Vascular Medicine

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The role of exercise training in peripheral arterial disease

Richard V. Milani and Carl J. Lavie
Vasc Med 2007 12: 351
DOI: 10.1177/1358863X07083177
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Vascular Medicine 2007; 12: 351358

The role of exercise training in peripheral arterial disease

Richard V Milani and Carl J Lavie
Abstract: Peripheral arterial disease (PAD) is currently a major health problem affecting 812 million Americans, 1540% of whom will have intermittent claudication that
can lead to substantial impairment in their ability to carry out normal daily activities
as well as perform the recommended cardiovascular exercise. Supervised exercise
training is an effective tool in the treatment of claudication and is currently a recommended first-line therapy for patients with this condition. In addition to improving
pain-free walking distance and quality of life, supervised exercise training can
improve many cardiovascular risk factors, possibly reducing the risk for subsequent
myocardial infarction, stroke, and death. This paper will review the benefits of supervised exercise training in patients with PAD.
Key words: claudication; exercise therapy; peripheral arterial disease; risk factors

Introduction
Peripheral arterial disease (PAD) currently affects
812 million Americans and by the year 2050 it is
expected to reach a prevalence of 19 million
Americans.1 The most common underlying etiology,
atherosclerosis, is a disease that impacts multiple territories, leaving PAD patients at high risk for subsequent coronary and cerebrovascular events including
myocardial infarction, stroke, and death.1,2 The risk of
developing PAD can be predicted by age and welldefined atherosclerotic risk factors including tobacco
use, diabetes mellitus, hypertension, hypercholesterolemia, and hypertension. Although about half of
all people with PAD are asymptomatic or have atypical symptoms, the most frequent symptom of mild to
moderate PAD is intermittent claudication, defined as
walking-induced pain, cramping, aching, tiredness,
heaviness in one or both legs (most often calves) that
does not go away with continued walking and is
relieved with rest.3,4 Moreover, claudication can
severely limit the performance of daily physical activities and often impairs the normal personal, social, and
occupational functional capacity of these patients,
thus representing a disability.5 Claudication currently
afflicts 5% of Americans over 55 years of age and is
present in 1540% of patients with PAD.6,7

Department of Cardiovascular Disease, Ochsner Clinic

Foundation, New Orleans, LA, USA
Address for correspondence: Richard V Milani, Ochsner Heart and
Vascular Institute, Ochsner Clinic Foundation, 1514 Jefferson
Highway, New Orleans, LA 70121, USA. Tel: 1 504 842 5874;
Fax: 1 504 842 5875; E-mail: rmilani@ochsner.org

Contemporary treatment of claudication is dichotomized into two major goals: (1) improve walking ability
and functional status by reducing claudication symptoms and preserving limb viability; and (2) reduce
the risk of cardiovascular events by treatment of the
underlying systemic atherosclerosis. The first of
these goals is directed at improving symptoms and
consists of exercise training, pharmacotherapy (primarily cilostazol), and revascularization (surgical or
percutaneous).8 Of these, supervised exercise training
is currently recommended as first-line treatment and is
the only one of these interventions that can additionally reduce concomitant cardiovascular risk. This
review will focus on the benefits of exercise training in
improving symptomatic claudication and its effect on
cardiovascular risk.

Baseline assessment
Hemodynamic assessment is an integral component in
the initial evaluation of patients with PAD and the
most commonly used measurement to diagnose
and assess the hemodynamic severity of PAD is the
ankle-to-arm ratio of systolic blood pressure
(anklebrachial index or ABI). The ABI has been validated against angiographic confirmation of PAD and
found to be 95% sensitive and almost 100% specific.9
Measurements can be readily obtained with standard
blood pressure cuffs and a hand-held Doppler device.
An ABI below 0.90 indicates the presence of PAD
with ratios of 0.700.90 suggesting mild PAD,
0.400.70 moderate PAD, 0.40 severe PAD, and
values 1.3 likely due to non-compressible arteries.

