The term peripheral arterial disease (PAD) refers to noncoronary, occlusive atherosclerotic vascular disease. However, by convention most epidemiologic studies use the term PAD to refer to arterial disease of the lower extremities. It is estimated that about 10 to 11 million Americans have PAD. Unfortunately, a number of factors have contributed to the underrecognition of the true burden of PAD, including the lack of physician and patient awareness, the failure to appreciate that the majority of patients with PAD have atypical symptoms or are asymptomatic, and the underutility of safe and inexpensive noninvasive diagnostic tools such as measurement of the ankle–brachial index (ABI).

It is sometimes helpful to gain an appreciation of this in the context of other perhaps better known cardiovascular conditions such as atrial fibrillation that, by best estimates, affects 2.3 million people in the United States. A better perspective may be gleaned from a cross-sectional study of primary care practices across the United States of nearly 7000 patients that demonstrated the incidence of PAD in patients above the age of 70 years or those between the age of 50 and 69 who had a history of either smoking or diabetes to be almost one-third, yet only half of their physicians were aware of this diagnosis (1).

NATURAL HISTORY OF PAD: CONCEPT OF GLOBAL VASCULAR CARE

PAD is underdiagnosed, and as a consequence, is also undertreated. It needs to be recognized that PAD is not just a disease of the lower extremities, but in fact is a manifestation of systemic atherosclerosis and is a marker for adverse cardiovascular outcomes with a 5-year risk of cardiovascular morbidity and mortality as high as 50%. In terms of limb-related outcomes, during the same 5-year period, only a quarter of these patients will have progression in their leg symptoms and less than half of these patients will require an intervention or progress to amputation (2).

With endovascular techniques now occupying a dominant role in the management of PAD and at times assuming the role of default treatment, it is imperative to understand that in these patients their most serious problem is not their limitation in walking, but their risk of a future adverse cardiovascular event in the form of a myocardial infarction (MI), stroke, or cardiovascular-related death. Hence, the concept of “global vascular care.” The first priority in formulating a treatment plan for patients with PAD should be modification of known risk factors for the progression of atherosclerosis and cardiovascular event reduction. Medical therapy is always the primary therapy for patients with PAD, including those patients who undergo an endovascular or surgical intervention. In other words it has universal application, either as a standalone or as an adjunct to more invasive forms of therapy and not as an alternative.

There are a number of features unique to patients with vascular disease, including but not limited to the fact that these patients tend to be older, have age-related issues, and also have a high prevalence of comorbid conditions. This adds to the complexity in managing patients with vascular disease.

The cornerstones of medical care in patients with PAD are

• Risk factor modification
  
• Pharmacologic therapy
  
• Exercise therapy

RISK FACTOR MODIFICATION

In the ensuing portion of this chapter, those modifiable risk factors most associated with PAD will be discussed, with an emphasis on particular nuances and variation in approach to each in light of available evidence as well as current recommendations.

Smoking Cessation

Cigarette smoking has the strongest correlation with PAD than any other cardiovascular condition. It is also directly related to progression of PAD to limb loss. In smokers, the larger inflow vessels of the lower extremity are typically involved. In patients with PAD who smoke, complete smoking cessation and long-term abstinence forms the cornerstone of therapy. It represents the most important modifiable risk factor since it can favorably alter the natural history of the disease. There are data that confirm an objective improvement in ankle pressure and treadmill walking distance when comparing those patients who stop smoking versus those who continue to smoke (3). Additionally, smoking cessation reduces the severity of limb outcomes such as critical limb ischemia and amputation (4). There is also a direct dose–response relationship between the number of cigarettes smoked and the rate of lower extremity bypass graft patency (5).

Treatment options consist of behavior-modification counseling and short-term tobacco dependency pharmacotherapy that includes sustained release bupropion hydrochloride (Wellbutrin, Zyban), nicotine supplements (gum, inhaler, transdermal patches, nasal spray), and more recently Varenicline (Chantix, Pfizer). PAD patients who smoke may also represent one of those unique patient subsets in which one should not hesitate in endorsing less conventional therapies such as hypnotherapy, acupuncture, or laser therapy.

