This trial compared 75 mg of clopidogrel per day pirin is also effective in maintaining vascular-graft pa- with 325 mg of aspirin per day in more than 19,000 tency and may prevent thrombotic complications of patients with recent myocardial infarction, recent is- peripheral arterial disease. Clopidogrel has FDA ap- chemic stroke, or peripheral arterial disease (6452 pa- proval for the prevention of ischemic events in patients tients).15 The patients with peripheral arterial disease with peripheral arterial disease and may be more effec- either had claudication with an ankle–brachial index tive than aspirin in these patients.
value of 0.85 or less or a history of claudication withprevious peripheral bypass surgery, angioplasty, or NONPHARMACOLOGIC THERAPY
amputation. Thus, these patients were symptomatic FOR CLAUDICATION
and had moderately severe peripheral arterial disease.
Goals of Therapy
Clopidogrel was associated with an overall reductionof 8.7 percent in the primary end point of fatal or Patients with claudication have marked impairment nonfatal ischemic stroke, fatal or nonfatal myocardial in exercise performance and overall functional capac- infarction, or death from other vascular causes (P= ity. Their peak oxygen consumption measured dur- 0.04) (Fig. 5). This result led to FDA approval of ing graded treadmill exercise is 50 percent of that in clopidogrel for the secondary prevention of athero- age-matched normal subjects, indicating a level of im- sclerotic events in patients with atherosclerosis, in- pairment similar to that among patients with New cluding those with peripheral arterial disease. In the York Heart Association class III heart failure.72 In CAPRIE trial, both clopidogrel and aspirin were well addition, patients with claudication typically report tolerated. However, a recent report described the oc- great difficulty in walking short distances, even at a currence of thrombotic thrombocytopenic purpura slow speed. Reduced walking capacity is associated early in the course of treatment with clopidogrel.68 with impairment in the performance of activities of The estimated risk of thrombotic thrombocytopenic daily living and in the quality of life.28,73 Improving purpura is 4 per million patients, a level that does mobility and improving the quality of life are impor- not warrant routine hematologic monitoring.
tant treatment goals for patients with peripheral ar- In the CAPRIE trial, there were differences in the treatment effect among patients with stroke, myocar-dial infarction, and peripheral arterial disease. In the Exercise Therapy
6452 patients with peripheral arterial disease, the The primary nonpharmacologic treatment for clau- primary end point occurred at an annual rate of 4.9 dication is a formal exercise-training program, as dem- percent in patients given aspirin and 3.7 percent in onstrated in over 20 randomized trials (albeit many patients given clopidogrel, an adjusted risk reduction with small samples).74 Exercise improves not only max- of 23.8 percent. This treatment effect was greater than imal treadmill walking distance, but also the quality that in patients with myocardial infarction or stroke, of life and community-based functional capacity (i.e., but the differences could also have occurred by chance the ability to walk at defined speeds and for defined distances).75 A rigorous exercise-training program maybe as beneficial as bypass surgery and may be more Other Antiplatelet Drugs
beneficial than angioplasty.76,77 A meta-analysis of ran- Picotamide inhibits thromboxane A synthase and domized trials found that exercise training increased blocks thromboxane A receptors. In an 18-month maximal treadmill walking distance by 179 m (95 per- trial in 2304 patients with peripheral arterial disease, cent confidence interval, 60 to 298).31 This degree of N Engl J Med, Vol. 344, No. 21 · May 24, 2001 · www.nejm.org · 1615
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Vasodilator Drugs
Vasodilator drugs, such as papaverine, were the first medications studied for the treatment of claudication, but several controlled trials have found no evidenceof clinical efficacy of drugs of this class.83 There are several pathophysiologic explanations for this finding.
During exercise, the portion of a resistance vessel lo- cated distally to a stenosis or occlusion dilates in re- sponse to ischemia. Vasodilators do not affect these vessels, whose dilation is due to endogenous factors,but they may decrease resistance in other vessels, lead- ing to a “steal” of blood flow away from the under- perfused muscle. Vasodilators can also lower systemic pressure, leading to a reduction in perfusion pressure.
Thus, current data do not support the use of vasodi- Figure 5. Results of the Clopidogrel versus Aspirin in Patients
at Risk of Ischaemic Events (CAPRIE) Trial.