2007 SAGE Publications

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352

RV Milani and CJ Lavie

The evaluation of walking ability in claudicants

most commonly employs motorized treadmills programmed to provide less intense progressive workloads (i.e. the GardnerSkinner, Hiatt, or Naughton
protocols) than are commonly used in evaluating
patients for coronary artery disease. The treadmill test
should record the onset of leg symptoms, laterality,
specific muscle groups involved, the presence of associated coronary ischemic symptoms and signs, and
total walking time.8 Exercise should be stopped when
mandated by symptoms or if objective measures of
myocardial ischemia manifest. Another option, particularly in elderly patients, is the 6-minute walk test,
which can serve as an alternative objective method of
assessing walking endurance.10,11 From these walking
assessments come two frequently used measures in
reporting outcomes from interventions: maximum
walking distance and time (or claudication distance
and time) and pain-free walking distance and time (or
initial claudication distance and time).12
Finally, health-related quality of life issues should
be assessed using validated questionnaires. The
two most commonly used instruments in the PAD
population are the non-disease specific Medical
Outcomes Study SF-36 and the disease-specific
Walking Impairment Questionnaire (WIQ), both of
which assess functional status in the community and
have been independently validated in patients with
PAD.13,14
Exercise training and its effects on
claudication symptoms
Peak oxygen consumption in patients with claudication is generally 50% of age-matched normal individuals, indicating a level of impairment similar to
patients with New York Heart Association class III
heart failure.12,15,16 Because of the limitations imposed
by claudication symptoms, many patients develop progressive functional impairment due to superimposed
deconditioning from restricting physical activities.
Self-reported walking distance has been reported to
decline at the rate of 8.4 meters per year.17 This leads
to reduced muscle mass, and a lack of muscle strength
and endurance, exacerbating their physical infirmity.18
This cycle of disability can lead to marked and
progressive impairment over time such that many
patients become housebound or dependent on others
(Figure 1).19
Exercise training can be promoted in two formats:
unsupervised home-based exercise and supervised
hospital or clinic-based exercise training. Although
home-based programs can generate several health
benefits, the usefulness of unsupervised exercise
programs is not well established as an effective initial
treatment of claudication and significant symptomatic
improvement in walking distance has not been

consistently demonstrated with this format of exercise prescription.20 In contrast, the data supporting
the efficacy of supervised exercise programs to alleviate claudication symptoms are impressive.2124
Supervised exercise has been shown to improve
maximal treadmill walking distance more effectively
than pharmacotherapy with pentoxifylline and/or
cilostazol (Figure 2).25,26 Exercise-induced improvements in walking ability enhance routine daily activities, quality of life and community-based functional
capacity.27 A meta-analysis of 21 randomized and
non-randomized trials of exercise training revealed
that pain-free walking time improved an average of
180% and maximal walking time increased by
120%.21 A separate meta-analysis from the Cochrane
Collaboration evaluating only randomized, controlled
trials concluded that exercise improved maximal
walking ability by an average of 150%.24 Improvements in walking ability were most often attained
when each exercise session lasted longer than 30 minutes, sessions took place at least three times per week,
when the exercise modality was walking to nearmaximal pain, and when the program lasted at least
6 months.8,21 A rigorous exercise-training program
may be as beneficial as bypass surgery and more beneficial than angioplasty.28,29
As a result of these data, the recent ACC/AHA
guidelines for management of patients with PAD
advocate supervised exercise rehabilitation as a IA
recommendation for the initial treatment of patients
with intermittent claudication.8 As per these guidelines, exercise training should be performed for a minimum of 3045 minutes, in sessions performed at least
three times per week for a minimum duration of
12 weeks. The key elements of a successful exercisetraining program are listed in Table 1.
The mechanisms by which exercise training yields
improvements in walking ability remain speculative.
Exercise training improves oxygen extraction and
muscle carnitine metabolism in the leg.30,31 Following
a program of exercise training, humans with heart failure will increase expression of vascular endothelial
growth factor (VEGF) messenger RNA in skeletal
muscle,32 and animal models reveal an increase in collateral development.33,34 Moreover, exercise increases
levels of circulating endothelial progenitor cells
(EPC), monocyte/macrophage-derived angiogenic
cells, and reduces EPC apoptosis.35,36 In an animal
model, exercise training induces neoangiogenesis.35 In
spite of this data, human studies in PAD patients with
improved walking ability following exercise training
have not demonstrated increases in leg blood flow,
suggesting other mechanisms for the large improvements observed following exercise training.19,28,37
Exercise training stimulates endothelial-dependent
vasodilatation.38,39 By periodic exposure to repeated
episodes of exercise-induced hyperemia, the increased
blood flow augments vascular expression of nitric

