Abstract
Purpose. Peripheral arterial disease (PAD), defined as the presence of atherosclerotic occlusive vascular disease of the extremities, is a marker of systemic atherosclerosis, and has emerged as a strong risk factor for cardiovascular morbidity and mortality. Early diagnosis and aggressive medical therapy can significantly reduce cardiovascular risk profiles in such patients.

Methods. An Ovid and Medline search was used to identify relevant publications pertaining to PAD. Included were randomized, blinded, placebo-controlled studies, current accepted committee reviews, and reviews pertaining to PAD. An analysis of cardiovascular risk stratification and risk reduction in patients with PAD was performed. Current recommended medical treatment options were reviewed in terms of risks, benefits and number needed to treat (NNT) analysis.

Results. Smoking cessation, on average, will prevent 1 cardiovascular mortality for 13.5 patients abstaining for 1 year.¹⁹ Treatment of 38 patients with moderate exercise for one year would prevent one cardiovascular death.²² Aspirin therapy will prevent one major cardiovascular event [defined as stroke, myocardial infarction (MI) or cardiovascular death] in 106 patient years; clopidogrel therapy will prevent one major cardiovascular event in 84 patient years;³ ticlopidine therapy for similar time period will prevent 1 major cardiovascular event (defined as stroke, MI or cardiovascular death) in 61 patient years treated;²³ angiotensin converting enzyme inhibitors (ACEI) will prevent 1 major cardiovascular event (defined as stroke, MI or cardiovascular death) in 119 patients years;²⁹ HMG-CoA reductase inhibitors have proven beneficial with a decrease in events (defined as all cause mortality, cardiovascular mortality, major coronary events and coronary and non-coronary revascularization) seen with 50–70 patients treated for 1 year, independent of serum lipid levels.²⁷

Conclusion. PAD should be treated with a multi-disciplinary approach, including smoking cessation, exercise and medications. Medical therapy should be comprised of a statin, an antiplatelet agent and/or an ACEI. Perspective trials comparing different combinations of these three pharmacological classes of agents in PAD are warranted.

Introduction
Peripheral arterial disease (PAD), defined as the presence of atherosclerotic occlusive vascular disease of the extremities, is a common yet often under-diagnosed medical condition with a peak incidence in the 6th and 7th decades. PAD affects about 5 million adults in the United States.¹ The major risk factors for PAD are cigarette smoking, age > 40, diabetes mellitus, hypertension and hyperlipidemia. Of these, cigarette smoking has the greatest relative risk in patients with PAD. The presence of atherosclerotic disease in the lower extremity vasculature is often indicative of disease in cerebrovascular and coronary arteries. PAD is a proven risk factor for an impending major cardiovascular event.² Early diagnosis and aggressive treatment of risk factors has been proven to reduce the incidence of morbidity and mortality as a result of major cardiovascular events.³ Current medical therapies, their benefits, and potential side effects for patients with PAD will be reviewed (Table 1).

Prevalence and Detection
Multiple studies have highlighted clinical limitations in defining and diagnosing PAD.4–6 One such study estimated the prevalence of PAD to be 2.5% in those < 60 years of age, 8.3% in those 60–69 years of age, and 18.8% in those 70 or older. In this and other similar studies, it was found that diagnosing PAD based on intermittent claudication greatly underestimated actual disease prevalence, while use of pulse abnormalities often overestimated it.^4,5 In a study by Criqui et al. intermittent claudication occurred in about 2.2% of men and 1.7% of women; pulse abnormalities occurred in 20.3% of men and 22.1% of women. Total PAD prevalence, based on noninvasive testing, was 11.7%, with increasing rates with age and elevated lipid levels.⁵

In a multicenter cross-sectional study, PAD was detected in 1865/6979 subjects 50 years of age or older, a prevalence of 29%.6 PAD was defined by an ankle brachial index (ABI) 0.90. The overall prevalence of atherosclerotic disease in this group was PAD 13%, CAD and PAD 24%, CAD only 16%, 47% had neither (Figure 1). Also, among all patients with PAD, only 8.7% had classic signs of claudication. Of the patients with prior diagnoses of PAD, 83% were aware of their diagnoses, but only 49% of their physicians had documentation of PAD at the time of screening.

