Download Peripheral Arterial Disease: Evaluation, Risk Factor Modification

PeriPheral Arterial Disease
Peripheral Arterial Disease: Evaluation, Risk
Factor Modification, and Medical Management
Anil Verma, MD, MPH, Amit Prasad, MD, Ghasan H. Elkadi, MD, and Yung-Wei Chi, DO
Abstract
• Objective: To review the evaluation and medical
management of peripheral arterial disease (PAD).
• Methods: Review of the literature.
• Results: PAD is a highly prevalent but underrecognized and undertreated condition associated
with significant morbidity and mortality. PAD is an
important manifestation of systemic atherosclerosis,
which reduces arterial blood to the lower extremities
during exercise or rest. It has a strong association
with the well-defined atherosclerotic risks factors
such as diabetes mellitus, cigarette smoking, advanced age, hyperlipidemia, and hypertension and
can have a varied clinical presentation. PAD can be
diagnosed accurately with a comprehensive history
and physical examination and simple, noninvasive,
tests. Given the association of PAD with significant
morbidity and mortality and multiple atherosclerotic
risk factors, aggressive risk factor modification and
secondary prevention strategies such as antiplatelet
therapy, lipid lowering therapy, smoking cessation,
diabetes control, and antihypertensive treatment
should be considered in patients with PAD. Therapeutic angiogenesis using gene-based growth factors and stem cell–based therapies remain a promising future option for the treatment of PAD.
• Conclusion: Clinicians should have a high index of
suspicion for PAD in patients with atherosclerotic risk
factors. These patients will benefit from early detection of PAD and aggressive management.[1]
Peripheral arterial disease (PAD) is a common manifestation
of systemic atherosclerosis and affects a significant subset
of the population. Its incidence increases with known cardiovascular risk factors, and PAD commonly coexists with
coronary and cerebrovascular diseases. Asymptomatic PAD
is several times more common than symptomatic PAD, so
the diagnosis of PAD is often overlooked. The prevalence of
PAD in all patients over age 70 and diabetes patients over
age 50 is approximately 29% [1]. However, only about 11%
to 14% of patients are routinely screened for PAD in the
primary care setting [2]. PAD is considered to be coronary
74 JCOM February 2011 Vol. 18, No. 2
heart disease equivalent but few patients undergo aggressive risk factor reduction (Figure 1).
The diagnosis of PAD is important for 2 reasons. First,
symptomatic PAD results in claudication, ischemic rest pain,
and potential limb loss. These symptoms result in poor functional status and quality of life [3]. Secondly, atherosclerosis
is a chronic, progressive, systemic disease with multifactorial
etiology including hypertension, diabetes, smoking, and hyperlipidemia. However, the sensitivity and positive predictive
value of these traditional variables in identifying patients at
high risk for cardiovascular events is low [4]. The presence
of asymptomatic PAD confers on average a 30% risk of myocardial infarction, stroke, and vascular death over 5 years [5].
Thus, early detection of PAD is fundamental to implementing
early risk factor modification and disease management.
Epidemiology
Approximately 27 million people in North America carry
the diagnosis of PAD. The distribution is the same in men
and women and incidence increases with age. About 21% to
29% of patients over age 50 who have diabetes or a smoking
history have PAD. Five percent of patients over age 40 with
1 or more risk factors develop PAD [6]. The most common
manifestation of PAD is claudication, but fewer than 50% of
patients with PAD are symptomatic [6,7]. In a study of 460
patients with PAD, 19.8% had no symptoms, 28.5% had atypical leg pain, and only 32.6% had classic claudication [6].
Risk Factors
The risk factors for PAD are similar to those for coronary
heart disease and include age, hyperlipidemia, hypertension, diabetes mellitus, and smoking. The strongest predictors for the development of PAD are age, diabetes, and
tobacco use [8,9].