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Exercise training in PAD

353

Figure 1 The cycle of disability and benefits of exercise training in PAD patients with claudication.

oxide and prostacyclin, thereby promoting vasodilatation.40 We and others have shown that exercise training improves hemorheology, thereby facilitating
oxygen delivery to ischemic skeletal muscle.4143
Although coronary patients demonstrate significant
improvements in blood viscosity and tissue oxygen
extraction following formal exercise training, these
benefits may be even more applicable for patients with
PAD.
Walking efficiency is reduced in patients with claudication in that walking patterns change to favor stability over speed.19,4446 As a result of this less
efficient alteration in biomechanics, the oxygen cost
of walking is increased. Following a program of exercise training, walking economy has been shown to
improve in PAD patients and in patients with other
chronic diseases, as evidenced by a decrease in oxygen consumption at submaximal workloads.12,4749

Calf muscle strength and endurance has been shown to

be improved following treadmill-walking training and
this is associated with improved walking capacity.50
However, a separate investigation suggests that
improvement in lower-limb muscle strength may not
fully account for enhanced walking distance following
exercise training. A recent study randomized PAD
patients to a 24-week upper versus lower-limb aerobic
exercise training program and compared them to a
non-exercise control group.51 Claudication distance
and maximum walking distance improved similarly in
both training groups as well as higher levels of
reported pain. This data would suggest that exercising
patients could tolerate a higher level of cardiovascular
stress and claudication pain, accounting for the
improvements in walking performance following exercise training, and provides an alternative exercise (arm
crank) for patients unable or unwilling to negotiate

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RV Milani and CJ Lavie

Table 1 Key elements of a therapeutic claudication

exercise training program.
Primary clinician role
Establish the PAD diagnosis using the ABI measurement or other objective vascular laboratory evaluations
Determine that claudication is the major symptom
limiting exercise
Discuss risk/benefit of claudication therapeutic alternatives, including pharmacological, percutaneous,
and surgical interventions
Initiate systemic atherosclerosis risk modification
Perform treadmill stress testing
Provide formal referral to a claudication exercise
rehabilitation program
Exercise guidelines for claudication
Warm-up and cool-down period of 510 minutes
each
Figure 2 Mean improvement in maximal walking
distance following medical interventions in patients with
claudication.

treadmill walking. Supporting this concept are reports

utilizing alternative exercise programs including
polestriding and high-intensity interval training, each
yielding as good or greater improvements in walking
performance than standard exercise methods.52,53
However, Gardner reported contrasting results in a
randomized trial of high- and low-intensity exercise
training, where similar improvements in walking performance were observed provided that a few additional minutes of walking is accomplished in the
low-intensity group to elicit a similar volume of exercise.54
Patient enrollment into medically supervised exercise programs should mirror traditional cardiac rehabilitation and exercise training where supervised
exercise can be carried out with electrocardiographic,
heart rate, and blood pressure monitoring available.
The typical program requires the performance of
treadmill or track-based exercise for 4560 minutes
monitored by a nurse or exercise physiologist. Most
commonly, treadmill exercise is employed and the initial workload is set to a speed and grade that elicit
claudication symptoms within 35 minutes. Patients
are asked to continue to exercise at this workload until
they achieve moderate severity claudication, at which
time the patient can rest briefly until symptoms
resolve. The exerciserestexercise cycle is repeated
throughout the exercise session. Over time, pain-free
and maximal walking distance increase such that periodic adjustments in speed and grade are required by
rehabilitation personnel in order to elicit claudication
symptoms. Typical benefits of such a program include
a greater than 100% improvement in maximal claudication, significant improvement in walking speed and
distance, and improvements in physical function and
vitality by questionnaire (SF-36).8,21,23,24,43,47 As
patients augment their exercise capacity, rehabilitation

