_____

The New England Journal of Medicine -- May 24, 2001 -- Vol. 344, No. 21
REVIEW ARTICLE

Drug Therapy: Medical Treatment of Peripheral Arterial Disease and
Claudication

William R. Hiatt
  _____


  _____

Peripheral arterial disease, which is caused by atherosclerotic occlusion of
the arteries to the legs, is an important manifestation of systemic
atherosclerosis. The age-adjusted prevalence of peripheral arterial disease
is approximately 12 percent, and the disorder affects men and women equally
( Table 1
<http://www.nejm.org/content/figs/2001/0344/0021/1608.asp?section=T1> ). ( 7
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-7> , 8
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-8> ) Patients
with peripheral arterial disease, even in the absence of a history of
myocardial infarction or ischemic stroke, have approximately the same
relative risk of death from cardiovascular causes as do patients with a
history of coronary or cerebrovascular disease ( Table 2
<http://www.nejm.org/content/figs/2001/0344/0021/1608.asp?section=T2> ).
 12 <http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-12> , 15
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-15> ) In
patients with peripheral arterial disease, the rate of death from all causes
is approximately equal in men and women and is elevated even in asymptomatic
patients. The severity of peripheral arterial disease is closely associated
with the risk of myocardial infarction, ischemic stroke, and death from
vascular causes. The lower the ankle-brachial index ( Figure 1
<http://www.nejm.org/content/figs/2001/0344/0021/1608.asp?section=F1> ), the
greater the risk of cardiovascular events. ( 17
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-17> , 18
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-18> ) Patients
with critical leg ischemia (the most severe clinical manifestation of
peripheral arterial disease), who have the lowest ankle-brachial index
values, have an annual mortality of 25 percent. ( 19
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-19> )
The major risk factors for peripheral arterial disease are older age (over
40 years), cigarette smoking, and diabetes mellitus. Hyperlipidemia,
hypertension, and hyperhomocysteinemia are also important risk factors. ( 5
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-5> , 8
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-8> , 20
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-20> ) Because
of the presence of these risk factors, the systemic nature of
atherosclerosis, and the high risk of ischemic events, patients with
peripheral arterial disease should be considered candidates for
secondary-prevention strategies that include aggressive risk-factor
modification and antiplatelet-drug therapy. ( 21
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-21> , 22
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-22> )
Nevertheless, patients with peripheral arterial disease are undertreated
with regard to the use of lipid-lowering and antiplatelet drugs, as compared
with patients with coronary artery disease. ( 23
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-23> , 24
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-24> )

Clinical Manifestations

Approximately one third of patients with peripheral arterial disease have
typical claudication ( Table 1
<http://www.nejm.org/content/figs/2001/0344/0021/1608.asp?section=T1> ),
defined as pain in one or both legs on walking, primarily affecting the
calves, that does not go away with continued walking and is relieved by
rest. ( 25
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-25> ) In
patients with claudication, the severity of the condition increases slowly;
25 percent have worsening claudication, and 5 percent undergo an amputation
within five years. ( 26
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-26> ) Less
than 5 to 10 percent of patients have critical leg ischemia (ischemic pain
in the distal foot, ischemic ulceration, or gangrene), but their risk of
limb loss is substantial. ( 19
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-19> ) More
than 50 percent of patients identified as having peripheral arterial disease
on the basis of an abnormal ankle-brachial index value do not have typical
claudication or limb ischemia at rest but, instead, have other types of leg
pain on exertion, with reduced ambulatory activity and quality of life. ( 27
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-27> , 28
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-28> ) Thus,
most patients with peripheral arterial disease have a reduced functional
capacity that limits their ability to perform daily activities.
The goals of treatment for patients with claudication are to relieve their
exertional symptoms, improve their walking capacity, and improve their
quality of life. These goals are similar for patients with critical leg
ischemia, with the additional goals of relieving ischemic pain at rest,
healing ischemic ulceration, and preventing limb loss. The overall approach
to the diagnosis and treatment of peripheral arterial disease was
extensively reviewed in a recent consensus publication that provides a
comprehensive discussion of the medical and surgical therapies for the
disease. ( 29
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-29> ) This
review will focus on risk-factor modification and antiplatelet therapies, as
well as strategies for symptomatic relief in patients with peripheral
arterial disease. Diagnosis and management are summarized in Figure 2
<http://www.nejm.org/content/figs/2001/0344/0021/1608.asp?section=F2>  and
Figure 3
<http://www.nejm.org/content/figs/2001/0344/0021/1608.asp?section=F3> .