Age
The incidence of PAD increases with age. The prevalence of
PAD in patients over the age of 40 is approximately 4.3%. In
From the Department of Cardiology, Ochsner Clinic Foundation, New Orleans,
LA.
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clinical review
*
90
*
80
PAD
CAD
90
*
67
70
Medication use, %
88
*
*
57
60
52
*
50
40
40
30
34
31
37
33
27
19
20
10
0
Statins
Beta
blockers
ACE
inhibitors
Calcium
inhibitors
Aspirin
Nitrates
Figure 1. Differential medication use in patients with peripheral arterial disease (PAD) and coronary artery disease (CAD).
* P < 0.001 (Adapted from Welten GM, Schouten O, Hoeks SE, et al. Long-term prognosis of patients with peripheral arterial
disease: a comparison in patients with coronary artery disease. J Am Coll Cardiol 2008;51:1588–96.)
patients over the age of 70 or age 50 to 69 with risk factors,
the prevalence of PAD is as high as 29% [1]. Studies estimate
that approximately 25% of patients over the age of 55 in a
general medical practice have PAD [10].
Diabetes
In the National Health and Nutrition Examination Survey
(NHANES), about 26% of patients with PAD also had
diabetes [11]. In population-based studies such as the
Framingham Heart Study and Edinburgh Artery Study, the
relative risk of developing PAD increases by 1.5 to 4 times in
patients with diabetes [7, 12].
Tobacco Use
Smokers have a 4 times higher lifetime risk of developing PAD
than nonsmokers [7]. Tobacco use has a stronger association
with PAD than CAD [7]. Former smokers have an elevated
risk of PAD that is intermediate between current smokers and
nonsmokers. There is, however, a reduction in mortality and
critical limb ischemia in patients who stop smoking [13].
In smokers, a diagnosis of PAD is made approximately
a decade earlier than in nonsmokers. Results from the
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Edinburgh Artery Study [14] found that the relative risk
of intermittent claudication was 3.7 in smokers compared
with 3.0 in previous smokers (who had discontinued
smoking for less than 5 years). A recent 4.5-year follow-up
study of over 400 patients with documented PAD demonstrated that continued smoking was the most powerful
predictor of disease progression as defined by an anklebrachial index (ABI) decrease of < 0.3 [15]. Tobacco cessation slows the progression of PAD in critical limb ischemia
and reduces the 10-year death rate due to vascular cause
over 30% [16].
Other important risk factors for the development of PAD
include hypertension, hypercholesterolemia, hyperhomocysteinemia, and elevated CRP (Figure 2) [9,17]. These risk
factors are weaker predictors for the development of PAD
compared with smoking and diabetes.
Clinical Manifestations and Medical Evaluation
Patients with PAD are frequently asymptomatic, with less
than 20% of patients reporting typical symptoms of intermittent claudication of leg discomfort on exertion that is
relieved with rest [18]. Frequently, these patients may presVol. 18, No. 2 February 2011 JCOM 75
PeriPheral Arterial Disease
Smoking
Diabetes
Hypertension
Hypercholesterolemia
Hyperhomocysteinemia
C-Reactive Protein
.5
1
2
3
4
5
Relative Risk
Figure 2. Risk of developing lower extremity peripheral arterial disease. The range for each risk factor is estimated from epidemiologic studies. The relative risks take into consideration current smokers vs. former smokers and nonsmokers; the presence
vs. the absence of diabetes and hypertension; and the highest vs. the lowest quartile of homocysteine and C-reactive protein
levels. The estimate for hypercholesterolemia is based on a 10% risk for each 10-mg/dL rise in total cholesterol. (Adapted from
reference 9.)
ent with atypical symptoms including leg fatigue, difficulty
walking, and nonspecific leg pain. Among patients with
asymptomatic PAD, about 5% to 10% develop symptoms of
PAD over 5 years [1].
Clinicians should maintain a high index of suspicion
when assessing patients for PAD. Complaints of lower
extremity pain with findings such as hair loss, cool extremities, or poorly palpable pulses should alert the physician to
conduct a thorough history and physical examination, elicit
symptoms, determine the true initial and absolute claudication distances, and impact on functional capacity and quality
of life.