Types of exercise
Treadmill and track walking are the most effective
exercise for claudication
Resistance training has conferred benefit to individuals with other forms of cardiovascular disease, and
its use, as tolerated, for general fitness is complementary to but not a substitute for walking
Intensity
The initial workload of the treadmill is set to a
speed and grade that elicit claudication symptoms
within 35 minutes
Patients walk at this workload until they achieve
claudication of moderate severity, which is then
followed by a brief period of standing or sitting
rest to permit symptoms to resolve
Duration
The exerciserestexercise pattern should be
repeated throughout the exercise session
The initial duration will usually include 35 minutes
of intermittent walking and should be increased
by 5 minutes each session until 50 minutes of
intermittent walking can be accomplished
Frequency
Treadmill or track walking three to five times per
week
Role of direct supervision
As patients improve their walking ability, the exercise workload should be increased by modifying the
treadmill grade or speed (or both) to ensure that
there is always the stimulus of claudication pain
during the workout.
As patients increase their walking ability, there is the
possibility that cardiac signs and symptoms may
appear (e.g. dysrhythmia, angina, or ST-segment
depression). These events should prompt physician
re-evaluation.
Reproduced from ref. 19. Copyright 2002 Massachusetts Medical Society. All rights reserved.

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Exercise training in PAD

personnel should continually evaluate patients for

symptoms and signs of coronary ischemia as higher
heart rates and blood pressures (double product) are
achieved, thus increasing myocardial oxygen requirements.
Exercise training and its effect on
cardiovascular risk factors
Sedentary behavior is one of the leading preventable
causes of death, and an inverse relationship exists
between volume of physical activity behavior and allcause mortality. Regular physical activity decreases
the risk of multiple medical conditions including cardiovascular disease, type 2 diabetes, osteoporosis,
depression, obesity, breast cancer, colon cancer, and
falls in older adults.55 Although there are less data in
patients with PAD, a graded relationship of decreasing
CAD rates with increasing levels of activity is noted in
the general population and in patients with established
CAD.56 However, in a recent preliminary report from
Japan, supervised exercise training has been reported
to improve survival in patients with PAD. After a mean
follow-up of 5.4 years, event-free survival was higher
in those PAD patients completing supervised exercise
training than in those who did not (80.5% versus
56.7%).57
Physical activity both prevents and treats many
established atherosclerotic risk factors including
elevated blood pressure, insulin resistance and glucose
intolerance, elevated triglyceride concentrations, low
levels of high-density lipoprotein cholesterol (HDL-C)
concentrations, and obesity56 (Table 2). Furthermore,
the prevalence of the metabolic syndrome (a constellation of obesity, glucose intolerance, reduced HDL-C,
elevated triglycerides, and hypertension), which is
associated with a marked increase in cardiovascular
risk, can be dramatically reduced following exercise
training.58 Moreover, other less established risk factors
which can impact patients with PAD59 can be favorably
improved by supervised exercise training including
hs-CRP, homocysteine, blood rheology, autonomic
function, depression, and psychosocial stress.42,6064

Table 2 Benefits of exercise training in cardiovascular

risk reduction.
Improvement in exercise capacity
Improvement in lipids (primarily HDL-cholesterol and
triglycerides)
Reduction in obesity indices
Reduction in blood pressure
Reduction in inflammation (hs-CRP)
Improvement in autonomic function
Improvement in blood rheology
Improvement in insulin resistance/glucose intolerance
Reduction in depression and psychosocial stress

