Full Article
Given the significant dilemma of peripheral arterial
disease and its strong association with diabetic complications
in the lower extremity, this author reviews
pertinent diagnostic keys and assesses the current
research on treatment options.
By Kazu Suzuki, DPM, CWS
Peripheral arterial disease (PAD),
formerly known as arteriosclerotic
obliterans (ASO) or peripheral
vascular disease (PVD), is extremely
underdiagnosed and undertreated.
Although PAD is commonly regarded
as a nuisance and “leg cramping” problem,
current clinical evidence indicates
PAD is a reliable predictor of death
resulting from major cardiovascular
ischemic events such as myocardial
infarction (MI), stroke and critical limb
ischemia (CLI).1
Diabetes is a significant risk factor for
PAD. Insulin resistance is strongly
linked to the development of PAD and
type 2 diabetes increases the chance of
developing PAD by three- to fivefold.2
When an estimated 30 percent of all
patients with diabetes in the United
States have PAD, the correlation
between the two pathologies is undeniable.3 Patients with diabetes have a
25 percent lifetime risk of developing
diabetic foot ulcers (DFUs) and
researchers have found that 50 percent
of patients with DFUs have PAD.4,5
Peripheral arterial disease and CLI, as
well as DFUs, are all risk factors of
major leg amputation with associated
high morbidity and mortality rates,
and a decrease in one’s quality of life.
Peripheral arterial disease represents
stenosis of peripheral arterial blood
flow typically caused by atherosclerosis,
which is characterized by chronic
inflammation of arterial walls and the
formation of multiple cholesterol
plaques within the arteries.This affects
the arms, legs, carotid arteries and renal
arteries. Since PAD affects the legs
most often, “lower extremity PAD” is
often simply called PAD.
As one of the most common cardiovascular
diseases, PAD affects an
estimated 8 to 12 million people in
the U.S. It carries a mortality rate of
30 percent over five years. Indeed, the
mortality rate of PAD is higher than
that of coronary artery disease (21
percent) and stroke (28 percent).6
Major risk factors for PAD are
advanced age, diabetes and smoking.
According to American College of
Cardiology (ACC)/American Heart
Association (AHA) PAD guidelines, the
risk of PAD progressively increases with
age starting at 50. In fact, at age 70 or
older, patients are automatically considered
high-risk for PAD, even without a
history of diabetes or smoking.7
The PARTNERS study enrolled
approximately 7,000 primary care
patients and screened them for PAD.
The study diagnosed 29 percent of
“at-risk” participants with PAD.
However, physician awareness of PAD
was strikingly low in this study.8
The general public equally underestimates
the incidence of PAD. In a recent
survey of 2,501 adults (age 50 or older),
only 25 percent knew of PAD but they
were familiar with stroke (74 percent)
and coronary artery disease (67 percent).
In fact, PAD was less recognized
than rare genetic diseases such as Lou
Gehrig’s disease and cystic fibrosis.9
Given those factors, PAD is grossly
under-recognized by both patients and
doctors despite the fact that the disease’s
known morbidity and mortality exceed
that of myocardial infarction (MI) and
stroke. Indeed, symptomatic PAD can
progress in five years to non-fatal MI or
stroke (20 percent occurrence) or death
from cardiovascular event (another 20
percent occurrence).10
The REACH registry enrolled
more than 68,000 international
patients and found a 16 percent overlap
of polyvascular disease. This translates
into one in six PAD patients having overlapping obstructive disease in
coronary arteries and/or cerebral
arteries. In this study, the patients with PAD had a 21 percent chance of dying within one year.
What You Should Know
About PAD And Critical Limb
Ischemia
In milder forms,PAD can be completely
asymptomatic in up to 50 percent of
cases. Even though “asymptomatic
PAD” sounds benign, it was actually
associated with higher mortality rates
than individuals without PAD.11
As leg artery stenosis progresses,
patients may develop calf pain from
walking.This claudication is due to the
lack of blood flow to meet the ambulatory
demand from lower extremity
muscles. Although claudication is often
associated as a textbook case of PAD, it
may account for as few as 10 percent of
PAD patients.7 As the obstruction of the
blood flow becomes worse, the patient’s
disease may progress to CLI.