A careful assessment of atherosclerotic risk factors should
be made in patients suspected of having PAD, particularly
those with advanced age, diabetes, smoking, chronic kidney
disease, and hyperlipidemia. Physical examination of the
vascular system requires careful inspection, palpation, and
auscultation. Atherosclerosis in other vascular beds should
also be investigated, and it is imperative to examine the heart
and neck for carotid bruit and the abdomen for an abdominal aortic aneurysm. Abnormal pedal pulses, femoral artery
76 JCOM February 2011 Vol. 18, No. 2
bruit, delayed venous filling time, cool skin, and abnormal
skin color are some of the common physical findings in
patients with PAD.
Noninvasive Studies
Ankle-Brachial Index
Measuring the pressure in the ankle arteries and assessing
the ABI is the initial test of choice when assessing for PAD.
The ABI is a comparison of systolic blood pressure in the
dorsalis pedis and/or posterior tibial arteries of the lower
limb with that of the brachial artery using a continuous wave
doppler device. It has a 95% sensitivity and 100% specificity
[19]. ABI is simple, inexpensive, reliable, and a reproducible
method of identifying PAD.
The severity of PAD is indicated by a lowered ABI and is
a potent predictor of cardiovascular events such as ischemic
stroke, myocardial infarction and premature mortality [20].
Prevalence of PAD defined by ABI are reported to be 2.5%
at 40 to 59 years of age, 8.3% at 60 to 69 years, and 18.8% at
70 to 79 years [21]. High ABI values ( > 1.3) are suggestive of
medial calcification most commonly seen in patients with
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diabetes and/or with renal insufficiency [4,5]. The association between high ABI and mortality is similar to that of
low ABI and mortality.
Exercise treadmill testing combined with pre- and postexercise ABI can help in differentiating between claudication
and pseudoclaudication. It can also provide a functional assessment of the patient with PAD and is a reliable method of
detecting PAD if the resting ABI is normal but there is still a
high index of suspicion of PAD. Exercise normally produces
significant vasodilatation leading to increased blood flow
to the extremities. This will not occur in the presence of a
fixed arterial obstruction, and a significant pressure gradient
develops with a subsequent fall in pressure during exercise.
ABIs do not provide anatomically detailed information on
specific arterial segment involvement. Anatomical information is usually provided by duplex ultrasound examination
or contrast-based imaging modalities.
Pulse Volume Recordings and Segmental Limb Pressures
Location and extent of PAD can be further defined by
segmental limb systolic pressure measurements. Doppler measurements are obtained from plethysmographic
cuffs placed over the brachial artery and various points
on the lower limb, including upper thigh, lower thigh
upper calf, ankle, metatarsal, and digit. Segmental limb
pressure measurement has the same limitations as ABI
regarding noncompressibility of vessels. Segmental
pressure measurements usually obtained with pulse
volume recordings have a reported diagnostic accuracy
of 97% [22].
Pulse volume recordings detect changes in pulse contour
and can be analyzed. A normal wave form has a steep upstroke, sharp systolic peak, narrow pulse width, a dicrotic
notch, and a down slope bowing to baseline [23]. It should
be emphasized that a pulse volume recording constitutes a
qualitative, not quantitative, study; it is less accurate than
duplex ultrasound in localizing a specific lesion.
Duplex Ultrasound
Color-assisted duplex ultrasonography is a noninvasive
and safe diagnostic modality useful in identifying and
confirming the specific location, morphology, and extent of
suspected PAD. It can help in delineating between stenotic
and occlusive lesions and may provide functional information such as velocity gradients across stenoses. Duplex
ultrasonography uses the Doppler principle in assessing
the severity of arterial stenosis based on the change of measured peak systolic velocity and end-diastolic velocity. It is
limited in its variability of skill of the technologist, length
of the examination, body habitus, bowel gas, signal dropout
due to vascular calcification, and the presence of multiple
stenoses with close proximity (tandem lesions).