Modification of Risk Factors

Smoking Cessation
Smoking cessation slows the progression to critical leg ischemia and reduces
the risks of myocardial infarction and death from vascular causes. ( 30
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-30> ) It is
not certain whether smoking cessation reduces the severity of claudication.
The authors of a meta-analysis of published data concluded that smoking
cessation did not improve maximal treadmill walking distance. ( 31
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-31> )
Smoking-cessation programs, nicotine-replacement therapy, and the use of
antidepressant drugs such as bupropion should be encouraged. ( 32
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-32> )
Treatment of Hyperlipidemia
Several large clinical trials have determined the benefits of lowering
cholesterol concentrations in patients with coronary artery disease. ( 33
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-33> ) In
patients with peripheral arterial disease, therapy with a statin not only
lowers serum cholesterol concentrations, but also improves endothelial
function, as well as other markers of atherosclerotic risk, such as serum
P-selectin concentrations. ( 34
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-34> , 35
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-35> ) A
meta-analysis was performed of randomized trials of lipid-lowering therapy
in 698 patients with peripheral arterial disease who were treated with a
variety of therapies, including diet, cholestyramine, probucol, and
nicotinic acid, for four months to three years. ( 36
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-36> ) The
total mortality was 0.7 percent in the treated patients, as compared with
2.9 percent in the patients given placebo -- a nonsignificant difference.
This analysis also demonstrated that lipid-lowering therapy reduced disease
progression, as measured by angiography, and the severity of claudication.
Several trials have evaluated the effects of lipid-lowering therapy on
atherosclerosis in the peripheral vessels. In the Cholesterol Lowering
Atherosclerosis Study, 188 men with evidence of both coronary and peripheral
arterial disease were treated with diet and then randomly assigned to
placebo or colestipol plus niacin. Lipid-lowering therapy was associated
with stabilization or regression of femoral atherosclerosis. ( 37
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-37> ) The St.
Thomas trial, in which 25 men were treated with diet, cholestyramine,
nicotinic acid, or clofibrate for an average of 19 months, demonstrated a
beneficial effect of therapy on femoral atherosclerosis. ( 38
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-38> ) In
contrast, the Probucol Quantitative Regression Swedish Trial evaluated 303
patients with peripheral arterial disease who were treated with diet and
cholestyramine and then randomly assigned to receive probucol or placebo for
three years. ( 39
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-39> ) This
study found no beneficial effect of probucol (a drug that lowers serum
low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol
concentrations and has antioxidant properties) on femoral atherosclerosis or
ankle-brachial index values.
In a recent study of plasma apheresis to reduce serum Lp(a) lipoprotein
concentrations, 42 patients with coronary artery disease were randomly
assigned to simvastatin plus apheresis or simvastatin alone and followed for
two years. ( 40
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-40> ) There
was a 19 percent reduction in serum Lp(a) lipoprotein concentrations in
patients receiving combined therapy, as compared with a 15 percent increase
in patients receiving simvastatin alone (P<0.001). Peripheral arterial end
points were assessed with duplex ultrasonographic imaging of the femoral and
tibial vessels. At the end of the study, the number of patients in the
simvastatin-only group with hemodynamically important new stenoses in their
peripheral vessels had increased from 6 to 13, as compared with a decrease
from 9 to 7 patients in the simvastatin-plus-apheresis group (P=0.002).
Although apheresis is not a practical means of treating hyperlipidemia, this
study suggests that high serum Lp(a) lipoprotein concentrations are
important in the development of peripheral arterial disease.
Two studies evaluated the effects of lipid-lowering therapy on clinical end
points in the leg. The Program on the Surgical Control of the
Hyperlipidemias was a randomized trial of ileal-bypass surgery for the
treatment of hyperlipidemia in 838 patients. ( 41
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-41> ) After
five years, the relative risk of an abnormal ankle-brachial index value was
0.6 (95 percent confidence interval, 0.4 to 0.9; absolute risk reduction, 15
percentage points; P<0.01), and the relative risk of claudication or
limb-threatening ischemia was 0.7 (95 percent confidence interval, 0.2 to
0.9; absolute risk reduction, 7 percentage points; P<0.01), as compared with
the control group. In a subgroup of patients treated with simvastatin in the
Scandinavian Simvastatin Survival Study, the relative risk of new
claudication or worsening of preexisting claudication was 0.6 (95 percent
confidence interval, 0.4 to 0.9; absolute risk reduction, 1.3 percentage
points), as compared with patients randomly assigned to placebo. ( 42
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-42> )
In summary, lipid-lowering therapy has benefit in patients with peripheral
arterial disease, who often have coexisting coronary and cerebral arterial
disease. The current recommendation for patients with peripheral arterial
disease is to achieve a serum LDL cholesterol concentration of less than 100
mg per deciliter (2.6 mmol per liter) and a serum triglyceride concentration
of less than 150 mg per deciliter (1.7 mmol per liter). ( 43
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-43> ) A statin
should be given as initial therapy, but niacin is an important drug because
it increases serum HDL concentrations and lowers serum triglyceride
concentrations without worsening glucose metabolism in these patients. ( 44
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-44> )
Treatment of Diabetes Mellitus
Intensive control of blood glucose prevents the microvascular complications
of diabetes, but its effect on macrovascular complications is less certain.
The Diabetes Control and Complications Trial compared intensive and
conventional insulin therapy in 1441 patients with type 1 diabetes.
Intensive therapy was associated with a trend toward a reduction in
cardiovascular events (P=0.08) but had no effect on the risk of peripheral
arterial disease. ( 45
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-45> ) The
results were similar in 3867 patients with type 2 diabetes in the United
Kingdom Prospective Diabetes Study, which compared intensive drug treatment
using sulfonylurea or insulin with dietary therapy. Intensive drug therapy
was associated with a trend toward a reduction in myocardial infarction
