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					Clinical Case
          A.P. is a 68 year old male with a history of hypertension and Type 2 diabetes mellitus. He has a 40-year
history of smoking one pack of cigarettes per day and has recently cut back to one half a pack per day. He presents
to the office at his wife’s insistence with the complaint of difficulty walking. Over the past three months, he has
experienced cramping in his legs that occurs after walking about two city blocks. The pain is quickly relieved after
sitting down. He denies any other complaints. Physical examination reveals a left carotid bruit, soft femoral bruits
bilaterally, and diminished pedal pulses. The remainder of the examination is unremarkable. The patient is
suspected of having peripheral arterial disease.


Clinical Questions
#1 How reliable is the physical examination in detecting the presence of lower extremity peripheral arterial disease?

#2 Are further diagnostic tests necessary and, if so, which should be ordered?

#3 What treatment plan should be initiated?


Introduction
         Peripheral arterial disease (PAD) is common. More than 4.2 million people in the United States are
affected(1). This number has increased and will be expected to increase more as Western society ages. The annual
incidence of PAD has been described as 2 percent in the 40 year old age group, 4.2 percent in the 50 year age group,
6.8 percent in the 60 year age group, and 9.2 percent in the 70 year age group. Unfortunately, 50 to 90 percent of
patients with symptoms will never complain to their physicians. Many contribute symptoms to the normal aging
process(2). The challenge for physicians is to identify those with PAD or those at risk. It is important to be familiar
with the diagnosis and treatment of this disease.


Goals of this Discussion
          Peripheral arterial disease is a broad subject with different etiologies and vascular distribution. The focus
of this talk will be on lower extremity arterial disease secondary to atherosclerosis. The natural history, risk factors,
and morbidity/mortality will be discussed. Diagnosis with physical examination and noninvasive tests will be
addressed. Therapy is a broad subject within itself. This discussion will focus on nonsurgical treatment.


Classification
         The symptoms and signs of PAD depend on the severity. The severity of the disease guides therapy. The
Fontaine classification of PAD is useful. It consists of four stages based on clinical features(3).

         STAGE 1           Silent (asymptomatic)
         STAGE 2           Symptoms with walking, relieved with rest (intermittent claudication)
         STAGE 3           Symptoms at rest (rest ischemia)
         STAGE 4           Skin ulceration or gangrene

         Stages 1 and 2 are the most common. Fontaine stage 2 is characterized by the symptom of intermittent
claudication. Intermittent claudication can be defined as pain with walking that is relieved by rest. Stages 3 and 4
represent advanced disease best treated with surgical intervention. The focus of this discussion will be on the first
two stages. These stages represent a potential point in which to identify and prevent progression of this disease.


Natural History of PAD
         Mortality as a direct consequence from PAD seems relatively low. In fact, PAD has been described as
having a relatively benign course as far as the legs are concerned. The natural course of PAD after five to ten years
remains stable in 70 to 80 percent of patients. Symptoms are unchanged or have improved in most patients.
However, 20 to 30 percent of patients will have progressive symptoms which require surgical intervention. Only 10
percent or less will require amputation. Disease progression is greatest in patients with low ABIs, chronic renal
disease, diabetes, and continued smoking (6). The effects and impact of PAD should not be underestimated. Even
though direct mortality from PAD is low, the morbidity associated with a decrease in the quality of life is
substantial.


Morbidity and Mortality
         Cardiovascular disease represents the most common cause of morbidity and mortality in patients with PAD.
Fifty percent of patients with intermittent claudication in the Framingham study developed cardiovascular disease
within ten years. In the Quebec Vascular Study, which followed 4570 men, patients with intermittent claudication
had a four times greater risk of nonfatal coronary ischemic events than the normal population(4). The average life
expectancy of patients with intermittent claudication (Fontaine Stage 2) is decreased by ten years. The most
common cause of mortality is related to coronary events (2).
         Cerebrovascular disease is also an important cause of morbidity and mortality in patients with PAD.
Morbidity and mortality from cerebrovascular disease is less common than cardiovascular events but is recognized
as increased in patients with PAD(4).