In the subgroup of patients with peripheral arterial disease, theprimary end point of fatal or nonfatal myocardial infarction, fa- Pentoxifylline
tal or nonfatal stroke, or death from other vascular causes oc- Pentoxifylline is a methylxanthine derivative that curred at an annual rate of 4.9 percent in those taking aspirin improves the deformability of red cells and white cells, and 3.7 percent in those taking clopidogrel, a reduction of 23.8percent. This reduction was greater than that in the subgroups lowers plasma fibrinogen concentrations, and has an- of patients with myocardial infarction or stroke.15 Horizontal tiplatelet effects.84 The drug was approved in 1984 for bars denote 95 percent confidence intervals.
the treatment of claudication. In one of the first ran-domized trials, pentoxifylline increased maximal tread-mill walking distance by 12 percent as compared withplacebo, but there was no difference between the twogroups in the increase in maximal treadmill walkingdistance as compared with base-line values (Table 3).85 improvement should translate into longer walking dis- Another study found a nonsignificant increase of 21 percent in maximal treadmill walking distance in pa- Although exercise therapy is clearly effective, it has tients treated with pentoxifylline as compared with several limitations. The best results require a motivat- placebo.86 Similarly, in a recent study pentoxifylline ed patient in a supervised setting, typically modeled was no more effective than placebo in increasing max- after cardiac rehabilitation.78 However, supervised ex- imal treadmill walking distance or functional status as ercise-training programs are not covered by medical assessed by questionnaires.87 A meta-analysis of the insurance, which prevents their widespread use. Ex- pentoxifylline studies found a net benefit of 44 m in ercise training must also be maintained on a regular the maximal distance walked on a treadmill (95 per- basis, or the benefits will be lost. Thus, although ex- cent confidence interval, 14 to 74).31 This and anoth- ercise is recommended as the initial treatment for pa- er meta-analysis and two systematic reviews of pentox- tients with claudication (Fig. 3), lack of availability and ifylline concluded that the drug may have a small effect insurance coverage limit the overall effectiveness of on walking ability, but that the data are insufficient to Several studies have examined the mechanisms by which exercise training exerts its benefits. Exercise Cilostazol
training is not associated with substantial changes in Cilostazol was approved in 1999 by the FDA for blood flow to the legs, and the changes that occur do the treatment of claudication. The primary action of not predict the clinical response.79 Despite the absence cilostazol is to inhibit phosphodiesterase type 3, there- of a hemodynamic effect, exercise training improves by increasing intracellular concentrations of cyclic oxygen extraction in the legs.80 The intermediary me- AMP. Cilostazol undergoes extensive hepatic me- tabolism of skeletal muscle is also favorably affected tabolism by the 3A4 isoform of cytochrome P450 by training, as evidenced by an improvement in mus- (CYP3A4) and to a lesser extent by the 2C19 and cle carnitine metabolism.81 Finally, alterations in gait 1A2 isoforms. Although the drug does not inhibit and walking efficiency may contribute to the training the cytochrome CYP450 enzyme system, other drugs response. At submaximal workloads, training results that inhibit CYP3A4 may increase serum cilostazol in a decrease in oxygen consumption and thus im- concentrations.103 Cilostazol inhibits platelet aggrega- tion, the formation of arterial thrombi, and vascular 1616 · N Engl J Med, Vol. 344, No. 21 · May 24, 2001 · www.nejm.org
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smooth-muscle proliferation and causes vasodilata- perior to both placebo and pentoxifylline.87 In three tion.104-106 However, as discussed above, vasodilator of the trials, cilostazol also improved several aspects and antiplatelet drugs do not improve claudication- of physical functioning and the quality of life, as as- limited exercise performance, and therefore the mech- sessed by questionnaires.89-91 The drug also causes anism of effect of cilostazol in peripheral arterial dis- small increases in ankle–brachial index values and rais- es serum HDL cholesterol concentrations.90 Type 3 phosphodiesterase inhibitors such as milri- The predominant side effect of cilostazol is head- none were developed as inotropic agents for the treat- ache, which affects 34 percent of patients taking 100 ment of heart failure. In patients with chronic heart mg twice daily, as compared with 14 percent of pa- failure, milrinone treatment was associated with an in- tients taking placebo (data presented to the FDA Car- crease in mortality.107 In comparison with milrinone, diovascular and Renal Drugs Advisory Committee cilostazol has fewer cardiac inotropic effects but equiv- on July 9, 1998). In addition, transient diarrhea, pal- alent vasodilating and platelet-inhibiting properties.108 pitations, and dizziness have been described. Cilosta- Four randomized, placebo-controlled trials of cil- zol can be administered with aspirin, but there are ostazol enrolling 1534 patients with claudication have no data on the safety of coadministration of cilosta- been published (Table 3 and Fig. 6).87,89-91 In all four zol with clopidogrel. Because of concern about the trials, cilostazol (100 mg twice daily) improved both risk of death with this class of drugs, data from more pain-free and maximal treadmill walking distance, as than 2000 patients who were followed for up to six compared with placebo. Cilostazol (50 mg twice dai- months were presented to the FDA. Death from car- ly) also increased maximal treadmill walking distance.91 diovascular causes occurred in 0.6 percent of cilosta- In one trial, cilostazol (100 mg twice daily) was su- zol-treated patients and 0.5 percent of placebo-treat- TABLE 3. DRUG THERAPIES FOR PATIENTS WITH CLAUDICATION.