(P=0.05) but had no effect on the risk of death or amputation due to
peripheral arterial disease (relative risk 0.6; 95 percent confidence
interval, 0.4 to 1.2). ( 46
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-46> ) These
data suggest that intensive blood glucose control in patients with either
type 1 or type 2 diabetes may not favorably affect peripheral arterial
disease.
Treatment of Hypertension
Hypertension is a major risk factor for peripheral arterial disease (as
recognized by the Joint National Committee ( 22
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-22> )), but
data are not available to clarify whether treatment will alter the
progression of the disease or the risk of claudication.
Beta-adrenergic-antagonist drugs have been thought to have unfavorable
effects on symptoms in patients with peripheral arterial disease. ( 22
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-22> ) This
concern arose from several early case reports of worsening claudication and
decreases in blood flow in the legs in patients taking these drugs. ( 47
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-47> ) In one
study, either atenolol or the calcium-channel-blocking drug nifedipine,
given alone, did not adversely affect skin temperature in the extremities or
maximal treadmill walking distance, but the combination of the two drugs
reduced maximal treadmill walking distance by 9 percent. ( 48
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-48> ) In other
studies, both selective and nonselective beta-adrenergic-antagonist drugs
had no adverse effects on the peripheral circulation in patients with
peripheral arterial disease. ( 49
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-49> ) A
meta-analysis and a critical review of these studies concluded that
beta-adrenergic antagonists are safe in patients with peripheral arterial
disease, except in the most severely affected patients, in whom the drugs
should be administered with caution. ( 50
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-50> , 51
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-51> )
The use of angiotensin-converting-enzyme inhibitors in patients with
peripheral arterial disease may confer protection against cardiovascular
events beyond that expected from blood-pressure lowering. In the Heart
Outcomes Prevention Evaluation Study, 4051 of the 9297 patients (44 percent)
had evidence of peripheral arterial disease (ankle-brachial index values of
<0.90). ( 52
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-52> ) In the
entire study population, the primary end point of death from vascular
causes, nonfatal myocardial infarction, or stroke occurred in 17.7 percent
of the placebo group, as compared with 14.1 percent of the ramipril group.
The efficacy of ramipril did not differ significantly between patients with
peripheral arterial disease and those without it ( Figure 4
<http://www.nejm.org/content/figs/2001/0344/0021/1608.asp?section=F4> ).
This study not only underscores the importance of including patients with
peripheral arterial disease in trials of the secondary prevention of
cardiovascular disease, but also suggests that angiotensin-converting-enzyme
inhibitors reduce the risk of ischemic events in these patients.
Additional Approaches to Risk Modification
A high serum homocysteine concentration is an independent risk factor for
peripheral arterial disease and also increases the risk of death from
cardiovascular causes. ( 20
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-20> )
Homocysteine facilitates the oxidation of LDL cholesterol. Furthermore, by
causing the formation of reactive oxygen species, homocysteine can promote
endothelial dysfunction and the proliferation of vascular smooth-muscle
cells, leading to acceleration of atherosclerosis. ( 53
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-53> ) The
causes of high serum homocysteine concentrations include genetic defects in
homocysteine metabolism, alterations in vitamin B12 metabolism, and dietary
folate deficiency. Supplementing the diet with B vitamins and fortification
of food with folate lower serum homocysteine concentrations. ( 54
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-54> ) Despite
the ease of therapy with vitamin supplements, there are no clinical trials
demonstrating that reducing serum homocysteine concentration is beneficial
in patients with peripheral arterial disease.
Estrogen therapy reduces several cardiovascular risk factors in
postmenopausal women. In a population-based study of 2196 women who had
undergone natural menopause, estrogen treatment for one year or more was
associated with a decrease in the incidence of peripheral arterial disease,
defined by an ankle-brachial index value of <0.90 (odds ratio, 0.5; 95
percent confidence interval, 0.2 to 0.8). ( 55
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-55> ) The
Heart and Estrogen/Progestin Replacement Study evaluated the effects of
estrogen therapy in 2763 postmenopausal women with coronary artery disease.
( 56 <http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-56> ) The
incidence of peripheral arterial events (defined as aortic or carotid
surgery or revascularization or amputation of the foot or leg) was
unaffected by therapy. In addition, estrogen therapy has been associated
with reduced graft patency in women undergoing femoropopliteal bypass
surgery, possibly as a result of the prothrombotic effects of the therapy.
 57 <http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-57> )
Thus, at present, estrogen has no role in the treatment of peripheral
arterial disease in postmenopausal women; however, the presence of
peripheral arterial disease is not a contraindication to estrogen therapy in
women with indications for such therapy.
Antiplatelet-Drug Therapy
In patients with cardiovascular disease, antiplatelet drugs reduce the risks
of nonfatal myocardial infarction, ischemic stroke, and death from vascular
causes. These conclusions are based primarily on meta-analyses of studies of
antiplatelet-drug therapy (primarily aspirin) conducted by the Antiplatelet
Trialists' Collaboration, which included 102,459 patients who had clinical
evidence of cardiovascular disease (acute or prior myocardial infarction,
ischemic stroke, or other vascular diseases, including peripheral arterial
disease). ( 58
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-58> ) The
principal conclusion was that antiplatelet-drug therapy reduced the risk of
fatal or nonfatal cardiovascular events from 11.9 percent in the control
group to 9.5 percent in the treatment group. Thus, aspirin is recommended
for secondary disease prevention in patients with cardiovascular disease.
The data supporting the use of antiplatelet drugs in patients with
peripheral arterial disease are described below.
Aspirin
The analysis by the Antiplatelet Trialists' Collaboration included a
subgroup of 3295 patients with claudication. In these patients, the risk of
myocardial infarction, stroke, or death from vascular causes after a mean of
27 months of follow-up was 9.7 percent in patients who received antiplatelet