Risk Factors
         Risk factors for PAD are similar to those for cardiovascular disease. Four of the most accepted ones are
diabetes mellitus, cigarette smoking, hyperlipidemia, and hypertension. Murabito et al. developed a risk profile for
intermittent claudication (Fontaine Stage 2) using data from the Framingham Heart Study. A total of 381 people
(215 men, 166 women) were identified as developing intermittent claudication. Odds ratios were calculated for
significant risk factors: 2.6 for diabetes mellitus, 2.2 for moderate hypertension (systolic>160, diastolic>100), 1.4
for each 10 cigarettes smoked per day, and 1.2 for each 40 mg/dl increase in serum cholesterol over 170(5). The
Quebec Vascular Study identified similar risk factors as the Framingham Study with the exception of increased
serum cholesterol which was not confirmed as a risk factor. This study found smoking to be most important with a
two to four times greater risk over nonsmokers (4).


Clinical Symptoms
          Symptoms of PAD are variable depending on the severity and location of occlusion. Patients can present
with complaints of buttock, thigh, calf, or foot claudication. Three general patterns of presentation have been
recognized. The first is found in patients between the ages of 40 and 60. These are most often men who smoke.
The chief complaint is weakness and exercise related aching of the pelvic girdle musculature and thighs. Impotence
is often a complaint in this population. The atherosclerotic lesions are most prominent in the distal aorta and
proximal branches. The second pattern is seen in men and women over the age of 65 who complain of calf aching
or burning. The symptoms occur at a predictable level of exertion. The most prominent location of occlusion is in
the femoral and popliteal arteries. The third pattern is recognized in patients of both sexes with diabetes mellitus.
Pain usually occurs in the anterior tibial muscles and foot while walking. The major location of occlusion is seen in
the distal tibial and peroneal arteries(7).
          The history along with the physical examination can often establish the diagnosis of PAD. The clinician
can avoid further testing in many patients with a high degree of certainty. Identifying patients with risk factors
along with the bedside physical examination is an accurate means to diagnose PAD. For patients in whom the
diagnosis is not clear based on history and physical, noninvasive tests are most often employed.


Physical Examination
        In 1942, Buerger described several physical examination findings of peripheral vascular disease. Some
have been accepted but others have been described as unreliable. A critical review by McGee et al. attempted to
determine the usefulness of the physical examination in patients with suspected PAD of the lower extremities. The
review was conducted through a MEDLINE search between 1966 and 1997. Criteria for inclusion included a well
defined study population, a well-defined physical examination maneuver, and comparison of the physical
examination finding to an accepted diagnostic test.
          The diagnostic test most used was the ankle brachial index (ABI). This is a simple, noninvasive test.
Blood pressure is obtained in the ankle with a doppler placed on the dorsal pedal artery or posterior tibial artery.
Blood pressure is then obtained in the arm. The ABI is calculated by dividing the highest systolic pressure obtained
in the ankle by the systolic pressure obtained in the brachial artery. Values less than 0.9 establish the presence of
PAD and values less than 0.5 denote severe disease.
         Seven physical diagnosis findings were reviewed. Sensitivity, specificity, and likelihood ratios were
calculated using the ABI as the standard.



#1 Abnormal pedal pulses
         -Christensen et al (132 patients) defined abnormal pedal pulses as both dorsal pedal and posterior tibial
pulses not palpable.
                  ABI              Sensitivity       Specificity     Likelihood Ratio +
                  <0.9               0.63               0.99               44.6
                  <0.5               0.95               0.73                3.5

         -Stoffers et al (2455 patients) defined abnormal pedal pulses as posterior tibial/dorsal pedal pulse being
absent/absent or absent/weak.
                  ABI               Sensitivity      Specificity      Likelihood Ratio +
                  <0.9                0.73             0.92                 9.0

         -Boyko et al (631 patients) defined abnormal pedal pulses as posterior tibial/dorsal pedal pulse being
absent/absent or absent/weak or weak/weak. (Data from Boyko et al were calculated from examination of both
limbs. The findings from each limb were presented separately, therefore two values are given for each finding.)
                 ABI              Sensitivity       Specificity       Likelihood Ratio +
                 <0.5             0.65/0.80         0.78/0.79              3.0/3.8