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Noninvasive Angiography
Computerized tomographic angiography (CTA) and magnetic resonance angiography (MRA) are the recent advances
in noninvasive imaging that have been rapidly embraced
to define the vascular anatomy with greater speed and improved resolution. Noninvasive angiographic imaging has
the advantage over invasive contrast angiography of allowing 3-D reconstruction of the images, which permits evaluation of bifurcation lesions, eccentric plaques, and areas of
vessel overlap. Inherently, noninvasive imagings with CTA
and MRA have less risk of vascular complication compared
to invasive catheter based angiography.
CTA allows acquisition of high-resolution volumetric
data of vascular structure in cross-sectional images, which
are then formatted into 3-D angiographic images. With the
advent of 64-channel multidetector CT scanners, advantages
of CTA over MRA include better patient acceptance, faster
speed of scanning, better spatial resolution, and the ability to evaluate previously stented arteries and use of less
contrast medium [24]. CTA is able to characterize a lesion in
a multiplane view, allowing for evaluation of plaque and calcification. It is also able to visualize segments immediately
distal to the arterial occlusion. CTA has been found to be diagnostically equivalent to invasive angiography in multiple
studies [25]. Disadvantages of CTA include beam hardening
artifacts from the vessel calcification, which makes stenosis
harder to evaluate. Additionally, use of intravenous contrast
is a concern in subjects with borderline renal function.
MRA has advantages over CTA in that potentially nephrotoxic iodinated contrast and ionizing radiation are not
required for imaging. For fear of device malfunction, patients
with implantable defibrillators and permanent pacemakers may not undergo magnetic resonance studies. Gadolinium-enhanced MRA when compared with color duplex
ultrasound was found to have better sensitivity for detecting
arterial segments, with greater than 50% diameter stenosis
(98% vs. 88%) but similar specificity (96% vs. 95%) [26]. There
is current agreement between MRA and catheter angiography of 91% to 97% in diagnosing significant peripheral arterial disease [27]. The major disadvantages of MRA include
higher cost, claustrophobic patients, and patients who have
contraindications to MR imaging (ie, pacemaker/defibrillator). Nephrogenic systemic fibrosis, a potentially debilitating
systemic disorder, has been linked with the use of gadolinium-based contrast agents, predominantly in patients with
acute renal failure or end-stage renal disease [28]. Overall,
both CTA and MRA are useful in patient selection and planning for endovascular and/or surgical treatment of PAD.
Invasive Catheter-Based Angiography
Invasive contrast angiography is considered the “gold standard” for defining both normal vascular anatomy and vasVol. 18, No. 2 February 2011 JCOM 77
PeriPheral Arterial Disease
cular pathology against which all other imaging methods
are compared for accuracy. It also has the added advantage
of digital subtraction angiography with its enhanced imaging technique compared with unsubtracted angiography. In
addition, hemodynamic consequences of the stenosis can be
assessed by measuring a pressure gradient across a stenosis.
Invasive contrast angiography carries the risks associated
with vascular access, catheter trauma, and systemic complications associated with contrast reactions. Rates of major
complications of peripheral vascular angiography range
from 1.9% to 2.9% [29]. Invasive contrast angiography is now
reserved for patients with PAD who are being considered for
endovascular revascularization.
Medical Treatment
Tobacco Cessation
Multiple modalities for tobacco cessation such as behavioral
therapy, nicotine replacement, and medications (bupropion
and varenicline) are more effective than a single modality
[30]. Varenicline acts as a partial agonist at the alph-4-beta2 nicotinic acetylcholine receptor and has been associated
with higher smoking cessation rates than either placebo or
bupropion. Patients who smoke should be encouraged to
quit smoking primarily to reduce their risk of cardiovascular events and to reduce progression of PAD.