therapy, as compared with 11.8 percent in control patients -- a reduction of
18 percent. However, the reduction was not statistically significant.
Similar nonsignificant results were obtained in a subgroup of 1928 patients
who had received peripheral arterial grafts or had undergone peripheral
angioplasty. The interpretation of these results has varied. The American
College of Chest Physicians recommends aspirin at doses of 81 to 325 mg per
day for patients with peripheral arterial disease. ( 59
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-59> ) In
contrast, a Food and Drug Administration (FDA) expert panel found
insufficient evidence to approve the labeling of aspirin as indicated for
patients with peripheral arterial disease. ( 60
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-60> )
Despite the lack of a statistically significant effect of aspirin in
reducing the overall risk of ischemic events in patients with peripheral
arterial disease, aspirin may favorably affect the peripheral circulation.
For example, in the Physicians' Health Study, a primary-prevention trial,
aspirin reduced the subsequent need for peripheral arterial surgery. ( 61
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-61> ) The
Antiplatelet Trialists' Collaboration found that aspirin therapy
significantly improved vascular-graft patency in 3226 patients with
peripheral arterial disease who were treated with bypass surgery (with a
saphenous-vein or prosthetic graft) or peripheral angioplasty and followed
for an average of 19 months. ( 62
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-62> ) Overall,
there was a 43 percent reduction in the rate of vascular-graft occlusion: 25
percent in the control group as compared with 16 percent in the aspirin
group. All the antiplatelet regimens contained aspirin. Aspirin alone was as
effective as the combination of aspirin and dipyridamole, sulfinpyrazone, or
ticlopidine in preventing graft occlusion, and high-dose aspirin (600 to
1500 mg per day) was as effective as low-dose aspirin (75 to 325 mg per
day).
Ticlopidine
Ticlopidine is a thienopyridine drug that inhibits platelet activation by
blocking platelet adenosine diphosphate receptors. In patients with
peripheral arterial disease, ticlopidine was more effective than placebo in
reducing the risk of fatal or nonfatal myocardial infarction or stroke. ( 63
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-63> )
Ticlopidine may reduce the severity of claudication and the need for
vascular surgery. ( 64
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-64> , 65
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-65> ) However,
enthusiasm for this drug is tempered by the substantial risk of
thrombocytopenia, neutropenia (which occurs in 2.3 percent of treated
patients), and thrombotic thrombocytopenic purpura (which occurs in 1 in
2000 to 4000 patients), for which extensive hematologic monitoring is
required. ( 66
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-66> , 67
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-67> ) This
concern has led to the development of other drugs in the thienopyridine
class.
Clopidogrel
Clopidogrel is a thienopyridine drug that has fewer hematologic side effects
than ticlopidine. The primary data that support the use of clopidogrel were
derived from the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic
Events (CAPRIE) trial. This trial compared 75 mg of clopidogrel per day with
325 mg of aspirin per day in more than 19,000 patients with recent
myocardial infarction, recent ischemic stroke, or peripheral arterial
disease (6452 patients). ( 15
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-15> ) The
patients with peripheral arterial disease either had claudication with an
ankle-brachial index value of 0.85 or less or a history of claudication with
previous peripheral bypass surgery, angioplasty, or amputation. Thus, these
patients were symptomatic and had moderately severe peripheral arterial
disease. Clopidogrel was associated with an overall reduction of 8.7 percent
in the primary end point of fatal or nonfatal ischemic stroke, fatal or
nonfatal myocardial infarction, or death from other vascular causes (P=0.04)
( Figure 5
<http://www.nejm.org/content/figs/2001/0344/0021/1608.asp?section=F5> ).
This result led to FDA approval of clopidogrel for the secondary prevention
of atherosclerotic events in patients with atherosclerosis, including those
with peripheral arterial disease. In the CAPRIE trial, both clopidogrel and
aspirin were well tolerated. However, a recent report described the
occurrence of thrombotic thrombocytopenic purpura early in the course of
treatment with clopidogrel. ( 68
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-68> ) The
estimated risk of thrombotic thrombocytopenic purpura is 4 per million
patients, a level that does not warrant routine hematologic monitoring.
In the CAPRIE trial, there were differences in the treatment effect among
patients with stroke, myocardial infarction, and peripheral arterial
disease. In the 6452 patients with peripheral arterial disease, the primary
end point occurred at an annual rate of 4.9 percent in patients given
aspirin and 3.7 percent in patients given clopidogrel, an adjusted risk
reduction of 23.8 percent. This treatment effect was greater than that in
patients with myocardial infarction or stroke, but the differences could
also have occurred by chance ( Figure 5
<http://www.nejm.org/content/figs/2001/0344/0021/1608.asp?section=F5> ).
Other Antiplatelet Drugs
Picotamide inhibits thromboxane A2 synthase and blocks thromboxane A2
receptors. In an 18-month trial in 2304 patients with peripheral arterial
disease, there was a nonsignificant 19 percent reduction in fatal and
nonfatal ischemic events in the picotamide group, as compared with the
placebo group. ( 69
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-69> ) No
further studies have been performed with this drug. Ketanserin is an
antagonist of S2 serotonin receptors that has antiplatelet effects. In a
large trial of ketanserin in 3899 patients with peripheral arterial disease,
the mortality rate was slightly, but not significantly, higher in the
ketanserin group (perhaps in relation to prolongation of the QT interval),
and the drug did not relieve claudication. ( 70
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-70> , 71
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-71> )
In summary, patients with peripheral arterial disease have systemic
atherosclerosis and are at high risk for cardiovascular disease and death.
Although the data are not conclusive, aspirin should be considered the
primary antiplatelet drug for preventing ischemic events in patients with
peripheral arterial disease. Aspirin is also effective in maintaining
vascular-graft patency and may prevent thrombotic complications of
peripheral arterial disease. Clopidogrel has FDA approval for the prevention
of ischemic events in patients with peripheral arterial disease and may be
more effective than aspirin in these patients.