In this study, PVD was slightly more prevalent than previously described.⁶ Classic claudication symptoms were present in a small fraction of patients with PAD. Additionally, underdiagnosis of PAD in the primary care setting was a common barrier to effective risk modification and treatment.⁶

Medical Therapy: For Symptom Relief
Peripheral arterial disease is associated with lower extremity claudication and decreased exercise tolerance secondary to lower extremity symptoms. This combination of atherosclerosis and decreased ability to exercise can lead to accelerated progression of atherosclerotic disease and increased risk of major adverse cardiovascular events (MACE).^7,8

Exercise
Edwards et al. looked at how exercise, mainly polestriding (walking with modified ski poles with movement in a pattern similar to cross-country skiing) affects lower extremity intermittent claudication as compared to non-exercise controls. The polestriding group improved duration and distance of tolerated exercise, whereas the control group decreased duration of exercise. Exercise tolerance, as measured by incremental treadmill test protocol, increased from baseline by 51% after 24 weeks in the polestriding group. Exercise tolerance in the non-exercise control group decreased from baseline by 7% after 24 weeks.⁹ Another study compared treadmill walking versus non-exercise controls. It was shown that exercise increased walking time to onset of claudication by 88%, time to maximal pain by 70%, and 6-minute walk distance by 21%.¹⁰ These studies illustrate the importance of exercise rehabilitation therapy in the treatment of PAD and claudication. However, supervised exercise therapy is often not covered by insurance plans and therefore, exercise therapy requires a highly motivated and compliant patient population.

Antiplatelet Therapy
Inhibition of platelet aggregation is the cornerstone of treatment in PAD and other atherosclerotic diseases. Ticlopidine, a first generation ADP-receptor antagonist, has been used for symptomatic therapy of PAD. Ticlopidine was shown to increase pain-free walking distance, maximum walking distance and ABI both at rest and post exercise. However, use of ticlopidine has fallen out of favor, given its hematopoetic adverse reactions.^11,12

Cilostazol & Pentoxifylline
If exercise therapy is unsuccessful, primary care physicians have the option of symptomatic therapy using pentoxifylline or cilostazol.¹³ Pentoxifylline is FDA-approved for the treatment of claudication. This drug is believed to act as a rheolytic agent, allowing red blood cells to alter shape and thus decreasing the viscosity of blood. Cilostazol is a phosophodiesterase III inhibitor that acts to raise levels of cyclic adenosine monophosphate (camp), which leads to inhibition of platelet aggregation and vasodilatation. Cilostazol, however, should be used with caution in patients with New York Heart Association class III or IV congestive heart failure symptoms.

In a randomized, double-blind, placebo-controlled, multicenter trial, pentoxifylline and cilostazol were compared in the treatment of claudication and exercise intolerance. All patients in this study had PVD, defined by an ABI < 0.90, and were treated with either 400 mg pentoxifylline orally three times per day, 100 mg cilostazol orally twice a day or placebo for 24 weeks. They had exercise tolerance assessments using a graded treadmill exercise protocol at initiation, and every four weeks thereafter. Treatment with cilostazol improved mean maximal walking distance starting at week 4, with a 54% increase at week 24. Alternatively, maximal walking distance was increased by 27% in the pentoxifylline-treated group, and 27% in the placebo-treated group. Cilostazol also improved ABI whereas pentoxifylline and placebo did not. Cilostazol was superior to pentoxifylline and placebo in the treatment of claudication and exercise intolerance. Pentoxifylline showed no statistically significant benefit over placebo.