Antiplatelet Therapy
Aspirin therapy for patients with PAD is widely recommended by professional society guidelines including those
of the American College of Cardiology/American Heart Association and the Inter-Society Consensus for Management
of Peripheral Arterial Disease [18]. The evidence for aspirin
therapy in patients with coronary and cerebrovascular disease has been established by a number of large-scale trials
[31], but these trials lack patients with PAD.
The Antithrombotic Trialists Collaboration (ATC) was a
meta-analysis that contained a subgroup of 9214 patients with
PAD. There was a 22% reduction in the primary end point
of vascular death, nonfatal stroke, and nonfatal myocardial
infarction in patients receiving antiplatelet therapy. Remarkably, only one-third of the trials included in this meta-analysis
utilized aspirin monotherapy as the antiplatelet therapy [32].
A meta-analysis of the 5 aspirin monotherapy trials in the
ATC showed no significant benefit of aspirin in the reduction
of the primary end point [33]. A more recent meta-analysis of
18 trials including aspirin monotherapy in patients with PAD
also failed to show a statistically significant reduction in the
primary end point. [34]. Larger prospective studies would
be necessary to draw firm conclusions about the net clinical
benefit of aspirin in patients with PAD.
Clopidogrel has been used as an alternative to aspirin. This indication is based primarily on a subset of the
78 JCOM February 2011 Vol. 18, No. 2
CAPRIE trial. CAPRIE enrolled 19,185 high–cardiovascular
risk patients and randomized them to receive either clopidogrel 75 mg/d or aspirin 325 mg/d. Of these, 6452 patients
had PAD. After 3 years, the PAD subpopulation had a 23.8%
relative risk reduction in MI, stroke, or cardiovascular death
in favor of clopidogrel [35].
There is little evidence to support dual antiplatelet therapy in PAD. The CHARISMA trial had 3096 patients with
PAD. These patients were randomized to dual antiplatelet
therapy with aspirin 75 to 162 mg/d and clopidogrel 75 mg/
d or aspirin 75 to 162 mg/d with placebo. Dual antiplatelet
therapy showed a nonsignificant reduction of 7.1% in the
composite end point of death, MI, or stroke at a median of
28 months [36].
Warfarin is not indicated for PAD. The WAVE trial
enrolled 2161 patients with PAD and randomized them to
receive warfarin (goal INR, 2–3) with an antiplatelet agent
or an antiplatelet agent alone. The warfarin group had no
reduction in primary end point and had a statistically significant increase in major bleeding events [37].
Exercise Therapy
Supervised exercise therapy is the first line of treatment
in the management of intermittent claudication (Figure 3).
A meta-analysis by the Cochrane collaboration including
randomized controlled trials examining exercise training
for intermittent claudication showed improved maximal
walking ability by an average of 150% [38]. In addition to
relieving symptoms, exercise training has prognostic implications. McDermott et al demonstrated that patients who
walk 3 times weekly experienced less functional decline at
1-year follow-up [39].
Several studies have shown that patients with asymptomatic PAD have impaired walking distance and speed.
This casts doubt as to whether these patients are truly
asymptomatic or have adapted to reduce their exertion and
minimize their symptoms [40]. Various studies have suggested that supervised exercise training may provide benefit
for these “asymptomatic” patients [40].
Exercise training as a practical matter is fraught with difficulties. Patients are often not motivated to exercise since it
induces pain and discomfort. Moreover, patients who were
told to “go out and walk” did not derive the same benefit as
those in a supervised exercise program similar to cardiac rehabilitation. Deficiencies in funding and reimbursement are
the major reasons for lack of supervised exercise programs
for patients with PAD [41].