Nonpharmacologic Therapy For Claudication

Goals of Therapy
Patients with claudication have marked impairment in exercise performance
and overall functional capacity. Their peak oxygen consumption measured
during graded treadmill exercise is 50 percent of that in age-matched normal
subjects, indicating a level of impairment similar to that among patients
with New York Heart Association class III heart failure. ( 72
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-72> ) In
addition, patients with claudication typically report great difficulty in
walking short distances, even at a slow speed. Reduced walking capacity is
associated with impairment in the performance of activities of daily living
and in the quality of life. ( 28
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-28> , 73
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-73> )
Improving mobility and improving the quality of life are important treatment
goals for patients with peripheral arterial disease.
Exercise Therapy
The primary nonpharmacologic treatment for claudication is a formal
exercise-training program, as demonstrated in over 20 randomized trials
(albeit many with small samples). ( 74
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-74> ) Exercise
improves not only maximal treadmill walking distance, but also the quality
of life and community-based functional capacity (i.e., the ability to walk
at defined speeds and for defined distances). ( 75
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-75> ) A
rigorous exercise-training program may be as beneficial as bypass surgery
and may be more beneficial than angioplasty. ( 76
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-76> , 77
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-77> ) A
meta-analysis of randomized trials found that exercise training increased
maximal treadmill walking distance by 179 m (95 percent confidence interval,
60 to 298). ( 31
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-31> ) This
degree of improvement should translate into longer walking distances on
level ground.
Although exercise therapy is clearly effective, it has several limitations.
The best results require a motivated patient in a supervised setting,
typically modeled after cardiac rehabilitation. ( 78
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-78> ) However,
supervised exercise-training programs are not covered by medical insurance,
which prevents their widespread use. Exercise training must also be
maintained on a regular basis, or the benefits will be lost. Thus, although
exercise is recommended as the initial treatment for patients with
claudication ( Figure 3
<http://www.nejm.org/content/figs/2001/0344/0021/1608.asp?section=F3> ),
lack of availability and insurance coverage limit the overall effectiveness
of exercise therapy.
Several studies have examined the mechanisms by which exercise training
exerts its benefits. Exercise training is not associated with substantial
changes in blood flow to the legs, and the changes that occur do not predict
the clinical response. ( 79
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-79> ) Despite
the absence of a hemodynamic effect, exercise training improves oxygen
extraction in the legs. ( 80
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-80> ) The
intermediary metabolism of skeletal muscle is also favorably affected by
training, as evidenced by an improvement in muscle carnitine metabolism.
 81 <http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-81> )
Finally, alterations in gait and walking efficiency may contribute to the
training response. At submaximal workloads, training results in a decrease
in oxygen consumption and thus improved walking efficiency. ( 82
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-82> )