Statins
HMG-Co-A reductase inhibitors have beneficial effects and pleotropic effects in addition to reduction of LDL-cholesterol levels. They have been shown to be involved in improving endothelial dysfunction, stabilizing atheromatous plaques, enhancing fibrinolysis and inhibiting thrombosis.^14,15 One study illustrated the antithrombotic mechanism of action.¹⁶ Simvastatin was shown to inhibit the activation of prothrombin, factor V and factor XIII, while increasing the inactivation of factor Va and impairing fibrinogen proteolysis.¹⁶

Several studies have evaluated the benefits of statin therapy on walking performance (walking distance and length of pain-free exercise), ABI and intermittent claudication. Crique et al. showed improved 6-minute walk performance and increased walking velocity in participants receiving statin therapy independent of total cholesterol levels.¹⁷ Another study by Barbati et al. found that 6 months of statin therapy combined with exercise improved mean pain-free walking distance by 90 meters over subjects treated with exercise alone. Subjects in the statin plus exercise group also had greater improvement in rest and post-exercise ABI, with increases of 0.09 and 0.19, respectively, over controls.¹⁸

Secondary Event Reduction
Smoking Cessation
Smoking cessation is an integral part of risk reduction in atherosclerotic disease. One published study reported a higher risk of myocardial infarction (MI) or death in patients with established coronary artery disease (CAD) who continued to smoke versus those who had quit smoking.¹⁹ According to data collected in this study, the NNT varied according to age to prevent one cardiovascular death. Patients aged 60–64, and those 70 years of age and older, had an NNT of 5; patients aged 55–59 had an NNT of 11, while patients 65–69 years of age had an NNT of 33. Therefore, the average NNT for smoking cessation is 13.5 to prevent one cardiovascular mortality (Table 2).¹⁹

To help patients successfully achieve tobacco cessation, physicians may choose to use nicotine replacement therapy, bupropion or a combination of both. One double-blind, placebo-controlled study compared nicotine replacement therapy versus bupropion versus a combination of both for smoking cessation.20 Abstinence rates after 12 months of therapy were 15.6% for the placebo group, 16.4% for the nicotine replacement group, 30.3% for the bupropion group and 35.5% for patients in the combination therapy group.²⁰

Exercise
In January 2005, the American Heart Association released a scientific statement recommending cardiac rehab to patients with PAD and claudication.²¹ A study by Walker et al. looked at changes in all-cause and cardiovascular mortality in patients with and without atherosclerotic disease, based on physical activity level.²² Focusing mainly on the data in those with atherosclerotic disease, the all-cause mortality event rate per 1000 patient years was 46.2 in the inactive group, 20.6 in the mildly active, 10.8 in the moderate activity group and 24 in the vigorously active. An absolute risk reduction in all cause mortality of 35.4/1000 is found when comparing the inactive to the moderately active groups. Therefore, 28 patients treated for one year would reduce all cause mortality by one. In the same group of patients, the cardiovascular mortality rate per 1000 patient years was 31.4 in the inactive group, 15.4 in the mildly active, 5.4 in the moderate activity group and 17 in the vigorously active. An absolute risk reduction in cardiovascular mortality of 26/1000 is found when comparing the inactive to the moderately active groups. Treatment of 38 patients with moderate exercise for one year would therefore prevent about one cardiovascular event in patients with previously diagnosed atherosclerotic disease (Table 2).²²

Antiplatelet Therapy
Aspirin and/or clopidogrel are now the mainstay of therapy. Aspirin works by blocking prostaglandin synthesis, decreasing thromboxane A2 levels with a resultant decrease in platelet aggregation. Clopidogrel, a thienopyridine derivative, inhibits platelet aggregation by blocking platelet ADP receptors.

A clinical review on oral antiplatelet therapy in cerebrovascular disease, CAD and PVD showed significant risk reduction in patients treated with ticlopidine versus those treated with placebo.²³ Patients with PAD treated with ticlopidine showed a 34% reduction in risk of coronary and cerebrovascular events.

The Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial was a randomized, blinded, multicenter international study designed to evaluate the role of aspirin versus clopidogrel in cardiovascular risk reduction. Nineteen thousand one hundred eighty five (19,185) patients with a history of MI, ischemic stroke or PAD were randomized to receive either aspirin 325 mg once a day or clopidogrel 75 mg once a day. Secondary fatal and nonfatal vascular events were then recorded. Patients treated with clopidogrel had an annual relative risk reduction of 8.7% over those treated with aspirin. Therefore, for every 1000 patient years of treatment, aspirin and clopidogrel would be expected to prevent 19 and 24 major cardiovascular events, respectively.^3,12 Aspirin therapy will prevent one major cardiovascular event (defined as stroke, MI or cardiovascular death) in 106 patient years. Clopidogrel therapy will prevent one MACE in 84 patient years (Table 2).³

Statins
Dyslipidemia, mainly elevated low-density lipoprotein (LDL) and low high-density lipoprotein, has been shown to increase atherosclerosis and incidence of MACE. Therapy with HMG-Co-A reductase inhibitors has become the standard care after diet and exercise therapy has been attempted. HMG-Co-A reductase inhibitors have been shown to significantly reduce total cholesterol levels, LDL levels and risk of MACE.^24–26 In addition, they have been shown to be involved in improving endothelial dysfunction, stabilizing atheromatous plaques, enhancing fibrinolysis and inhibiting thrombosis.^14,15 A combination of both the cholesterol-lowering and pleotropic effects make statin therapy a class 1, level of evidence A recommendation for patients with established PAD.

A published multi-study analysis showed a 13% reduction in all-cause mortality, a 17% reduction in cardiovascular death, a 27% reduction in MACE, a 25% reduction in cerebrovascular accident (CVA) and a 24% reduction in any major vascular event in patients treated with simvastatin for five years.²⁷ HMG-CoA reductase inhibitors have proven beneficial, with a reduction in events (defined as all cause mortality, cardiovascular mortality, MACE, coronary and non-coronary revascularization) seen with 50–70 patients treated for 1 year (Table 2).²⁷ Beneficial effects were seen independent of lipid levels, age or sex.

Angiotensin Converting Enzyme Inhibitors
Angiotensin converting enzyme inhibitors (ACEI) work by inhibiting the renin-angiotensin system. Initially, they were introduced for the treatment of hypertension. Today, ACEI are used in the treatment of hypertension, cardiomyopathy and diabetic nephropathy. Since their introduction, evidence pointing to their role in vascular risk reduction has been mounting. The Heart Outcomes Prevention Evaluation (HOPE) study was a landmark in evaluating the reduction of cardiovascular risk with ACEI therapy.28 In fact, the trial was terminated early after only four and a half years, given the overwhelming benefit of ACE inhibition on cardiovascular risk reduction.

The HOPE study was a multicenter (267 total), international (19 countries), double-blinded, placebo-controlled trial. Nine thousand two hundred ninety-seven high-risk patients (patients older than 55 years of age with PAD or diabetes plus one or more cardiovascular risk factors) were randomized to receive ramipril (10 mg once per day orally) versus placebo. Daily, 4645 patients were randomly assigned to receive 10 mg ramipril, 4652 patients were assigned to receive placebo. Patients in the treatment arm received ramipril 2.5 mg daily for one week, followed by 5 mg daily for three weeks and then 10 mg daily thereafter. All patients received vitamin E 400 IU daily or matching placebo. Follow-up was scheduled at month 1, 6 and then every 6 months thereafter. The primary endpoint of MI, stroke or death from cardiovascular event was then recorded. Secondary outcomes were death from any cause, need for revascularization, hospitalization for unstable angina or heart failure and diabetes complications.