Treatment of Hypertension
Hypertension is strongly linked to the development of
atherosclerosis and is a major risk factor for PAD. Hypertension guidelines support blood pressure lowering
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clinical review
Confirmed PAD Diagnosis
No significant
functional disability
• No claudification treatment required
• Follow-up visits at least
anually to monitor for development of leg, coronary, or
cerebrovascular ischemic
symptoms
Lifestyle-limiting symptoms with
evidence of inflow disease*
Lifestyle-limiting symptoms
Supervised exercise
program
Pharmacological
therapy:
Cilostazol
(Pentoxifylline)
Further anatomic definition by
more extensive noninvasive
or angiographic diagnostic
techniques
Three-month trial
Endovascular therapy
or surgical bypass per
anatomy
Three-month trial
Preprogram and
postprogram exercise
testing for efficacy
Clinical improvement:
Follow-up visits at least
annually
Significant disability despite medical therapy and/or inflow endovascular
therapy, with documentation of outflow†
PAD, with favorable procedural anatomy
and procedural risk-benefit ratio
Evaluation for additional endovascular or
surgical revascularization
Figure 3. Treatment of claudication. *Inflow disease should be suspected in individuals with gluteal or thigh claudication and
femoral pulse diminution or bruit and should be confirmed by noninvasive vascular laboratory diagnostic evidence of aortoiliac
stenoses. †Outflow disease represents femoropopliteal and infrapopliteal stenoses (the presence of occlusive lesions in the
lower extremity arterial tree below the inguinal ligament from the common femoral artery to the pedal vessels). (Adapted from
reference 18.)
in patients with atherosclerosis. Angiotensin-converting
enzyme (ACE) inhibitors have a very important role in
patients with PAD [42–45]. ACE inhibitors may increase
pain-free interval and maximum walking time in patients
with symptomatic PAD [46]. Beta-adrenergic blocking
drugs have previously been discouraged in PAD because
of the possibility of worsening claudication symptoms, but
this has not been supported in the randomized controlled
trials. Thus, beta-adrenergic blockers can be considered in
patients with PAD [47].
Treatment of hypertension primarily involves pharmacotherapy but nondrug interventions must also be initiated in tandem; weight reduction, limited salt intake, and
regular exercise play significant roles [48]. According to
the Joint National Committee 7 guidelines, hypertension
in PAD can be managed with any class of blood pressure–
lowering agent and they advocate initial use of a diuretic
in most cases [49]. Certain compelling indications such as
coronary artery disease, diabetes mellitus, heart failure,
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and chronic kidney disease obligate the use of angiotensin inhibitors, beta blockers, or aldosterone antagonists as
first-line agents [50]. The recommended blood pressure
goal for patients with PAD is less than 140/90 mm Hg. If
patient also has diabetes, the goal shifts to less than 130/80
mm Hg [49].
Treatment of Hyperlipidemia
Aggressive lipid lowering is recommended in patients with
existing PAD, as hyperlipidemia is known to be one of the
many conventional atherosclerotic risk factors involved in
the disturbance of the normal homeostatic function of the
endothelium and vascular wall [51]. A subgroup analysis
of the Heart Protection Study demonstrated that in patients
with PAD (even in the absence of a prior myocardial infarction or stroke), aggressive low-density lipoprotein cholesterol
(LDL) lowering was associated with a marked reduction in
cardiovascular events [52]. PAD represents equivalent risk to
that of established coronary artery disease, and aggressive
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Antiplatelet activity
Vasodilation
Increase HDL-C
Cilostazol
Decrease triglycerides
Inhibition of vascular smooth
muscle cells
Antithrombotic activity
Increase blood flow
Mild increase in heart rate
Figure 4. Proposed effects of cilostazol.
cholesterol lowering must be offered to all patients with PAD
to reduce subsequent adverse cardiovascular events. The
guidelines advocate lowering LDL to less than 100 mg/mL
and triglyceride levels to less than 150 mg/mL with further
LDL reductions to less than 70 mg/mL has also been suggested [48]. Treatment with simvastatin and atorvastatin
in hypercholesterolemic patients with PAD resulted in an
increase in pain-free and total walking distance as well as
improved physical function compared with placebo [53,54].