Drug Therapy for Claudication

Vasodilator Drugs
Vasodilator drugs, such as papaverine, were the first medications studied
for the treatment of claudication, but several controlled trials have found
no evidence of clinical efficacy of drugs of this class. ( 83
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-83> ) There
are several pathophysiologic explanations for this finding. During exercise,
the portion of a resistance vessel located distally to a stenosis or
occlusion dilates in response to ischemia. Vasodilators do not affect these
vessels, whose dilation is due to endogenous factors, but they may decrease
resistance in other vessels, leading to a "steal" of blood flow away from
the underperfused muscle. Vasodilators can also lower systemic pressure,
leading to a reduction in perfusion pressure. Thus, current data do not
support the use of vasodilators for claudication.
Pentoxifylline
Pentoxifylline is a methylxanthine derivative that improves the
deformability of red cells and white cells, lowers plasma fibrinogen
concentrations, and has antiplatelet effects. ( 84
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-84> ) The drug
was approved in 1984 for the treatment of claudication. In one of the first
randomized trials, pentoxifylline increased maximal treadmill walking
distance by 12 percent as compared with placebo, but there was no difference
between the two groups in the increase in maximal treadmill walking distance
as compared with base-line values ( Table 3
<http://www.nejm.org/content/figs/2001/0344/0021/1608.asp?section=T3> ).
 85 <http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-85> )
Another study found a nonsignificant increase of 21 percent in maximal
treadmill walking distance in patients treated with pentoxifylline as
compared with placebo. ( 86
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-86> )
Similarly, in a recent study pentoxifylline was no more effective than
placebo in increasing maximal treadmill walking distance or functional
status as assessed by questionnaires. ( 87
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-87> ) A
meta-analysis of the pentoxifylline studies found a net benefit of 44 m in
the maximal distance walked on a treadmill (95 percent confidence interval,
14 to 74). ( 31
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-31> ) This and
another meta-analysis and two systematic reviews of pentoxifylline concluded
that the drug may have a small effect on walking ability, but that the data
are insufficient to support its widespread use. ( 31
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-31> , 88
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-88> , 101
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-101> , 102
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-102> )
Cilostazol
Cilostazol was approved in 1999 by the FDA for the treatment of
claudication. The primary action of cilostazol is to inhibit
phosphodiesterase type 3, thereby increasing intracellular concentrations of
cyclic AMP. Cilostazol undergoes extensive hepatic metabolism by the 3A4
isoform of cytochrome P450 (CYP3A4) and to a lesser extent by the 2C19 and
1A2 isoforms. Although the drug does not inhibit the cytochrome CYP450
enzyme system, other drugs that inhibit CYP3A4 may increase serum cilostazol
concentrations. ( 103
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-103> )
Cilostazol inhibits platelet aggregation, the formation of arterial thrombi,
and vascular smooth-muscle proliferation and causes vasodilatation. ( 104
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-104> , 105
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-105> , 106
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-106> )
However, as discussed above, vasodilator and antiplatelet drugs do not
improve claudication-limited exercise performance, and therefore the
mechanism of effect of cilostazol in peripheral arterial disease is unknown.
Type 3 phosphodiesterase inhibitors such as milrinone were developed as
inotropic agents for the treatment of heart failure. In patients with
chronic heart failure, milrinone treatment was associated with an increase
in mortality. ( 107
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-107> ) In
comparison with milrinone, cilostazol has fewer cardiac inotropic effects
but equivalent vasodilating and platelet-inhibiting properties. ( 108
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-108> )
Four randomized, placebo-controlled trials of cilostazol enrolling 1534
patients with claudication have been published ( Table 3
<http://www.nejm.org/content/figs/2001/0344/0021/1608.asp?section=T3>  and
Figure 6
<http://www.nejm.org/content/figs/2001/0344/0021/1608.asp?section=F6> ).
 87 <http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-87> , 89
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-89> , 90
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-90> , 91
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-91> ) In all
four trials, cilostazol (100 mg twice daily) improved both pain-free and
maximal treadmill walking distance, as compared with placebo. Cilostazol (50
mg twice daily) also increased maximal treadmill walking distance. ( 91
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-91> ) In one
trial, cilostazol (100 mg twice daily) was superior to both placebo and
pentoxifylline. ( 87
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-87> ) In three
of the trials, cilostazol also improved several aspects of physical
functioning and the quality of life, as assessed by questionnaires. ( 89
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-89> , 90
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-90> , 91
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-91> ) The drug
also causes small increases in ankle-brachial index values and raises serum
HDL cholesterol concentrations. ( 90