Critical limb ischemia is a severe
obstruction of the arteries and blood
flow to the legs. There are approximately
between 500 and 1,000 new
cases of CLI every year per every 1
million Americans.
Critical limb ischemia often manifests
with non-healing or gangrenous
ulcers, and ischemic “rest pain,” which
is caused by a “critical” lack of blood
flow to sustain the lower extremity tissue.
In fact, CLI is often described as a
“heart attack of the legs.” It is a serious
condition that carries a high probability
of limb loss with a need for urgent
intervention because the ischemic condition
will not improve on its own.
The TASC-II data for unreconstructable
CLI show dismal outcomes.
Approximately 40 percent of
these patients will lose their leg
within six months and up to 20 percent
will die. Of those CLI patients
who received leg amputations, 30
percent will die within two years, 15
percent will have above-knee amputations
and 15 percent will have
bilateral leg amputations.2
Counterintuitively, leg amputation
will not always result from “slow and
gradual worsening of claudication
over many years.” Instead, more than
half of below-knee amputation (BKA)
cases from ischemia suffer no leg
symptoms whatsoever as recently as
six months prior to amputation.12
These data also support the fact that
the majority of PAD patients present
with asymptomatic “silent” disease.
Essential Diagnostic Insights
Diagnosing PAD starts with taking a
history and focusing on the identification
of risk factors such as age over 50,
smoking, diabetes, hyperlipidemia and
hypertension. The presence of other
cardiovascular diseases, as well as typical
or atypical leg symptoms, also suggests
PAD.
Physical exam and pulse palpations
are valuable, but should never be the
sole basis of PAD diagnosis. A recent
meta-analysis found that our physical
examinations are not sufficiently
accurate or reliable enough to “rule in
or rule out” PAD. The study recommended
using some kind of objective
“Doppler” test to diagnose/rule out
PAD with confidence.13
As a wound care physician, I
approach all new patients presenting to
our wound care centers with a high
index of suspicion for PAD.As ischemic
leg wounds do not heal, a patient presenting
with chronic wound is likely to
have undiagnosed PAD.
As noted above, non-invasive objective
perfusion assessment tools are
essential, not supplemental, for PAD
diagnosis. Given the right diagnosis,
these non-invasive perfusion tests are
often reimbursable (CPT code 93922-
93923) if one performs a thorough
exam and keeps printable records
along with the clinical interpretations.
Ankle brachial index (ABI).The
ABI is a commonly performed
macroperfusion test with a handheld
Doppler. If the ABI is below 0.9, it is
considered diagnostic of PAD. Both
the ABI and toe brachial index (TBI)
are useful screening tools for ischemia if the patients do not have calcified leg
arteries, which is often the case with
elderly, diabetic and dialysis patients.
Accordingly, one should use ABI and
TBI only for making the PAD diagnosis
(when the ABI is 0.9 or lower),
and never to “rule out” the presence
of PAD when it is seemingly normal
(ABI 0.9 or higher).
As one would expect, the ABI may
not correlate with wound healing
probability for patients with diabetes
or those in chronic renal failure.14
Although the ACC/AHA guidelines
recommend the use of a “resting ABI”
test in diagnosing at-risk individuals,
the level of evidence is graded “C”
(only consensus opinion of experts).7
Our wound care center also uses
pulse volume recordings (PVR), which
is an alternative macroperfusion test
that is not affected by calcified arteries.
Pulse volume recording uses blood
pressure cuffs and transducers, which document the qualitative waveforms
that reflect the pressure difference in
pulsatile arterial inflow during systole.
Skin perfusion pressure (SPP). The SPP is a microperfusion test that
measures blood pressure of skin capillaries.
Since it uses a laser beam to scan
only the superficial skin layer, it is not
affected by leg artery calcifications.