Hyperlipidemia

The major lipid-related risk factors include elevated LDL, elevated triglyceride, and low HDL levels. Lipoprotein (a) has also been identified as an independent risk factor for PAD (6). Demonstrable evidence of the effect of lipid lowering on the progression of PAD was observed in a subgroup analysis of the 4S (Scandinavian Simvastatin Survival Study) study that showed a 38% risk reduction in the development or worsening of claudication (7). Current National Cholesterol Education Panel (NCEP) guidelines and The Adult Treatment Panel (8) (ATP) classify PAD as a “coronary artery disease equivalent” and thus shares the same aggressive targets as coronary artery disease (CAD). They recommend a target LDL-C level of 100 mg/dL, which invariably would require pharmacologic intervention. A more recently updated consensus panel has recommended lowering LDL-C levels to 70 mg/dL for high-risk patients (9), which may include patients who have undergone an endovascular intervention. The Heart Protection Study (10) brought to fore another paradigm: in patients with PAD, those who received statin therapy with simvastatin had a significantly lower rate of overall cardiovascular ischemic events, regardless of cholesterol level at baseline or the presence of manifest CAD. All current evidence points to future strategies of achieving even lower target LDL levels (“the lower the better”). Another demonstrable benefit noted in some smaller scale trials is that statins may also contribute to increasing pain-free and total walking distances as well as an improvement in overall functional status (11,12). This effect may be observed independent of the degree of lipid lowering, may manifest as soon as 3 months after sustained use, and may be consistent across different statin categories. Therefore, unless there exists a strong contraindication, all patients with PAD should be aggressively treated with a statin.

Hypertension

The goal in the management of hypertension in patients with PAD is to reduce the risk of stroke and MI. Care should be taken to avoid large decreases in blood pressure for that may cause the patient to experience a worsening of their claudication symptoms. However, it must also be pointed out that the use of beta-blockers in the management of hypertension in patients with PAD is by no means contraindicated, except perhaps in those with critical limb ischemia. This fact has been borne out in various randomized studies (13).

In patients with PAD, angiotensin-converting enzyme (ACE) inhibitors are considered the first-line antihypertensive class of choice, largely based on the outcomes of the HOPE (Heart Outcomes Prevention Evaluation) trial that demonstrated a 22% lowering in the composite endpoint of MI, stroke, and death in the PAD subgroup (14). Importantly, this was observed independent of the magnitude of blood pressure lowering and was true in patients with either symptomatic or asymptomatic forms of PAD. Similar to what has been observed in trials of statins, ACE inhibitors like ramipril have also been demonstrated to independently increase pain-free and total walking distances (15).

Another consideration is that hypertension in a patient with PAD may be secondary to renal artery stenosis, which has a higher prevalence in patients with PAD. Depending on the population studied, certain estimates would put the presence of renal artery stenosis in a PAD population to be as high as 40% in all patients referred for lower extremity angiography (16).

Diabetes

The risk of developing PAD increases in direct relationship to blood glucose impairment. Even patients with impaired glucose tolerance have an incidence of PAD nearly equal to that of those with full-blown diabetes (17). The pattern of vascular involvement typically includes the below-knee vessels including the tibial vessels, small vessels of the foot, and the microcirculation of the foot. Multilevel disease is also common.

Additionally, diabetic patients tend to progress to critical limb ischemia, the most malignant manifestation of PAD, at a greater rate than the nondiabetic population. This fact may further be complicated by sensory and/or motor neuropathy, which makes them more prone to injury and ulcer formation on the lower extremities and also contributes to delayed recognition. Diabetic patients also tend to have impaired collateral vessel formation as a compensatory mechanism that directly translates to consistently worse limb outcomes (amputation, rates of revascularization).

The role of intensive blood glucose control has been definitively proven to improve outcomes in terms of microvascular complications. However, its role in macrovascular manifestations of disease has been less clear. The Diabetes Control and Complications Trial in type I diabetic patients and the United Kingdom Prospective Diabetes Study (18) in type 2 diabetic patients, which compared conventional therapy with more aggressive therapy for blood sugar lowering, both demonstrated a trend toward the reduction of cardiovascular events such as MI, but had minimal effect on the development of PAD or complications such as death and amputation related to it. Although the macrovascular results have been underwhelming, it is still recommended to maintain tight glycemic control in diabetic patients with PAD, but also to emphasize the importance of controlling additional risk factors.