#2 Femoral arterial bruit present
       -Criqui et al (613 patients)
                  ABI               Sensitivity       Specificity       Likelihood Ratio +
                  <0.8                0.20              0.96                  4.7
       -Stoffers et al (2455 patients)
                  ABI               Sensitivity       Specificity       Likelihood Ratio +
                  <0.9               0.29               0.95                  5.7




#3 Venous filling time (>20 seconds) This is bedside maneuver performed by having the patient supine while
identifying a prominent pedal vein. The patient’s leg is than raised 45 degrees above the table for one minute. The
patient then sits up with legs dangling over the side of the table. The time in seconds is then recorded for the
previously identified pedal vein to rise above the surface of the skin.
         -Boyko et al (631 patients)
                   ABI               Sensitivity        Specificity     Likelihood Ratio +
                   <0.5              0.22/0.25          0.94/0.95           3.6/4.6
#4 Cool skin
        -Stoffers et al (2455 patients) defined finding as unilateral cooler skin.
                 ABI                Sensitivity        Specificity        Likelihood Ratio +
                 <0.9                  0.10               0.98                   5.8
        -Boyko et al (631 patients) defined finding as dorsal foot cooler to touch than ipsilateral calf.
                 ABI                Sensitivity        Specificity        Likelihood Ratio +
                 <0.5               0.65/0.80          0.46/0.47               1.2/1.5




#5 Color abnormality
        -Stoffers et al (2455 patients) defined color abnormality as pale, red, or blue color.
                 ABI                Sensitivity        Specificity       Likelihood Ratio +
                 <0.9                  0.35               0.87                  2.8
        -Boyko et al (631 patients) defined color abnormality as blue or purple color.
                 ABI                Sensitivity        Specificity       Likelihood Ratio +
                 <0.5               0.24/0.32          0.84/0.85              1.6/2.0




#6 Capillary refill time This test is performed by applying firm pressure to the plantar skin of the distal great toes
for five seconds. Transient local pallor is normal but a delay greater than five seconds before return of normal skin
color is considered delayed refill time.
          -Boyko et al (631 patients)
                   ABI                Sensitivity     Specificity        Likelihood Ratio +
                   <0.5               0.25/0.28       0.84/0.85               1.6/1.9




#7 Trophic changes
        Absent distal lower extremity hair growth
        -Boyko et al (631 patients)
                ABI                 Sensitivity        Specificity        Likelihood Ratio +
                <0.5                0.47/0.48          0.70/0.71                1.6
        Atrophic skin
        -Boyko et al (631 patients)
                ABI                 Sensitivity        Specificity        Likelihood Ratio +
                <0.5                0.43/0.50            0.70                 1.4/1.6



           This study concludes that the absence of pedal pulses, the presence of a femoral bruit, and abnormal venous
filling time are helpful in the diagnosis of PAD based on likelihood ratios. Capillary refill time, trophic changes,
and color abnormalities are less helpful. Temperature differences in the two studies (Stoffers and Boyko) differ in
their utility. The presence of a unilateral cold foot in the Stoffers study is predictive of disease. The presence of a
cooler foot in comparison to the proximal calf is not as reliable. This could be explained by the normal decrease in
cutaneous blood flow in the foot that often occurs in order to conserve body heat(8).
           The usefulness of a good history and physical examination may establish the diagnosis of PAD. For
example, our 68-year-old male smoker who complains of leg pain with walking and is found on physical exam to
have diminished pedal pulses as well as a femoral bruit has a high likelihood of having PAD. Further testing may
not be needed. However, for patients with some findings that may not be clear, noninvasive testing is indicated.
Angiography is rarely used unless a revascularization procedure is planned.


Noninvasive Tests
          The ankle brachial index (ABI) is the most commonly used noninvasive test to detect the presence of PAD.
Angiography is considered the gold standard but in many clinical trials the ankle brachial index is used as the
standard. The ABI is accepted as a reliable alternative with a high degree of sensitivity and specificity. The
sensitivity of ABI in angiographically proven occlusions and significant stenoses has been described as 96-97
percent with a specificity of 94-100 percent(8).
          One particular study looked at the accuracy of the ABI in determining the presence of PAD. Receiver
operating characteristic analysis was performed. The study was performed retrospectively in 441 patients. Only 53
of these patients (106 limbs) underwent angiography. Hemodynamically significant lesions by angiography were
considered to be total occlusions or fifty percent stenoses. The study concluded that obtaining an ABI to detect
PAD was justified with a ROC area of 0.95+/-0.02 (9).