The primary endpoint of MI, stroke or death from cardiovascular event occurred in 651 of the 4,645 patients treated with ramipril. In patients treated with placebo, 826 of the 4,652 reached the primary endpoint. In the ramipril and placebo group, 280 versus 377 patients, respectively suffered a cardiovascular death (26% relative risk reduction, p < 0.001). MI occurred in 459 versus 570 patients in the ramipril and placebo group, respectively (relative risk reduction of 20%, p < 0.001). Strokes occurred in 156 patients in the ramipril arm versus 226 patients in the placebo arm (32% relative risk reduction, p < 0.001). In patients receiving both ramipril and vitamin E, 338 reached the primary endpoint versus 421 patients who received only vitamin E (p = 0.001), As compared to 405 patients who received vitamin E placebo alone (p < 0.001), 313 patients receiving ramipril and vitamin E placebo reached primary endpoint. Therefore, it was concluded that treatment with ramipril reduced cardiovascular mortality (6.1 versus 8.1 %; p < 0.001), incidence of nonfatal MI (9.9 versus 12.3 %; p < 0.001) and stroke (3.4 versus 4.9 %; p < 0.001) irrespective of blood pressure reduction.
Ramipril therapy was also beneficial when comparing secondary outcomes. Treatment with ramipril reduced the incidence of revascularization, cardiac arrest, worsening angina, heart failure, newly diagnosed diabetes and complications related to diabetes. A trend towards fewer hospitalizations was observed in the ramipril therapy group. However, ramipril therapy had no effect on hospitalization secondary to unstable angina.
Ramipril therapy was beneficial among male and female patients with diabetes and those without in those younger and older than 65 years, in hypertensive and non-hypertensive patients, and in patients with and without micro-albuminuria. Benefits were also observed in patients with CAD and in those without evident CAD, in patients with and without a history of MI and in those with an ejection fraction greater than 40%. These results indicated a benefit of ramipril therapy in a broader range of patients than had previously been described.

A HOPE sub-study explored the prognostic importance of PAD (measured by using ABI) and the role of ramipril therapy within the HOPE study cohort. One thousand seven hundred fifteen patients were included in the HOPE study on the basis of having symptomatic PAD. Initial ABI measurements revealed a subnormal ABI (£ 0.9) in 3099 patients and an ABI of greater than 0.9 in 5887 patients. The mean systolic ankle pressure was 119.7 mmHg, and the mean systolic brachial pressure was 138.1 mmHg. Thus, the mean ABI for all HOPE study patients was 0.87. In the patients with clinical PAD, the ABI was 0.87 ± 0.22 versus 1.00 ± 0.18 in those without clinical PAD.

The ABI was highly correlated with cardiovascular and all-cause morbidity and mortality. In this study, patients with an ABI > 0.9 had a 13.8% incidence of cardiovascular morbidity and mortality; those with an ABI of 0.6–0.9 had an 18.7% incidence of cardiovascular morbidity and mortality; and those with an ABI < 0.6 had a 19.2% incidence of cardiovascular morbidity and mortality (Figure 2). All-cause mortality was 8.5%, 12.4% and 14.2% in each respective ABI group.

Much as with the HOPE trial, ramipril reduced the risk of cardiovascular events in patients with normal and abnormal ABI (symptomatic and non-symptomatic). Risk reduction, however, was doubled in patients with an ABI < 0.9, thus highlighting the importance of ABI measurement in cardiovascular risk stratification.29 According to this study, Angiotensin Converting Enzyme Inhibitors (ACEI) will prevent 1 cardiovascular event (defined as stroke, MI, or cardiovascular death) in 119 patient years (Table 2).