The pleotropic effects of statin therapy are many; in addition to its role in lowering LDL, it increases endothelial
nitric oxide production, inhibits smooth muscle migration,
exerts antithrombotic and antiplatelet effect [55], and it may
decrease inflammation as reflected by lower C-reactive
protein (CRP) levels [56]. Patients with low CRP levels have
better clinical outcomes than those with high CRP regardless
of their LDL levels [57]. Thus, all patients with PAD should
be on cholesterol-lowering therapy independent of baseline
cholesterol levels.
Treatment of Diabetes Mellitus
Diabetes mellitus is a potent risk factor for PAD and systemic atherosclerosis. About 20% to 30% of PAD patients
have diabetes, and this cohort has a high risk of lower limb
amputation (up to 15 times more likely) as well as adverse
cardiac and cerebrovascular outcomes [58]. The duration of
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diabetes and the degree of glycemic control are intimately
linked to the risk of PAD. For every 1% rise in glycated hemoglobin (A1C), there is a 28% increase in the risk of PAD
[59]. Intensive control of blood sugar effectively prevents microvascular complications, but its effects on macrovascular
complications such as intermittent claudication are less definitive [60]. American Diabetes Association guidelines advocate tight glycemic control in PAD patients with diabetes,
setting an A1C target of ≤ 7% [61]. Despite the association of
PAD with diabetes, there is lack of evidence that there is any
favorable effect of intensive glycemic control on the progression of PAD. Both the Diabetes Control and Complications
Trial [62] and the United Kingdom Prospective Diabetes
Study [60] found that intensive therapy was associated with
a trend toward a reduction in cardiovascular events but had
minimal effect on the risk of PAD. In diabetics, meticulous
attention to foot care, appropriate footwear, cleansing and
use of moisturizer, and inspection by patient and physicians
is necessary to reduce risk of skin ulceration, necrosis, and
subsequent amputation [18].
Claudication-Targeted Medical Treatment
Cilostazol
Cilostazol is a phosphodiesterase type 3 inhibitor that mediates a variety of physiologic responses (Figure 4) and was
approved in 1999 for the treatment of intermittent claudicawww.jcomjournal.com
clinical review
tion. Cilostazol is a vasodilator that inhibits smooth muscle
proliferation and platelet function [63]. Cilostazol has been
shown to improve maximal walking distance by 40% to 60%
compared with placebo after 12 to 24 weeks of therapy in
patients with intermittent claudication [64,65]. Cilostazol has
also found to be significantly more effective than pentoxifylline and placebo in patients with intermittent claudication
[66]. The AHA/ACC guidelines have a class I recommendation for the use of cilostazol (100 mg orally 2 times/day)
as an effective therapy to improve symptoms and increase
walking distance in patients with lower extremity PAD and
intermittent claudication (Figure 3) [18]. For those experiencing adverse effects or the elderly, a dose of 50 mg twice
daily is recommended. Common side effects associated with
cilostazol include headache, diarrhea, palpitations, and dizziness. Cilostazol is contraindicated in patients with heart failure because of class-associated proarrhythmic effects [67].
Pentoxifylline
Pentoxifylline is a methylxanthine derivative that purportedly improves the deformability of red cells, inhibits inflammatory response, and attenuates platelet aggregation. The
mechanism of pentoxifylline, however, was examined in
an in vivo study and showed no improvement in red cell
deformability, plasma viscosity, or fibrinogen levels [68]. A
meta-analysis of 13 studies looking at the use of pentoxifylline in intermittent claudication showed that there was an increase in total walking distance of 44 m (10–67 m). There was
no effect on ABIs or functional status [69]. The bulk of studies examining pentoxifylline show a mild improvement in
walking distances but there is a lack of compelling evidence
for the use of pentoxifylline in the treatment of intermittent
claudication [70–72]. As such, it has been given a class IIb
recommendation in the ACC/AHA practice guidelines [18].