          Exercise testing is commonly employed to detect patients suspected of having PAD who have normal
resting ABIs. Exercise ABI is analogous to cardiovascular testing with the assumption that ischemic areas will be
revealed when more blood flow is demanded. This test usually involves the patient walking on a treadmill followed
by obtaining the ankle brachial index. Two to thirteen percent of patients with abnormal indices are found only after
exercise(8).
          The accuracy of the ABI can be affected by occult upper extremity arterial disease, inability to find pulses,
and calcification of blood vessels. Calcification of blood vessels occurs mostly in patients with diabetes mellitus.
Calcification of vessels results in falsely elevated ankle pressures. This should be suspected in patients with clinical
signs and symptoms of PAD who have ABIs of 1.2 or higher. To overcome the falsely elevated ABI in patients with
calcified vessels, the toe systolic pressure index has been used. Normal indices are 0.6 or higher(10).
          In addition to ABI, ultrasound imaging can be used. The ABI will only detect the presence of stenosis but
not location. Ultrasound provides grey scale, duplex, and color flow imaging. Grey scale images identify plagues
and thrombi. Duplex images measure blood flow velocity through vessels. Color doppler imaging localizes
occlusions and stenoses. The sensitivity and specificity of these modalities varies between centers and is operator
dependent(10).
          An emerging diagnostic tool in PAD is magnetic resonance angiography (MRA). Once this test is more
standardized between centers and the cost decreases, MRA could become the diagnostic test of choice. In a small
study involving twenty patients, MRA of the lower extremities had a sensitivity of 100 percent and a specificity of
97 percent in detecting stenoses of 50 percent or greater. All twenty of these patients underwent angiography(11).


Treatment
          Once the diagnosis of PAD is made, a treatment plan should be initiated. Recognition that the major source
of mortality in these patients is from cardiovascular disease or cerebrovascular disease is important. Diagnostic tests
for cardiovascular and cerebrovascular disease should be guided by the history and physical. Treatment for PAD
can be divided into nonpharmacologic, pharmacologic, and revascularization. Again, revascularization is usually
reserved for patients with Fontaine stage three or four. The majority of patients have Fontaine stage one or two
disease. These patients should be treated by modifying/treating risk factors, exercise, medications, or a combination
of these.


Modifying Risk Factors
         Modifying risk factors is an important part of the treatment plan. Smoking cessation is imperative.
Smoking cessation has been shown to reduce disease progression and to decrease claudication symptoms(12).
Hyperlipidemia therapy should also be employed in the treatment of patients with PAD. The 4S trial showed that
treatment with simvastatin decreased progression and development of intermittent claudication by thirty-eight
percent(13). There are no controlled studies proving the benefit of glycemic control and hypertension control in
patients with PAD. However, intensive glycemic control has been shown to decrease the development of
microvascular lesions(14). Control of hypertension should be a goal to reduce the progression of cardiovascular and
cerebrovascular disease. Overly aggressive blood pressure control should be avoided as it can exacerbate lower
extremity ischemia. This is debatable and unfortunately there are no good guidelines to avoid worsening ischemia
by decreasing systemic pressure. If symptoms are exacerbated with antihypertensives, it may be reasonable to allow
a higher pressure and monitor for improvement in symptoms.