This test has clinically demonstrated
higher accuracy in PAD diagnosis
than ABI, and it predicts the wound
healing probability with approximately
90 percent accuracy.15-19
In our wound care center, we assess
the vascular status of lower extremity
wound patients with a laser-Doppler
based SPP monitor. If the foot/ankle
SPP is below 30 mmHg, it is diagnostic
of critical limb ischemia (CLI) and predictive
of wound healing failure.16 If the
SPP is above 40 mmHg, it is predictive
of good wound healing potential. In
general, if the SPP is over 50 mmHg,
one can effectively rule out PAD.17-18
One may substitute the SPP test
with a transcutaneous oximetry
monitor (TCOM), which is another
common microperfusion test.
However, the recent head-to-head
comparison studies of these two tests
favor SPP as it is more accurate in
wound healing prediction and less
time-consuming to perform.19
What The Current Research
Reveals About Blood
Markers For PAD
Peripheral arterial disease is in many
ways similar to cancer. Both diseases are
common and progressive with high
morbidity and mortality. They are also
very disabling and disfiguring (considering
leg amputations). The analogy
also holds true in the screening process
as earlier detection and treatment
would result in a better outcome.
Many studies have searched for
“PAD blood markers” — similar to
the prostate-specific antigen (PSA) for
prostate cancer for example — and the latest research shows that beta-2-
microglobulin, cystatin C, hs-CRP
and glucose have the highest correlation
with the presence of PAD, independent
of traditional risk factors such
as age, smoking and diabetes.20
This PAD blood test, which
researchers evaluated in four studies of
almost 1,000 patients, has demonstrated
that patients with a high index are seven
times more likely to have PAD than
patients with a low index score.21
Continued work may offer the hope of
implementing a simple blood test to
screen “at-risk” patients for asymptomatic
PAD in the near future.
A Pertinent Overview Of
Keys To Medical Treatment
Medical treatments are effective in preventing
the progression of PAD and
subsequently diminish the increased
risk of MI, stroke, CLI and death.7
The 2005 ACC/AHA Guidelines
recommend anti-platelet therapy
(aspirin and/or clopidogrel) to essentially
all PAD patients as it reduces the
need for revascularization while reducing
major cardiovascular events
(myocardial infarction, stroke, vascular
death).Although the clinical evidence is
less robust, statins and ACE inhibitors
are also recommended for PAD
patients. As PAD is a metabolic disease,
normalizing the risk factors is essential,
not to mention the importance of
smoking cessation and daily exercise.
To summarize, the medical management
of PAD calls for:
- immediate cessation of smoking;
- antiplatelet therapy (aspirin
and/or clopidogrel);
- control of lipids/cholesterol to achieve a LDL below 100 mg/dl (as
per the National Cholesterol
Education Program (NCEP) Adult
Treatment Panel (ATP) III guideline);
- control hypertension with the
goal of blood pressure below 130/80
(as per the JNC-7 guidelines from the
Joint National Committee on
Prevention, Detection, Evaluation and
Treatment of High Blood Pressure);
- control diabetes (with a goal of
achieving a HbA1c less than 7 percent);
and
- exercise for general cardiovascular
health and to treat claudication.
What About Surgical
Treatment Options?
If claudication is debilitating, an
ischemic ulcer threatens limb loss or
one discovers or diagnoses CLI, the
physician should refer the patient to
vascular specialists for immediate
intervention to increase blood flow
to the leg(s).2
Surgical treatment (leg bypass
and endarectomy). Vascular surgeons
can provide surgical treatments
of lower extremity PAD. This usually
requires harvesting autologous veins
from the patient and reconnecting
these to the diseased arteries to
“bypass” the blocked portion, creating
alternative blood flow to the legs and
feet. Vascular specialists may perform
an endarectomy, the surgical removal
of plaques, in conjunction with the
bypass procedure.