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-90> )
The predominant side effect of cilostazol is headache, which affects 34
percent of patients taking 100 mg twice daily, as compared with 14 percent
of patients taking placebo (data presented to the FDA Cardiovascular and
Renal Drugs Advisory Committee on July 9, 1998). In addition, transient
diarrhea, palpitations, and dizziness have been described. Cilostazol can be
administered with aspirin, but there are no data on the safety of
coadministration of cilostazol with clopidogrel. Because of concern about
the risk of death with this class of drugs, data from more than 2000
patients who were followed for up to six months were presented to the FDA.
Death from cardiovascular causes occurred in 0.6 percent of
cilostazol-treated patients and 0.5 percent of placebo-treated patients.
Myocardial infarction occurred in 1.5 percent of cilostazol-treated patients
and 1.1 percent of placebo-treated patients. Because of the experience with
milrinone, the cilostazol label includes a black-box warning that cilostazol
should not be given to patients with claudication who also have heart
failure.
Naftidrofuryl
Naftidrofuryl has been available for several decades in Europe for treating
claudication. Several mechanisms of action have been proposed, including
antagonism of 5-hydroxytryptamine receptors. A critical review of five
placebo-controlled trials concluded that naftidrofuryl improved pain-free
treadmill walking distance, but not maximal walking distance ( Table 3
<http://www.nejm.org/content/figs/2001/0344/0021/1608.asp?section=T3> ), and
was associated with fewer cardiovascular events than placebo. ( 109
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-109> ) This
drug is not available in the United States.
Levocarnitine and Propionyl Levocarnitine
In patients with peripheral arterial disease, metabolic abnormalities
develop in the skeletal muscles of the lower extremities. ( 110
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-110> ) These
abnormalities include impairment of the activity of the mitochondrial
electron-transport chain in the ischemic muscles and accumulation of
intermediates of oxidative metabolism (acylcarnitines). ( 111
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-111> , 112
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-112> )
Exercise performance is most impaired in patients with the greatest
accumulation of acylcarnitines in muscle. Thus, claudication is caused not
just by reduced blood flow, but also by alterations in skeletal-muscle
metabolism.
Levocarnitine and propionyl levocarnitine may improve metabolism and
exercise performance of ischemic muscles. Levocarnitine, 2 g twice daily,
improved maximal treadmill walking distance, but propionyl levocarnitine (an
acyl form of carnitine) was more effective than levocarnitine in improving
maximal treadmill walking distance. ( 113
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-113> ) In two
multicenter trials enrolling 730 patients, the pain-free and maximal
treadmill walking distance improved more in patients receiving propionyl
levocarnitine than in those receiving placebo. ( 95
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-95> , 96
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-96> ) The drug
also improved the quality of life more than placebo and had fewer side
effects. ( 96
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-96> )
Propionyl levocarnitine has not been approved for use in the United States.
Prostaglandins
Prostaglandins have been evaluated primarily for the treatment of patients
with critical leg ischemia. The primary end points of these trials were
relief of ischemic pain, healing of ischemic ulcers, and reduction in the
rate of amputation. ( 114
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-114> , 115
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-115> ) Fewer
studies have been performed in patients with claudication. A study of 90
such patients found that parenteral administration of prostaglandin E1 in a
formulation of lipid microspheres improved maximal treadmill walking
distance and quality of life. ( 97
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-97> ) Oral
analogues of prostaglandins have not been as well studied. A small trial
found that beraprost was moderately efficacious, but at higher doses it had
substantial side effects, such as headache, flushing, and gastrointestinal
intolerance. ( 99
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-99> ) A recent
study found that beraprost had positive effects on maximal treadmill walking
distance and the quality of life ( Table 3
<http://www.nejm.org/content/figs/2001/0344/0021/1608.asp?section=T3> ) and
reduced the rate of critical cardiovascular events. ( 100
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-100> ) The use
of prostaglandins in patients with peripheral arterial disease needs further
evaluation.
Other Drugs
Treatment with chelation, vitamin E, or testosterone has no effect on
claudication. ( 116
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-116> , 117
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-117> , 118
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-118> )
Treatments that have had promising results in preliminary studies include
buflomedil, Ginkgo biloba, inositol niacinate, defibrotide, verapamil,
anticoagulants, and arginine, but none of these have been evaluated in large
clinical trials. ( 119
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-119> , 120
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-120> , 121
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-121> , 122
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-122> , 123
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-123> , 124
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-124> , 125
<http://www.nejm.org/content/refs/2001/0344/0021/1608.asp#ref-125> )

