Figure 85.1. Ankle Brachial Index (ABI) and Mortality. Association of ABI with all-cause mortality in a meta-analysis of 16 cohort studies including 48,294 subjects and 480,325 person-years of follow-up.

Source: Reprinted with permission from Fowkes FG, Murray GD, Butcher I, et al. Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: A meta-analysis. JAMA. 2008;300(2):197–208. © 2008 American Medical Association. All rights reserved.

TREATMENT OF PAD

The goals of treatment for PAD are to reduce the risk of adverse cardiovascular outcomes, improve functional capacity and quality of life, prevent progression of disease, and maintain limb viability. Risk-factor modification and antiplatelet therapy are used to prevent myocardial infarction, stroke, and cardiovascular death (box 85.2), and pharmacotherapy and selective use of revascularization strategies are used to improve symptoms and to preserve limbs.

Box 85.2 PAD RISK REDUCTION THERAPIES

    Risk factor modification is indicated in patients with PAD as it is for other manifestations of atherosclerosis. Guideline statements support smoking cessation, lipid lowering, and blood pressure and glucose control. Patients with PAD who smoke cigarettes should be advised to stop smoking and offered smoking-cessation interventions. Statin therapy reduces the risk of myocardial infarction, stroke, and cardiovascular death in patients with PAD, as it does in patients with coronary artery disease. Therefore, statin therapy should be administered to patients with PAD to achieve a target LDL cholesterol of <100 mg/dL. Antihypertensive therapy reduces the risk of myocardial infarction, stroke, heart failure, renal insufficiency, and cardiovascular death. Any antihypertensive therapy drug that substantially lowers blood pressure may exacerbate symptoms, but it is more important to protect the patient from the systemic complications of hypertension. Both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers reduce myocardial infarction, stroke, and death in patients with atherosclerosis, including those with PAD, and beta-adrenergic blockers are indicated in patients with myocardial infarction, congestive heart failure, and several cardiac arrhythmias and can be used in patients with PAD. In a meta-analysis of 11 randomized controlled trials, beta-adrenergic blocker therapy did not worsen claudication in patients with PAD. Antihypertensive therapy should be administered to hypertensive patients with PAD to achieve target blood pressure according to guidelines, which is <130/80 mm Hg in patients with diabetes or renal insufficiency or <140/90 mm Hg in others. Optimal control of glucose in patients with diabetes reduces microvascular complications, such as nephropathy and retinopathy, but the data supporting optimal glucose control to reduce complications of atherosclerosis are less compelling. Studies have found no benefit, and possible harm, in lowering glycosylated hemoglobin <6.5%. Current guidelines recommend that patients with PAD be treated with glucose-lowering therapies to reduce the hemoglobin A1c (HbA_1c) to <7% in order to reduce microvascular complications and potentially improve cardiovascular outcomes. In light of newer studies, these recommendations will need further clarification.

    Antiplatelet therapy reduces total and cardiovascular mortality in patients with PAD. A Cochrane systematic review of 12 trials of 12,168 patients with symptomatic PAD found that antiplatelet therapy compared with placebo reduced all-cause mortality by 24% and cardiovascular death by 46% compared with placebo, but did not decrease total cardiovascular events.

    Two recent trials and a meta-analysis raised doubts about the efficacy of aspirin, particularly in patients with asymptomatic PAD. The Aspirin for Asymptomatic Atherosclerosis trial found that aspirin did not reduce vascular events in asymptomatic patients who did not have established cardiovascular disease but had an abnormal ABI detected at screening. Similarly, the Prevention of Arterial Disease and Diabetes (POPADAD) study found no benefit of aspirin in asymptomatic PAD subjects with diabetes. The CAPRIE study compared the efficacy of aspirin to the thienopyridine derivative, clopidogrel, in patients with acute myocardial infarction, recent ischemic stroke, or established PAD. Overall, clopidogrel reduced myocardial infarction, stroke, or cardiovascular death by 8.7% compared with aspirin. Among the subgroup of patients with PAD, clopidogrel reduced the risk of cardiovascular events by 23.8%. The CHARISMA study compared the combination of aspirin and clopidogrel to aspirin alone in patients with established cardiovascular disease and those at risk for cardiovascular disease. There was no benefit of dual antiplatelet therapy over aspirin alone on the primary endpoint of myocardial infarction, stroke, or cardiovascular death. A post hoc analysis found that dual antiplatelet therapy reduced the risk of cardiovascular events in patients with established coronary artery disease, cerebrovascular disease or PAD by 12%, but it tended to increase these events in patients with multiple risk factors. In the PAD subgroup, dual antiplatelet therapy reduced the rates of MI and hospitalization for ischemic events. In a recent trial, vorapaxar, an investigational protease-activated receptor-1 antagonist that inhibits platelet function, reduced the risk of adverse cardiovascular events by 12% in patients with established atherosclerosis, including prior MI, stroke, or PAD. Among the patients with PAD, vorapaxar reduced hospitalization rates for acute limb ischemia and peripheral artery revascularization. Current American College of Cardiology/American Heart Association practice guidelines recommend antiplatelet therapy to reduce the risk of myocardial infarction, stroke, or vascular death in patients with symptomatic PAD. These guidelines state also that antiplatelet therapy can be useful to reduce the risk of MI, stroke, or vascular death in asymptomatic individuals with PAD. Aspirin, in daily doses of 75–325 mg, is recommended as a safe and effective antiplatelet therapy. Clopidogrel, 75 mg/day, is recommended as an effective alternative antiplatelet therapy to aspirin.

