Clinical Case

Introduction

Goals of the Discussion

Classification

Natural History of PAD

Morbidity and Mortality

Risk Factors

Clinical Symptoms

Physical Examination

Noninvasive Tests

Treatment

Modifying Risk Factors

Exercise

Pharmacologic Therapy

Conclussion

Brian Fuller, MD

March 14, 2000

#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?

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.

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.

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.

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 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).

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.

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

#2 Femoral arterial bruit present

#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.

#4 Cool skin

#5 Color abnormality

#7 Trophic changes

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 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.

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.

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.

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.