As the bypass is an “open” surgical
procedure, there is a certain amount of
morbidity and mortality associated
with the procedure.There will also be
several days of hospitalization after the
procedure. In general, surgical bypass
procedures are known to be clinically
durable with good long-term
anatomical patency.2
A Closer Look
At The Potential Merits
Of Endovascular Therapy
Endovascular therapy. Most vascular
surgeons, as well as interventional cardiologists
and interventional radiologists,
provide endovascular therapy to treat
from “within the arteries.” It is now
possible to open up the narrowed arteries
in most cases, using balloon angioplasty,
stents, stent grafts and plaquedebulking
tools. In comparison to surgery,
these endovascular treatments may
have lower morbidity and mortality
with shorter hospital stays. Critics of
endovascular therapy point to its high
restenosis rate and the lack of longterm
data with newer devices.
In general, endovascular therapy is
recommended for short and focal segments
of stenosis, and for the treatment
of claudication.Vascular surgeons often reserve surgical bypass for longer segments
of diffuse and severe stenosis, and
for limb preservation purposes.2
The debate on whether surgical
bypass or endovascular treatment is
superior can be provocative. The
BASIL trial was designed to gain level
1 evidence by randomizing 452 CLI
patients to either surgery first or an
angioplasty first strategy. Interestingly,
the results of this study indicated a
“statistical tie” in terms of amputation-
free survival rates, all-cause mortality
and quality of life between the
two treatment groups.22
Recent outcome data of CLI intervention
show long-term limb salvage
rates of 80 to 90 percent, both in surgical
and endovascular approaches.23-25
This may indicate that we should
focus our energies on limb preservation
through the earliest possible detection and timely intervention of
PAD/CLI rather than feuding over
the superiority of two complementary
revascularization treatments.
Why Diabetic Foot Ulcers
And PAD Are A Deadly Mix
Diabetic foot ulcers are precursors to
85 percent of major leg amputations,
which lead to increased morbidity and
mortality rates rivaling that of many
cancers.4 Diabetes causes unique and
characteristic stenosis of tibial vessels
below the knee while diabetic neuropathy
masks the ischemic pain and
protective sensation. This presents a
“perfect storm” for limb loss.
The majority of wound patients in
the U.S. are known to have venous leg
ulcers. However, when one separates
the incidence anatomically into “foot
ulcers” versus “leg ulcers (above the
ankle joint),” we find that 75 percent
of the “foot ulcers,” which may directly
lead to limb loss, are “diabetic” and
“arterial” in etiology.2
The EURODIALE study compared
patients with DFUs to patients
with DFUs and PAD over a one-year
follow-up period. The study, which
involved 1,088 patients, showed the
“DFUs with PAD” group had poorer
healing rates, an increase in major
amputations and higher mortality
rates, especially with the presence of
infection, in comparison to patients
who had DFUs without PAD.26
Historically, diabetic foot care has
always focused on screening for
peripheral neuropathy. However,
Lavery, et al., showed that the presence
of PAD, not neuropathy, occurred
with significantly more ulcers, infections,
amputations and hospitalizations.
The study points out the “highrisk
PAD groups” accounted for only
20 percent of the study population
while representing 70 percent of
ulcers and 90 percent of amputations
and hospitalizations.27 These data suggest
that we should shift our focus on timely PAD detection for the sake of
better limb preservation and costeffective
use of our healthcare dollars.
Examining The Evidence
On The Use Of Adjunctive
Therapies For DFUs
To approach a new wound patient,
one begins with the initial assessment
of infection and ischemia, two essential
impediments of wound healing.
The wound infection is mostly a clinical
diagnosis based on symptoms,
appearance, drainage and odor.
Physicians should base the diagnosis of
ischemia (PAD) on objective perfusion
tests as previously stated.
Afterward, one should render the
“best practice” wound care treatment,
consisting of frequent debridement,
adequate offloading and moist wound
dressing, which are also important
treatment practices with definitive
clinical evidence.28
Diabetic foot ulcers are notorious
for non-healing. The “standard of
care”wound treatment only healed 31
percent of DFUs within five months.29
The ulcer area reduction in the first
four weeks is also a robust predictor of
complete wound closure in 12 weeks.