    Treatment of symptomatic PAD is indicated to improve functional status, alleviate discomfort, and preserve limb function and viability. Treatment for intermittent claudication includes exercise rehabilitation and pharmacotherapy, such as cilostazol. The principal treatment of disabling claudication and critical limb ischemia is revascularization. Exercise, particularly walking, improves walking distance in patients with claudication. A meta-analysis of studies that compared the efficacy of supervised exercise rehabilitation with no exercise found that peak walking distance increased by 120%, and the distance walked to the onset of claudication increased by 180%. Supervised exercise programs typically involve three to five sessions of treadmill or track walking per week for durations of 35–50 minutes per session for 3–6 months. Supervised exercise training even improved walking time more than endovascular intervention in the Claudication Exercise versus Endoluminal Revascularization (CLEVER) trial comprising patients with iliac artery stenosis. There is some evidence that home-based exercise programs, when guided by personal step-activated monitors, also are effective. Potential mechanisms accounting for exercise-related improvement in walking distance include upregulation of angiogenic growth factors and collateral blood vessel development, enhancement in endothelium-dependent vasodilation, improved hemorheology, increased oxidative capacity of leg skeletal muscle, and better walking biomechanics.

    There are only two drugs approved by the Food and Drug Administration for use in patients with intermittent claudication: pentoxifylline and cilostazol. Pentoxifylline is a methylxanthine derivative purported to improve hemorheology through a decrease in blood viscosity and improvement in red blood cell deformability. Several small studies have reported that pentoxifylline causes modest increases in walking distance, approximating 25%, and some have found no efficacy. Cilostazol is a phosphodiesterase III (PDE3) inhibitor that increases levels of cyclic adenosine monophosphate (cAMP), causes vasodilation, and inhibits platelet aggregation. The mechanism by which it improves claudication symptoms, however, is not known. Meta-analyses of multiple clinical trials have found that cilostazol increases maximal walking distance by approximately 40–50%. Cilostazol is contraindicated in patients with congestive heart failure, since other PDE3 inhibitors have been associated with increased mortality rates in these patients. Some studies have found that statins and angiotensin-converting enzyme inhibitors improve walking distance in patent with claudication, but these findings, though encouraging, require confirmation in additional clinical trials. Nutritional supplements, antioxidant vitamins, and chelating agents are not effective therapies for intermittent claudication. Therapeutic angiogenesis with a variety of angiogenic growth factors has not proven effective in improving symptoms in patients with PAD. Cell-based therapies with bone marrow derived progenitor cells are under investigation.

    Revascularization is indicated to treat patients with persistent, lifestyle-limiting claudication despite maximal medical therapy, and those with critical limb ischemia manifest as rest pain, nonhealing ulcer, or gangrene. The two options for revascularization are (1) endovascular reconstruction including percutaneous transluminal angioplasty (PTA) and stents and (2) open surgical reconstruction. The location, severity, and characteristics of the stenosis determine the feasibility and long-term success rates of endovascular interventions. The highest success rates are with short-segment stenoses in the iliac arteries. Iliac PTA and stenting is associated with 1-year patency rates of approximately 90% and 3-year patency rates of approximately 70%. PTA with or without stenting of the superficial femoral artery is associated with 60–70% 1-year patency rates and approximately 50% 3-year patency rates, depending on the length and severity of the lesion. Open surgical reconstruction includes aortoiliac/aortofemoral reconstruction, femoropopliteal bypass, and femorotibial or peroneal bypass, depending on the location of the lesions. Inflow disease affecting the aorta and iliac arteries is typically repaired prior to surgical treatment of outflow disease affecting the infrainguinal arteries, such as the superficial femoral, popliteal, tibial, and peroneal arteries. Aorto-bifemoral bypass is a durable operation with 5-year patency rates of approximately 85–90%. The 5-year patency rates for femoral-popliteal bypass depend on whether vein or synthetic material such as polyfluoroethylene (PTFE) is used for the bypass conduit and whether the distal anastomosis is placed above or below the knee. For example, 5-year assisted patency rates for an above-knee femoral-popliteal bypass using autogenous vein is approximately 75–80%, and 3-year patency rate for a femoral-tibial bypass graft using PTFE is approximately 25%. Operative mortality rates for aortobifemoral bypass and infrainguinal bypass procedures at high-volume academic centers approximate 1–3%.