*Net MWD is the net improvement in maximal treadmill walking distance with the drug as compared †NS indicates a result reported as not significant but with no P value provided.
‡Functional assessment involved the use of questionnaires to assess the effect of treatment on the quality of life. ND denotes not done.
N Engl J Med, Vol. 344, No. 21 · May 24, 2001 · www.nejm.org · 1617
Downloaded from www.nejm.org at TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER on April 19, 2010 . Copyright 2001 Massachusetts Medical Society. All rights reserved. The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne ed patients. Myocardial infarction occurred in 1.5 tive than levocarnitine in improving maximal treadmill percent of cilostazol-treated patients and 1.1 percent walking distance.113 In two multicenter trials enroll- of placebo-treated patients. Because of the experience ing 730 patients, the pain-free and maximal treadmill with milrinone, the cilostazol label includes a black- walking distance improved more in patients receiving box warning that cilostazol should not be given to pa- propionyl levocarnitine than in those receiving pla- tients with claudication who also have heart failure.
cebo.95,96 The drug also improved the quality of lifemore than placebo and had fewer side effects.96 Pro- Naftidrofuryl
pionyl levocarnitine has not been approved for use Naftidrofuryl has been available for several decades in Europe for treating claudication. Several mecha-nisms of action have been proposed, including antag- Prostaglandins
onism of 5-hydroxytryptamine receptors. A critical Prostaglandins have been evaluated primarily for the review of five placebo-controlled trials concluded that treatment of patients with critical leg ischemia. The naftidrofuryl improved pain-free treadmill walking primary end points of these trials were relief of ische- distance, but not maximal walking distance (Table 3), mic pain, healing of ischemic ulcers, and reduction in and was associated with fewer cardiovascular events the rate of amputation.114,115 Fewer studies have been than placebo.109 This drug is not available in the Unit- performed in patients with claudication. A study of 90 such patients found that parenteral administrationof prostaglandin E in a formulation of lipid micro- Levocarnitine and Propionyl Levocarnitine
spheres improved maximal treadmill walking distance In patients with peripheral arterial disease, meta- and quality of life.97 Oral analogues of prostaglandins bolic abnormalities develop in the skeletal muscles of have not been as well studied. A small trial found the lower extremities.110 These abnormalities include that beraprost was moderately efficacious, but at high- impairment of the activity of the mitochondrial elec- er doses it had substantial side effects, such as head- tron-transport chain in the ischemic muscles and ac- ache, flushing, and gastrointestinal intolerance.99 A re- cumulation of intermediates of oxidative metabolism cent study found that beraprost had positive effects (acylcarnitines).111,112 Exercise performance is most im- on maximal treadmill walking distance and the qual- paired in patients with the greatest accumulation of ity of life (Table 3) and reduced the rate of critical acylcarnitines in muscle. Thus, claudication is caused cardiovascular events.100 The use of prostaglandins in not just by reduced blood flow, but also by alterations patients with peripheral arterial disease needs fur- Levocarnitine and propionyl levocarnitine may im- prove metabolism and exercise performance of ische- Other Drugs
mic muscles. Levocarnitine, 2 g twice daily, improved Treatment with chelation, vitamin E, or testoster- maximal treadmill walking distance, but propionyl le- one has no effect on claudication.116-118 Treatments that vocarnitine (an acyl form of carnitine) was more effec- have had promising results in preliminary studies in- Figure 6. Results of Four Randomized, Placebo-Controlled Trials of Cilostazol for the Treatment of Clau-
The data are shown as the geometric mean ratios of the maximal treadmill walking distance (on thehorizontal axis) and 95 percent confidence intervals for cilostazol as compared with placebo.87,89-91 1618 · N Engl J Med, Vol. 344, No. 21 · May 24, 2001 · www.nejm.org
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Hamdee y

Hamdee Y. Attallah, M.D. Office Address: Division of Endocrinology, Diabetes and Metabolism Education: 1992 B.S. Wayne State University, Detroit, MI M.D. Wayne State University, Detroit, MI Training: 2001-2005 Postdoctoral research fellow, Endocrinology, Diabetes and Metabolism, Stanford University, Stanford, CA Clinical fellow, Endocrinology, Diabetes and M

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