Exercise
          Regular exercise training for patients with intermittent claudication is uniformly recommended by experts
in vascular medicine. The mechanism through which exercise improves symptoms is not known. It was once
thought that exercise led to increased collaterals in the ischemic limb but this has not been shown to be true.
Potential mechanisms through which exercise improves symptoms are improved metabolic capacity of the ischemic
tissues, change in walking patterns, and changes in pain tolerance(15).
          A meta-analysis looking at the benefits of exercise was performed(16). Studies that reported the results of
treadmill testing were included. Following supervised exercise programs, the initial time to onset of claudication
symptoms increased to 179 percent. The distance to maximal claudication symptoms increased to 122 percent.
Both of these results were significant (p<0.001). The exercise program that led to the best improvements was:

           -Duration of exercise greater than 30 minutes per session
           -At least three sessions of exercise per week
           -Walking used as the mode of exercise
           -Reaching near maximal claudication pain as an endpoint for exercise
           -Exercise program of greater than six months

          The benefits of supervised exercise programs are shown by the above meta-analysis. However supervision
is not possible or practical for all patients. A study was performed comparing the results of a supervised exercise
program to patients following a home exercise program. This was a small study involving forty-seven patients.
Both groups improved in claudication pain time and maximum walking time. At twelve weeks and six months, the
supervised group had a statistically significant increase in both claudication pain time and maximum walking time
over the home exercise group (p<0.004). This small study shows the superior benefits of supervised rehabilitation
exercise programs. However, home exercise is beneficial and should be used if supervision is not possible(17).
          Unfortunately, one third of patients with intermittent claudication cannot participate in exercise
rehabilitation because of comorbid conditions(2). Pharmacological therapy may be indicated in these patients.
Pharmacologic Therapy
          There are many medications that have been used in the treatment of PAD. There are currently two drugs
which are FDA approved for the treatment of intermittent claudication (Fontaine stage two). These are
pentoxifylline (Trental) and cilostazol (Pletal). Other drugs used can be classified as antiplatelet agents, metabolic
enhancing agents, prostaglandins, and vasodilators.
          Metabolic enhancing agents include naftidrofuryl and propionyl carnitine. Naftidrofuryl is an oral agent
with few adverse side effects. It is currently available only in Europe. The most common side effect was
gastrointestinal. Studies have shown statistically significant increases in maximal walking distance and reduction in
revascularization procedures. L-carnitine is also an oral agent that is well tolerated. There is some data that shows
clinically significant improvements in walking distance. However, larger studies are needed before these agents can
be recommended.
          Prostaglandins have been shown to decrease symptoms in patients with intermittent claudication.
However, the use of prostaglandins is limited because they require intravenous administration and have systemic
side effects(2).
          Vasodilators have overall not been shown to be very effective. This is thought to be secondary to maximal
vasodilation already being present in stenotic arteries. However, a study of Verapamil versus placebo in forty-four
patients did show some benefit of Verapamil. Maximal walking distances increased by 49 percent in patients treated
with verapamil which was statistically significant. The efficacy of verapamil is thought to be through changes in the
metabolic capacity of the ischemic tissues. Verapamil does not seem to result in significant vasodilation of stenotic
arteries(18).
          Aspirin, ticlopidine, dipyridamole (Persantine), and clopidogrel (Plavix) have all been used in patients with
PAD. Each of these agents has shown modest benefits in decreasing the symptoms of intermittent claudication.
Head to head studies have shown that ticlopidine and clopidogrel work better than aspirin(2). Again, however, these
results are modest and probably do not justify the increase cost/side effects associated with these newer agents.
Because of the increased risk of cardiovascular and cerebrovascular mortality in patients with PAD, aspirin should
be used unless contraindicated.