Therapeutic Angiogenesis
There is emerging data on therapeutic angiogenesis using
angiogenic growth factors and stem cell therapy to stimulate
collateral circulation in PAD. Many angiogenic agents have
been used, including vascular endothelial growth factor
(VEGF), hepatocyte growth factor (HGF), fibroblast growth
factor (FGF), and hypoxia-inducible factor-1 (HIF-1) [73].
The Therapeutic Angiogenesis with Recombinant Fibroblast Growth Factor 2 (rFGF-2) for Intermittent Claudication
(TRAFFIC) study, an early randomized trial in 190 patients
with infranguinal PAD, demonstrated that rFGF-2 provides
significant improvement in peak walking time and ABI
[74]. The Regional Angiogenesis with Vascular Endothelial Growth Factor in Peripheral Arterial Disease (RAVE)
study using intramuscular VEGF121 was negative as it did
not show any differences in symptom reduction between
placebo and the treated groups [75]. The hepatocyte growth
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factor plasmid provided encouraging results by demonstrating improving limb tissue perfusion as measured by transcutaneous oxygen tension (TcPO2) in the Study to Assess
the Safety of Intramuscular Injection of Hepatocyte Growth
Factor Plasmid to Improve Limb Perfusion in Patients
with Critical Limb Ischemia (HGF-STAT trial) [76]. On the
other hand, the results of a dose-ranging study of hypoxiainducible factor-alpha in a large cohort of patients randomized to 1 of 3 doses or placebo via intramuscular injection
was negative [77]. Recently, the results of the NV1-FGF Gene
Therapy on Amputation-Free Survival in Critical Limb
Ischemia (TAMARIS) trial [78] were presented at the AHA
2010 Scientific Session. The TAMARIS trial randomized
patients with critical limb ischemia unsuitable for revascularization to 8 intramuscular injections of NV1-FGF gene
therapy versus intramuscular injections of placebo. Death or
major amputation at 12 months occurred in 37% in the gene
therapy group versus 33% in the placebo group (P = 0.48),
demonstrating no benefit of from intramuscular NV1-FGF
therapy.
Tateishi-Yuyama et al [79] assessed the role of stem cell
transplantation using bone marrow–derived progenitor cell
in therapeutic angiogenesis. Improvements in measured
ABI, pain-free walking distances, and transcutaneous oxygen pressure at 24 weeks were observed with intramuscular
injection of bone marrow–derived progenitor cell in 22
patients with bilateral PAD. Similar efficacy and safety have
been reported in uncontrolled studies of limited size where
autologous bone marrow-derived progenitor cells were
used, but data concerning true efficacy are still at an early
stage and there is no clear evidence as to the best therapeutic
cells to use in PAD [79]. Although angiogenesis using genebased growth factors and stem cell–based therapies remains
a promising future option for the treatment of peripheral
vascular disease, it is still at the early investigational stages.
Summary
PAD is a highly prevalent but underrecognized and undertreated atherosclerotic condition associated with significant
morbidity and mortality. Physicians need to maintain a high
index of suspicion for the diagnosis of PAD. PAD can be diagnosed accurately with a comprehensive history, physical
examination, and methodologic noninvasive vascular tests.
It has a strong association with the well-defined risk factors
for atherosclerosis, such as diabetes, smoking, advanced
age, hyperlipidemia, and hypertension. Thus, aggressive
risk factor modification and secondary prevention strategies
such as antiplatelet therapy, lipid lowering therapy, smoking
cessation, diabetes control, and antihypertensive treatment
should be considered in patients with PAD. Cilostazol improves both pain-free maximal treadmill walking distance
and quality of life. Angiogenesis using gene-based growth
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PeriPheral Arterial Disease
factors and stem cell–based therapies remains a promising
future option for the treatment of PAD.
Corresponding author: Yung-Wei Chi, DO, UC Davis Medical Center,
Sacramento, CA 95817, [email protected].
14.
Financial disclosures: None.
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