355

Finally, perhaps the strongest cardiovascular risk factor

is a low functional capacity, and we and others have
demonstrated marked improvements in overall exercise
capacity in many different subgroups including elderly
people, women and obese patients.6568
An additional benefit of a comprehensive program of
exercise training is that it provides a framework for complimentary non-pharmacologic interventions that can
assist the patient towards achieving better health. Such
interventions include nutritional counseling with dietary
recommendations, smoking cessation, stress management, and educational classes on PAD, cardiovascular
risk factors and healthy behaviors.65,69 These interventions can be provided in group sessions, and can improve
adherence to therapy as well as assist in reducing
claudication symptoms and cardiovascular outcomes.
Diabetics as a unique population
It is estimated that more than 20% of the PAD population carries the diagnosis of diabetes mellitus.70,71
Although the beneficial effects of exercise training on
weight reduction and insulin resistance have been well
described, it is particularly important to avoid hypoglycemia during a program of sustained exercise training.72 For example, the potential for hypoglycemia in
type 2 diabetes is increased by the use of sulfonylureas, insulin secretagogues, or insulin injections and
so doses of these oral hypoglycemic agents or insulin
are often reduced during exercise training to prevent
hypoglycemia, since exercise increases sensitivity to
insulin.72 Therefore, a relatively important role of the
rehabilitation staff is to assist the patients and primary
care physicians with the monitoring and treatment of
glucose levels in patients with diabetes. Patients
should also be taught techniques of self-monitoring
for both blood pressure and glucose levels, as such
surveillance has led to significant alterations in dose of
medications.73
A major concern during exercise, particularly higher
intensity or when prolonged, is to avoid hypoglycemia.74 If the pre-exercise finger stick blood sugar
is below 90100 mg/dl, a source of simple carbohydrate, such as one fruit or starch exchange or two to
three glucose tablets containing 4 or 5 g of glucose
each, should be administered before starting exercise.72
Insulin should be administered preferably in abdominal
sites and not in sites used for exercise. In addition to the
finger stick glucose monitoring, the exercise area
should have glucose tablets or gels to administer to
patients during exercise, and glucagon emergency kits
containing 1 g glucagon if severe symptoms make it
impossible for oral glucose administration. If hypoglycemic episodes are frequent, significant reductions
in medications are needed. Likewise, for patients who
exercise in evening exercise classes, occasionally nocturnal hypoglycemia can be problematic, necessitating

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RV Milani and CJ Lavie

reductions in evening medications, taking an extra

source of complex carbohydrate at night, or occasionally changing exercise sessions to earlier in the day.
Although hyperglycemia is usually not as important a
problem in exercise programs as hypoglycemia, poor
glucose control can occasionally lead to severe hyperglycemia in type 2 diabetes.
Many patients with long-standing diabetes have
complications, including peripheral neuropathy,
retinopathy, nephropathy, and autonomic neuropathy.
Patients with peripheral neuropathy may have painful
burning, tingling, and numbness in the feet or foot
ulcers. In these situations, self-examination of the feet
before and after exercise is imperative, and shockabsorbing shoes with ample room for the distal foot
are needed.72,74
Impediments to success
Despite the efficacy of exercise training, it is currently
underutilized in clinical practice. The major problem
preventing more widespread use of supervised exercise training has been a lack of coverage by medical
insurance. Recently however, a new current procedural terminology (CPT) code was created for exercise
rehabilitation for patients with claudication (93668);
however, the Centers for Medicare & Medicaid
Services (CMS) has not at this time provided reimbursement for this code. Other barriers to participating
in a supervised exercise program include transportation and time issues for patients. Moreover, exercise
training does require a motivated patient who will
maintain exercise post-training on a continuous basis
over time, or the benefits will be lost. Available data
analyzing the implementation of unsupervised exercise in patients with PAD are not encouraging. In The
Netherlands, regular walking exercise programs were
not followed by almost 50% of patients with intermittent claudication.7577
Conclusions
Supervised exercise training for PAD patients with
claudication has been consistently effective in improving maximal walking distance and pain-free walking
distance and is currently regarded as first-line therapy
for these patients. Other complementary benefits of
this therapy may include a reduction in many cardiovascular risk factors.
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