Conclusions

Peripheral arterial disease is a highly prevalent manifestation of
atherosclerosis that is associated with a substantial risk of illness and
death and a marked reduction in ambulatory capacity and quality of life.
Unfortunately, peripheral arterial disease is undertreated with regard to
risk-factor modification, use of antiplatelet drugs, and treatment of
symptoms. Clinical trials specifically directed to patients with peripheral
arterial disease are needed to address the benefits of the treatment of
hyperlipidemia, diabetes, hyperhomocysteinemia, and other prevalent risk
factors. Despite these limitations, patients with peripheral arterial
disease should be considered candidates for secondary-prevention strategies,
just as are patients with coronary artery disease.
Angiotensin-converting-enzyme inhibitors may decrease the risk of ischemic
events. However, antiplatelet drugs are effective at reducing the risk of
fatal and nonfatal ischemic events in patients with peripheral arterial
disease. The data supporting the use of antiplatelet drugs are stronger than
those supporting the use of angiotensin-converting-enzyme inhibitors.
Aspirin should be considered in all patients, with clopidogrel an
alternative (and potentially more effective) drug.
Medical therapies to treat the symptoms of claudication and limited mobility
are now well established. A supervised walking-based exercise program should
be considered first for all patients because of the low risk and the
likelihood of marked improvement in functional capacity that is associated
with exercise. Drugs that improve functional status are also available.
Pentoxifylline has limited efficacy, but cilostazol improves both pain-free
and maximal treadmill walking distance and the quality of life. Several
other compounds, such as propionyl levocarnitine, are under investigation
for the treatment of claudication and critical leg ischemia.
Dr. Hiatt has received grant support from Bristol-Myers Squibb-Sanofi
Synthelabo, Cooke Pharma, Dupont Pharmaceuticals, Otsuka America
Pharmaceuticals-Pharmacia, Parke-Davis Pharmaceuticals, Sigma-Tau
Pharmaceuticals, and United Therapeutics. He has served on the speakers'
bureaus and steering committees of several of these corporations and has
also served on steering committees for Ajinomoto Pharmaceuticals, Berlex
Laboratories, Eli Lilly, and Welfide Corporation.
I am indebted to Ms. Lisa Cox for assistance in the preparation of the
manuscript, and to Dr. Eric Brass for critical review.

Source Information

From the Section of Vascular Medicine, Divisions of Geriatrics and
Cardiology, Department of Medicine, University of Colorado School of
Medicine, and the Colorado Prevention Center, Denver. Address reprint
requests to Dr. Hiatt at the Colorado Prevention Center, 789 Sherman St.,
Suite 200, Denver, CO 80203, or at [log in to unmask]
<mailto:[log in to unmask]> .
  _____


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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.