The New England Journal
of Medicine -- May 24, 2001 -- Vol. 344, No. 21
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). (7,8)
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). (12,15)
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), the greater the risk of cardiovascular events. (17,18)
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)
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. (5,8,20)
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. (21,22)
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. (23,24)
Approximately one third of patients with
peripheral arterial disease have typical claudication (Table
1), 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)
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)
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)
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. (27,28)
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)
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 and Figure
3.
Smoking Cessation
Smoking cessation slows the progression to
critical leg ischemia and reduces the risks of myocardial infarction and death
from vascular causes. (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)
Smoking-cessation programs, nicotine-replacement therapy, and the use of
antidepressant drugs such as bupropion should be encouraged. (32)
Treatment of
Hyperlipidemia
Several large clinical trials have
determined the benefits of lowering cholesterol concentrations in patients with
coronary artery disease. (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. (34,35)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)),
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)
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)
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)
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)
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. (50,51)
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)
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). 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)
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)
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)
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)
The Heart and Estrogen/Progestin Replacement Study evaluated the effects of
estrogen therapy in 2763 postmenopausal women with coronary artery disease. (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)
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)
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)
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)
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)
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)
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)
Ticlopidine may reduce the severity of claudication and the need for vascular
surgery. (64,65)
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. (66,67)
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)
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). 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)
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).
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)
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. (70,71)
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.
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)
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. (28,73)
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)
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)
A rigorous exercise-training program may be as beneficial as bypass surgery and
may be more beneficial than angioplasty. (76,77)
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)
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)
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), 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)
Despite the absence of a hemodynamic effect, exercise training improves oxygen
extraction in the legs. (80)
The intermediary metabolism of skeletal muscle is also favorably affected by
training, as evidenced by an improvement in muscle carnitine metabolism. (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)
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)
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)
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). (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)
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)
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)
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. (31,88,101,102)
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)
Cilostazol inhibits platelet aggregation, the formation of arterial thrombi,
and vascular smooth-muscle proliferation and causes vasodilatation. (104,105,106)
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)
In comparison with milrinone, cilostazol has fewer cardiac inotropic effects
but equivalent vasodilating and platelet-inhibiting properties. (108)
Four randomized, placebo-controlled trials
of cilostazol enrolling 1534 patients with claudication have been published (Table
3 and Figure
6). (87,89,90,91)
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)
In one trial, cilostazol (100 mg twice daily) was superior to both placebo and
pentoxifylline. (87)
In three of the trials, cilostazol also improved several aspects of physical
functioning and the quality of life, as assessed by questionnaires. (89,90,91)
The drug also causes small increases in ankle-brachial index values and raises
serum HDL cholesterol concentrations. (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), and was associated with fewer cardiovascular events than placebo. (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)
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). (111,112)
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)
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. (95,96)
The drug also improved the quality of life more than placebo and had fewer side
effects. (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. (114,115)
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)
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)
A recent study found that beraprost had positive effects on maximal treadmill
walking distance and the quality of life (Table
3) and reduced the rate of critical cardiovascular events. (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. (116,117,118)
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. (119,120,121,122,123,124,125)
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.
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].
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Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.