PHARMACOLOGIC THERAPY

The goals of pharmacologic therapy in claudicants are targeted toward increasing pain-free and maximal walking distances as well as improving overall functional status. Although not directed toward claudication symptoms, antiplatelet therapy is a primary consideration in all prescriptions for patients with PAD in light of the aforementioned strategy of global vascular care.

Antiplatelet Therapy

In the Physicians Health Study, low-dose aspirin demonstrated a 54% reduction in the risk of peripheral vascular surgery when compared with placebo (19), and in the antiplatelet trialists’ collaboration metaanalysis, there was a 23% overall reduction in a composite of MI, stroke, and vascular death (20). When an analysis was performed on those patients enrolled in these trials on the basis of PAD only, the outcomes were similar and this was true across the dose range of 75 to 350 mg.

The search for a more efficacious antiplatelet agent with less serious adverse effects led to the CAPRIE trial (21) that compared clopidogrel, which exerts its antiplatelet effect as an antagonist to the ADP P2Y₁₂ receptor, with low-dose aspirin. Although this study demonstrated the superiority of clopidogrel over aspirin in terms of reducing the composite outcome of ischemic stroke, MI, or vascular death (5.3% vs. 5.8%, relative risk reduction 8.7%, p = 0.043, mean follow-up 1.9 years), this finding was most pronounced in the PAD population. Although not the primary intent of the CHARISMA trial, a secondary analysis of patients with a prior history of MI, stroke, or peripheral vascular disease demonstrated the superiority of dual antiplatelet therapy combining aspirin with clopidogrel over aspirin alone (7.3% vs. 8.8%, p = 0.01, mean follow-up 28 months) (22). Thus in patients with PAD, clopidogrel is the preferred antiplatelet agent for overall reduction of future cardiovascular events (dose 75 mg once daily), and there is also evidence to support the use of more intensive regimens combining aspirin and clopidogrel as a secondary preventive strategy.

Pentoxifylline (Trental)

Pentoxifylline is a methylxanthine derivative that has multiple hypothesized mechanisms of action including lowering plasma fibrinogen concentration, altering the deformability of red cells and white cells, and also inhibiting platelet aggregation. It is also perhaps the one medication that has been in use for the longest period of time, but at this time there is considerable evidence to suggest that it is for the most part no more effective than placebo (23).

Cilostazol (Pletal)

Cilostazol is a phosphodiesterase type 3 inhibitor approved by the FDA in 1999 for the treatment of intermittent claudication. A dose of 100 mg twice daily (or 50 mg twice for older more fragile patients) has been demonstrated in a number of randomized placebo-controlled trials to improve pain-free and maximal treadmill walking distances (24,25).

Cilostazol has a number of postulated mechanisms of action that include inhibiting platelet aggregation and the formation of arterial thrombi and smooth muscle proliferation as well as a vasodilatory action. However, there are some distinctive considerations to keep in mind while prescribing cilostazol. First, any improvement will only be noticed after 3 weeks of sustained use, but before that one may experience adverse effects in the form of headache, palpitations, diarrhea, and dizziness. Reducing the dose of cilostazol to 50 mg twice daily may help reduce these effects. This medication is also contraindicated in patients with congestive heart failure. Although not specific to cilostazol, this recommendation represents an extrapolation from earlier studies with phosphodiesterase inhibitors such as milrinone that were associated with an increased mortality due to a proarrhythmic effect in a heart failure population. Thus far, this effect has not been borne out in the safety data from clinical trials for cilostazol.

NEWER DRUGS/INVESTIGATIONAL THERAPIES

Despite significant investigation, it is perhaps disappointing to note that other than cilostazol, there are not many other medications in mainstream use that improve pain-free walking distances in patients with symptomatic PAD.