-Pentoxifylline
          As stated above, pentoxifylline (Trental) and cilostazol (Pletal) are currently FDA approved for the
treatment of intermittent claudication. Pentoxifylline is a xanthine derivative classified as a hemorheologic agent.
The mechanism of action is thought to lead to increased flexibility of erythrocytes, inhibition of platelet aggregation,
and reduction of plasma fibrinogen. Pentoxifylline increases levels of cyclic AMP in erythrocytes. It has also been
shown to have vasodilation properties(19).
          The efficacy of pentoxifylline in patients with chronic PAD has been disputed. There are trials which show
improvement in symptoms but other studies fail to show objective evidence to support its use. A meta-analysis of
randomized controlled trials was conducted to evaluate the efficacy of pentoxifylline in improving walking distances
in patients with moderate intermittent claudication. Eleven trials were included in the analysis. The trials were
randomized, placebo-controlled, and double blind. The parameters were pain free walking distance and absolute
claudication time. Pain free walking distance was defined as the distance walked on a treadmill before the onset of
calf pain. Absolute claudication distance was defined as the maximum distance walked. Moderate intermittent
claudication was defined as pain free walking distance of 50 to 200 meters. The duration of symptoms ranged from
three months to less than five years. The dose of pentoxifylline ranged from 600 to 1800 mg/day and treatment
lasted from 2 to 26 weeks. No sub-group analyses could be performed. The meta-analysis for all trials found an
overall improvement in pain free walking distance of 29.4 meters (95% confidence interval 13.0 to 45.9). The
analysis for all trials also found an improvement in absolute claudication distance of 48.4 meters (95% confidence
interval 18.3 to 78.6). Both of these results were statistically significant.
          The meta-analysis concludes that pentoxifylline is effective in increasing pain free walking distance and
absolute claudication distance. An improvement of approximately 30 meters on a treadmill is equivalent to 90
meters on flat ground. A city block is approximately 70 meters(20). Pentoxifylline is reasonably well tolerated.
Gastrointestinal symptoms are most common and occur in about three percent of patients. Despite the tolerability of
the drug, arguments have been made as to the cost effectiveness of increasing walking distance by 90 meters.
However, in 1995, pentoxifylline was found using Medicare expenditure data to reduce average hospital costs per
patient by $1173(2).


-Cilostazol
          Cilostazol (Pletal) is a new therapeutic agent approved by the FDA in 1999 for patients with intermittent
claudication. Cilostazol is a cyclic nucleotide phosphodiesterase (PDE 3) inhibitor. The mechanism of action is
related to increasing levels of cyclic AMP in platelets and smooth muscles cells. Through this action, cilostazol is
thought to decrease platelet aggregation and to increase vasodilation. Cilostazol has also been found to improve
lipid metabolism by decreasing triglycerides and increasing HDL levels. No effect on LDL has been shown(21).
          Three recent trials have evaluated the efficacy of cilostazol. These studies are randomized placebo
controlled trials. All studies were similar in inclusion and exclusion criteria. The primary endpoints were
measurement of initial distance to claudication (ICD) and the absolute distance to claudication (ACD). Treadmill
testing was used to evaluate these endpoints. Noninvasive tests were used to confirm the presence of PAD.
          The first trial enrolled 81 patients from three centers. Baseline treadmill testing was done and patients with
ICD of 30 to 200 meters were included. A single blind lead in phase for 2 to 4 weeks was done prior to
randomization in an attempt to decrease placebo effect. Patients were randomized 2:1 to cilostazol 100mg bid or
placebo bid for 12 weeks. Treadmill testing was performed at weeks 2, 4, 8, and 12. There were no statistically
significant differences in subject characteristics receiving cilostazol versus placebo. An intent to treat analysis was
used. The group receiving cilostazol had an increase in ICD from 71.2+/-6.0 meters to 112.5+/-13.8 meters. The
placebo group had an increase in ICD from 77+/-8.4 meters to 84.6+/-13.7 meters. The ACD in the cilostazol group
increased from 141.9+/-21 meters to 231.7+/-36.9 meters. The ACD in the placebo group decreased from 168.6+/-
33.1 meters to 152.1+/-23.9 meters. These results were statistically significant at 12 weeks. The estimated
treatment effect was a 35% increase in ICD (p<0.01) and an increase in ACD of 41% (p<0.01). Adverse effects
were more common in the cilostazol treated group and included headaches (20% vs. 15%) and GI symptoms (44%
vs. 15%). The study concluded that cilostazol resulted in improvement in both ICD and ACD but recognized the
small enrollment of 81 patients(22).