Accordingly, one should use various
adjunctive treatments for aggressive
treatment of ulcers that do not
improve in the first few weeks of initial
treatment.30
Hyperbaric oxygen therapy
(HBO). Hyperbaric oxygen chambers
are currently located in over 750
facilities in the U.S. One can find a
directory of these HBO chambers at
www.uhms.org. Hyperbaric oxygen
uses high pressure (minimum 2.0
ATA) sturdy chambers made of metal
and acrylic materials that enclose the
patient, and “forcefeed” 100 percent
oxygen through their lungs.
The HBO causes hyperoxygenation,
which specifically counteracts
the factors known to impair wound
healing in DFUs. Medicare and most
private payors reimburse HBO treatment
of DFUs if the ulcers are deeper
than Wagner Grade III.31
The Cochrane Systematic Review
advocates the use of HBO in DFUs,
noting that HBO “significantly reduced
the risk of major amputation and may
improve the chance of healing at one
year.” The analysis predicts that HBO
averted one major leg amputation per
four patients treated.32
A recent Canadian study also
found that adjunctive HBO in DFU
treatment was more effective and
healed more wounds versus standard
care alone, resulting in a lowered
incidence of major leg amputations,
lowered treatment costs and
increased “quality of life.”33
Negative pressure wound therapy
(NPWT). Negative pressure
wound therapy is another adjunctive
therapy for DFUs with robust clinical
evidence.As NPWT dressings are compatible
with HBO treatment, physicians
often utilize NPWT and HBO simultaneously
for the treatment of DFUs.
Armstrong, et al., conducted a multicenter,
randomized controlled trial
on NPWT therapy involving 162
DFU patients who were assigned to
the negative pressure therapy group or
the standard “moist wound care”
group. The results indicated a faster
rate of granulation tissue formation
with more healed patients and a faster
rate to complete closure in the negative
pressure group in comparison to
the control group.34
Blume, et al., conducted another
multicenter randomized clincal trial of
342 patients with DFUs, and compared
NPWT with advanced moist wound
therapy (AMWT). In results that were
supportive of the Armstrong study,
Blume, et al., concluded that negative
pressure achieved faster granulation tissue
formation, healed more DFUs and
there was a decreased time to ulcer closure
in comparison to AMWT.35
Skin substitutes and topical
PDGF gel. Many bioengineered “skin
substitutes” indicated for the treatment
of DFUs are commercially available
today. Most of these products are composed
of processed human or animal
tissues that containing collagen, fibroblasts
and growth factors to promote
wound healing. These products have
been extensively researched for their
safety and efficacy, and are supported by
many randomized clinical trials. For
example, a randomized prospective trial
of bilayered living cell therapy enrolled
208 patients and showed a statistically
significant difference at the 12-week
follow-up visit with higher complete
wound healing with bilayered living
cell therapy (56 percent) versus the
control group (38 percent).36
Recombinant human plateletderived
growth factor (PDGF) gel
(becaplermin) is another topical product
designed to supplement the
growth factor that may be deficient in
chronic DFUs.The clinical efficacy of
becaplermin has been well established
but there is a recent safety concern
from an increased risk of death from
cancer in patients who had repeated
becaplermin treatments.37,38 One
should weigh the potential risk of
using becaplermin against the benefit
of each individual patient.
In Conclusion
Peripheral arterial disease is a progressive
and deadly disease that one must
detect and diagnose at the earliest
opportunity so physicians can institute
interventions and facilitate referrals
when appropriate to ensure the best
outcome possible. Similarly, it is important
to treat DFUs aggressively while
paying particular attention to the presence
of PAD to prevent major leg
amputation and its associated morbidity,
mortality and dramatic decline in the
patient’s quality of life.
Dr. Suzuki is the Medical Director of
Tower Wound Care Center at the CedarsSinai Medical Towers. He is also on the medical
staff of the Cedars-Sinai Medical Center
in Los Angeles and is a Visiting Professor of
Tokyo Medical and Dental University in
Tokyo, Japan. One can contact the author at
kazu88@gmail.com.
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