ABDOMINAL AORTIC ANEURYSMS

An aortic aneurysm is a pathological expansion of the aorta. The normal diameter of the infrarenal abdominal aorta is 2 cm. An abdominal aortic aneurysm (AAA) is usually designated when the diameter of the abdominal aorta is >3.0 cm. However, this does not account for variations in body size. Thus, an alternative definition is when there is a 50% or greater increase in the diameter of a segment of the abdominal aorta relative to the proximal normal segment.

    The pathophysiology of AAA formation differs from the intimal proliferative process that occurs in atherosclerotic occlusive conditions such as PAD. AAA formation involves inflammatory mediators and proteolytic degradation of the elastin and collagen fibers by matrix metalloproteinases. Subsequent weakening of the adventitia and media leads to aneurysmal disease by decreasing the aortic tensile strength, leading ultimately to aortic expansion and rupture.

EPIDEMIOLOGY OF AAA

The prevalence of AAA is greater in men than women and the prevalence increases with age. AAA occurs in approximately 3.5% of males and 1% of females over the age of 50 years. AAA develop less often in African Americans than in Caucasians. The annual incidence of AAA is approximately 40–50 per 100,000 men and 7–12 per 100,000 women. AAA accounts for over 15,000 deaths annually in the United States.

    A history of AAA affecting a first-degree relative is associated with an approximate twofold risk of having an AAA. A personal history of cigarette smoking increases the odds of AAA by 3.6-fold. Other risk factors include hypertension and hypercholesterolemia. For reasons that are not known, the risk of AAA is less in patients with diabetes. The risk of AAA rupture is related to the diameter of the aorta. The 5-year rupture rate is <2% for AAA <4 cm, 25% for those 5.0–5.9 cm, 35% for those 6.0–6.9 cm, and 75% for those 7.0 cm. Also rupture risk is increased by 4.5-fold in women compared with men and twofold in smokers compared with nonsmokers. Elevated blood pressure confers a more modest risk for rupture.

CLINICAL PRESENTATION

Most AAAs are asymptomatic. Occasionally an AAA will cause epigastric, lower back, or abdominal pain. AAAs are occasionally diagnosed when a pulsatile abdominal mass is detected on physical examination. Physical examination is accurate in diagnosing AAA in approximately 50% of patients in whom it is present. More often, AAA is an incidental finding when abdominal imaging is performed for an unrelated reason. Ruptured AAA is a catastrophic event in which the patient presents in extreme distress or dies from circulatory collapse.

DIAGNOSIS OF AAA

Imaging techniques are used to confirm the diagnosis of AAA. These include ultrasound, computed tomographic (CT) imaging, magnetic resonance imaging (MRI), and conventional contrast aortography (Figure 85.2). A plain x-ray may raise suspicion of an AAA if calcification along the wall of the dilated aorta is seen. Ultrasonography accurately determines the anterior-posterior, transverse, and longitudinal dimensions of an AAA. It is the most commonly used and least expensive method for diagnosing AAA. Its sensitivity for AAA ≥3.0 cm is virtually 100%. CTA is the preferred imaging modality for preoperative definition of aortic aneurysms. CTA can define the proximal and distal extension of AAA. It is especially useful when determining the feasibility of placement of an aortic endograft because it provides anatomic information such as the size and angulation of the neck as well as the relationship of the AAA to branch arteries. MRI and gadolinium-enhanced magnetic resonance angiography (MRA) are also used to characterize AAA. MRA can determine the diameter, proximal and distal extent of an AAA, and its relationship to branch arteries. As is the case with CTA, MRA is an accurate method to define aortic anatomy prior to placement of an aortic endograft. Contrast angiography is performed less frequently than the noninvasive imaging modalities because it is invasive, and it uses potentially nephrotoxic radiocontrast material. It is useful to define branch vessel anatomy and the longitudinal extent of aortic aneurysm. However, contrast angiography does not always provide accurate information about the diameter of an AAA, because it does not visualize the wall of the aneurysm, and lumen size may be misinterpreted if there is thrombus present.

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