Naftidrofuryl, a 5-hydroxytryptamine receptor antagonist, is available in Europe for treating claudication. A very recently concluded meta-analysis has confirmed a clinically meaningful improvement in walking distance in patients using this medication when compared to placebo (26). Prostaglandins have been extensively studied for their role in critical limb ischemia with limited evaluation in patients with intermittent claudication. At first, the route of administration of these agents was a major issue (i.e., need for intravenous administration). With the availability of beraprost sodium, an orally active prostaglandin I2 analog, there was a lot of enthusiasm in testing its use in patients with intermittent claudication. Earlier trials had shown improvement in pain-free and maximal walking distances. However, this was not borne out in later trials despite a consistent reduction in the rate of cardiovascular events (27).

Therapeutic angiogenesis studies have yielded mixed results to date. Many angiogenic factors have been employed, including vascular endothelial growth factor, hepatocyte growth factor, fibroblast growth factor 4, and hypoxia-inducible growth factor 1. Whereas the intramuscular injection of vascular endothelial growth factor directly into the lower extremities of patients with symptomatic PAD failed to demonstrate improved walking performance or quality of life (28), the TRAFFIC study, which involved the intra-arterial administration of recombinant fibroblast growth factor 1, demonstrated moderate improvement in exercise capacity in patients after a single dose (29). Current and future studies of growth factors appear to be predominantly focused on the role of this therapy in the subset of PAD patients with critical limb ischemia who have no viable revascularization option.

Exercise

There is clear and incontrovertible evidence that an exercise program in claudicants leads to statistically significant increases in walking distance. In fact, a Cochrane database review that included 10 different trials demonstrated an increase in walking time of 150%, which exceeded that achieved with angioplasty and rivaled the outcome of surgical revascularization (30). However, with this available evidence, exercise as a prescription is underutilized and the reasons for this may be multifactorial. One important issue is that unsupervised home exercise programs have been shown not to work. Another is the issue of reimbursement. With all evidence demonstrating the benefits of an exercise program performed in a supervised environment, the Centers for Medicaid and Medicare services (CMS) does not reimburse for such programs performed purely for vascular indications. However, it must also be pointed out that there will be several patients with PAD who have contraindications to exercise from a medical standpoint. Patients with PAD tend to be older and may have severe CAD and musculoskeletal or neurologic impairments not to mention other patient-related characteristics such as patient compliance with traveling far distances and incurring personal expense.

The exercise prescription—exercise is not simply an alternative for patients with no revascularization options, but like all other forms of medical therapy has application even for those patients who undergo an invasive procedure. An effective exercise program consists of sessions that last at a minimum of 30 minutes, a minimum of three times per week for a minimum of 6 months. The objective is to walk on a treadmill until near-maximal pain is achieved. The patient then rests and attempts to walk again. This walking distance determines the baseline, and the intensity of treadmill exercise is set to the workload that initially brings on the claudication pain. As the patient is able to walk farther into the pain, increases are made either in the speed or grade of the treadmill. If the patient can already walk at 2 mph (3.2 km/h), then an increase in grade is recommended. The goal of the program is to not only increase walking distance but also walking speed. The most objective measure of improvement is walking distance, since even significant improvements in distance do not translate into increases in ankle pressures. The mechanism that leads to improvement in walking distance is poorly understood. Another bonus that cannot be overlooked is the overall beneficial effects of exercise on the entire cardiovascular system, namely decreases, in systolic blood pressure and improvement in serum cholesterol (31). A further issue to reassure patients about is that walking to the point of pain does not have any detrimental effects from what would be assumed to be ischemic injury.

SUMMARY

PAD is often undiagnosed and undertreated despite the fact that patients with PAD have a systemic vascular risk equivalent to diabetic patients and a 5-year mortality rate worse than that associated with breast cancer. Medical therapy is not an alternative to other more invasive strategies, but is applicable universally and directed toward risk factor modification with certain special considerations. Pharmacologic interventions are targeted to treating modifiable risk factors, increasing walking ability, and halting progression to more severe forms of limb ischemia. Complete cessation of all forms of tobacco, aggressive lowering of lipids, control of hypertension, optimization of glucose control in the diabetic subset, addition of antiplatelet therapy, and consideration of a supervised exercise program are optimal.

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