A published clinical trial by The Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial Investigators further delineated the role of ACEI in decreasing vascular risk. This was a multicenter, international, double-blind placebo-controlled study in which 8290 patients were randomly assigned to receive either 4 mg trandolapril by mouth daily (n = 4158) or placebo (n = 4132). All randomized patients had stable coronary artery disease and normal or near normal left ventricular function. The primary endpoint was death from cardiovascular causes, nonfatal MI and coronary revascularization. Patients were then followed for a median of 4.8 years. The incidence of the primary endpoint was 22.5% in the placebo group and 21.9% in the trandolapril group (p = 0.43).³⁰

PEACE did not show the benefit demonstrated by previous trials. However, patients in the PEACE trial had significantly better baseline characteristics, as demonstrated by ejection fraction, serum creatinine, blood pressure, percent currently on lipid-lowering therapy and percent who underwent revascularization. In fact, patients in the placebo arm of the PEACE trial, when compared with the ramipril-treated patients in the HOPE trial, had a lower percentage of death from cardiovascular causes, nonfatal MI or stroke. Therefore, it is likely that the previously reported benefit of ACEI therapy was not apparent in the PEACE trial because the patients were at lower risk for cardiovascular events. Another possible explanation for the differing results in the PEACE trial is the use of a different ACEI, trandolapril. The possibility of varying efficacy amongst different ACEI should be considered when comparing the results of these two trials.³¹ The trial investigators concluded that ACEI therapy offers no cardiovascular benefit in patients with stable CAD and preserved ejection fraction who receive intensive standard therapy.

Angiotensin Receptor Blockers
The cardiovascular protective effect of angiotensin receptor blockers (ARB) is currently under investigation. Some studies show a reduction in cardiovascular events in patients treated with ARB32 and others do not.³³ Currently, there are studies evaluating ARB use post-MI, and in high-risk patient populations.^34,35

Conclusion
PAD, defined as the presence of atherosclerotic occlusive vascular disease of the extremities, is a common, yet often under-diagnosed, medical condition affecting about 5 million adults in the United States alone.¹ Given the systemic nature of atherosclerosis, the presence of PAD often implies diffuse vascular phenomena. PAD is a proven risk factor for an impending MACE.² Evidence regarding the diagnosis and treatment of PVD and its risk factors is growing.

Based on a NNT analysis, 38 patients treated for 1 year with moderate exercise therapy would reduce all-cause mortality by one.²² The NNT to prevent one cardiovascular mortality for tobacco cessation varied according to age. Patients aged 60–64, and those 70 and older, had an NNT of 5, patients aged 55–59 had an NNT of 11, while patients 65–69 years of age had an NNT of 33.¹⁹ Therefore, the average NNT for smoking cessation, to prevent one cardiovascular mortality is 13.5. Aspirin therapy will prevent one MACE (defined as stroke, MI or cardiovascular death) in 106 patients treated for 1 year. Clopidogrel therapy cardiovascular event benefits are evident with 84 patients treated for 1 year.³ Ticlopidine therapy for a similar time period will prevent 1 cardiovascular event (defined as stroke, MI or cardiovascular death) in every 61 patients treated; however, given its side-effect profile and need for frequent hematological monitoring, its use has fallen out of favor.²³ Ramipril has shown cardiovascular benefit (defined as stroke, MI or cardiovascular death) for every 119 patients treated for about 1 year.²⁹ HMG-CoA reductase inhibitors have shown a reduction in events (defined as all cause mortality, cardiovascular mortality, MACE and coronary and non-coronary revascularization) of 50–70, independent of serum lipid levels (Table 2).²³

To date, there have not been any head-to-head comparison trials analyzing the relative risk reduction of these therapies in patients with known PAD. However, it seems apparent that PAD should be treated using a multidisciplinary approach, including smoking cessation, exercise and medications. As previously stated, multiple pharmacological interventions have proven beneficial in reducing the risk of cardiovascular events. Today a poly-pharmaceutical approach to vascular risk reduction is often initiated. Given this practice, randomized clinical trials comparing different combinations of pharmacological classes of agents in PAD are warranted.