         A second study looking at cilostazol versus placebo enrolled 239 patients in a 16 week trial. Patients were
randomized to cilostazol or placebo after two baseline treadmill tests were done. A lead in phase was not done prior
to randomization. Treadmill testing was repeated at weeks 8, 12, and 16. The primary endpoint was ACD.
Additional variables included ABIs. Intent to treat analysis was used. The mean increase in ACD after 16 weeks
was 96.4 meters in patients treated with cilostazol. The ACD in the placebo group increased by 31.4 meters. The
ACD at week 16 showed a 29% increase in patients treated with cilostazol versus patients treated with placebo
(p=0.0001). The ABI increased in the cilostazol group from 0.64+/-0.02 to 0.70+/-0.02. The placebo group had an
increase of ABI from 0.68+/-0.02 to 0.69+/-0.02 (p=0.01 for cilostazol vs. placebo). The most frequent adverse
effects were headache, diarrhea, and dizziness. Mean triglyceride levels decreased by 48.8+/-10.8 mg/dl in the
cilostazol treated group and HDL increased from 47.6+/-1.2 to 52.8+/-1.4 mg/dl. Mean triglyceride levels decreased
and HDL levels increased to a lesser degree in the placebo group. The study concluded that cilostazol therapy
results in a significant increase in ACD(1).




          A third study evaluating the efficacy of cilostazol enrolled 516 patients. Patients were randomized to
cilostazol 50 mg bid, cilostazol 100 mg bid, or placebo bid. Treatment lasted 24 weeks. Patients were evaluated
three times at baseline and at weeks 4, 8, 16, 20, and 24 with exercise treadmill. Intent to treat analysis was used.
At week 24, ICD and ACD was statistically greater in both cilostazol treated groups than in the placebo group. The
mean ICD increased in the cilostazol 100 bid group from 70.4 meters to 137.9 meters, from 66.5 meters to 115.1
meters in the cilostazol 50 bid group, and from 72.4 meters to 95.5 meters in the placebo group. The mean ACD
increased from 129.7 meters to 258.8 meters in the cilostazol 100 bid group, from 131.5 meters to 198.8 meters in
the cilostazol 50 bid group, and from 147.8 to 174.6 meters in the placebo group. The cilostazol 100 bid group had
a 59% improvement in ICD and a 51% improvement in ACD. The cilostazol 50 bid had a 48% improvement in ICD
and a 38% improvement in ACD. These treatment results are compared to a 20% increase in ICD and a 15%
improvement in ACD in the placebo group. These results were statistically significant (p<0.01). Adverse side
effects were more common in cilostazol treated patients (p<0.05) and included headache, diarrhea, dizziness, and
palpitations. Statistically significant increases in HDL and decreases in triglycerides were seen in the treatment
groups versus placebo. The study concluded that treatment with cilostazol significantly improved walking distances
in patients with intermittent claudication(23).




         The three RCTs show a beneficial effect in treating PAD with cilostazol. Like pentoxifylline, the effects
have been described as modest. However, increasing pain free walking distance by thirty or more meters may
substantially improve quality of life. In the above mentioned studies, functional questionnaires were statistically
significantly improved.
Conclusion
         Peripheral arterial disease is a common disease in elderly patients. The prevalence is expected to increase
as society ages. The major source of mortality in these patients is secondary to cardiovascular and cerebrovascular
disease. Appropriate screening for cardiovascular and cerebrovascular disease should be done in these patients and
should be guided by the history and physical examination.
         The diagnosis of PAD can be made reliably with the history and physical examination. Noninvasive testing
can be done to assess the severity of disease or to establish the presence of disease in patients with equivocal
findings. Angiography should be done only if revascularization is planned. MRA is an emerging diagnostic tool
that may replace both noninvasive tests and conventional angiography in the future.
         Treatment for PAD should focus on modifying risk factors. Unless contraindicated, a supervised exercise
program should be initiated. Pharmacological therapy is diverse and shows only modest improvements. A trial of
medication is reasonable in patients who cannot exercise or who fail to improve with exercise.


Return to the Case
         A.P. was diagnosed as having PAD based on history and physical examination. He was started on aspirin
therapy and referred for exercise rehabilitation. He was also started on a lipid lowering agent for an LDL of 150.
His blood pressure and diabetes are well controlled. Smoking cessation has been encouraged and the patient is
attempting to quit. He has no symptoms from the carotid bruit, therefore, this is being followed. He underwent a
noninvasive cardiac study which did not suggest coronary ischemia. The patient is being followed and if he does
not respond well to the above measures, cilostazol or pentoxifylline may be started.
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