CHAPTER 96: DIAGNOSIS AND MANAGEMENT OF DISEASES OF THE PERIPHERAL ARTERIES

Peripheral vascular diseases are a diverse collection of disorders that affect all organ systems. Peripheral artery disease (PAD) is the vascular disease most commonly encountered by the cardiologist; however, disease of the lymphatics and veins is equally common globally. For the cardiologist or internist with an interest in vascular disorders, a systematic and comprehensive approach is required. This chapter will cover commonly encountered areas of vascular disease, specifically the diagnosis and management of PAD. Accompanying chapters on lymphedema, venous disease, and aortic and cerebrovascular disease will address these topics in more detail.

PAD caused by atherosclerosis is the most common cause of lowerextremity ischemic syndromes in Western societies.¹ PAD is a major cause of lifestyle changes, poor quality of life, loss of work, disability, and significant morbidity and mortality in the United States.^2,3 Symptoms of PAD are variable and, unfortunately, frequently lead to incorrect diagnoses.⁴ Risk factors for PAD are the same as those for coronary artery disease (CAD), with tobacco and diabetes having an even greater effect (Table 96–1).^5,6 Tobacco use, current and past, is associated with a two- to fourfold increase in relative risk for PAD.^7,8 Diabetes mellitus has a similar increase in relative risk.⁷ Other modifiable risk factors include hyperhomocysteinemia, hyperlipidemia, and hypertension.⁹ Even when asymptomatic, PAD has been shown to be a strong predictor of cardiovascular disease, nonfatal cardiovascular events (eg, myocardial infarction and stroke), and lower-extremity ulcerations and amputations.⁵ PAD has significant impact on mortality; individuals with PAD have a two- to sixfold higher relative risk of death over a 10-year period of time versus the general population.^10,11,12

Prevalence

PAD affects a large and increasing number of individuals worldwide.¹ Exact numbers for prevalence and incidence are confounded by varying methods for assessment and criteria for diagnosis.¹³ Expert and consensus statements estimate that 8 to 12 million people in the United States and 200 million people worldwide are affected by PAD.^14,15,16 It is estimated that 10 million people have symptomatic PAD and another 20 to 30 million have asymptomatic disease. Based on published US statistics, each year 413,000 patients with PAD are hospitalized, 88,000 lower-extremity angiograms are performed, and 30,000 patients undergo embolectomy or thrombectomy.¹⁷ Ten percent of individuals over 60 years of age have PAD, and the prevalence continues to increase with age.^5,18 It is estimated that nearly two-thirds of those affected by PAD over the age of 65 years are female.¹⁹

In the Framingham Offspring Study, the prevalence of PAD was determined in 1554 males and 1759 females from 1995 to 1998.²⁰ The mean age was 59 years. PAD, defined as an ankle-brachial blood pressure index (ABI) of < 0.90, was present in 3.9% of males and 3.3% of females. Lower-extremity bruits were present in 2.4% of males and 2.3% of females. However, the prevalence of claudication was only 1.9% in males and 0.8% in females, suggesting that only half of men and only a quarter of women had symptoms or recognized their symptoms.

The PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) study assessed the prevalence of PAD in US patients older than 70 years of age and those aged 50 to 69 years with a smoking history or diabetes.²¹ PAD was defined by an ABI of < 0.90; 29% of the population was found to have PAD. Nearly half of those with PAD had concurrent coronary or cerebral vascular disease.

Seven-thousand European individuals were evaluated for PAD in the Rotterdam study; 20% of patients older than 55 years of age and nearly 60% of men older than 85 years were found to have PAD.²² One to twenty percent of patients in these studies diagnosed with PAD had self-reported claudication or symptoms by Rose questionnaire; this supports the conclusion that most individuals with PAD remain either asymptomatic or limit their activities due to numerous variables. Nearly 10% of asymptomatic individuals have advanced PAD with severe obstruction to blood flow in their lower extremities.²³

Natural History

Death directly due to PAD is rare. Mortality and morbidity are more often due to concomitant coronary or cerebrovascular disease. The relative risk of all-cause death is two-to sixfold higher in PAD patients versus the general population.^10,11,12 The risk of death increases as the ABI decreases.^24,25 The 5-year mortality for an ABI < 0.85 is 10%; when the ABI is < 0.40, mortality approaches 50% per year.²⁶ Lower-extremity symptoms not associated with a decrease in the ABI do not demonstrate an increase in mortality.²⁷ By contrast, a decrease in ABI without symptoms still portends an increase in cardiovascular morbidity and mortality.²⁸ Patients with ABI > 1.40 and between 0.91 and 1.00 have a similar risk of having a myocardial infarction and/or stroke.²⁹ Projects like the Atherosclerosis Risk in Communities study and others have demonstrated that an ABI > 1.40 is associated with an increase in morbidity such as foot ulcers, congestive heart failure, and stroke, but not an increase in cardiovascular events.^30,31 An ABI between 0.90 and 0.99, which is classified as borderline, increases the risk of future walking impairment.³²

Although the cardiovascular mortality and morbidity of patients with PAD is sobering, the rate of progression of limb symptoms and need for limb revascularization or amputation are low.³³ Need for revascularization due to tissue loss (ulcer) or rest pain is 5% per year.¹³ Amputation rates are even lower, at approximately 1% per year.³⁴ For those who present with acute critical limb ischemia, 30-day amputation rates are 10% to 30%, with a 1-year mortality of 15%.³⁵ Individuals with acute limb ischemia of > 24 hours is associated with higher 30-day (25.7%) and 1-year amputation (37.1%), with a 30-day mortality of 34%.³⁶

Risk Factors

Numerous risk factors for PAD have been identified (Fig. 96–1).^14,37 The strongest correlation exists with advancing age; other comorbidities include tobacco abuse, diabetes mellitus, hypertension, hyperlipidemia, homocysteinemia, C-reactive protein, gender, and ethnicity.

Tobacco Abuse

Tobacco abuse is a strong risk factor for the development and progression of PAD.³⁸ Smoking is associated with increased PAD-related procedures, hospitalizations, and increased costs.³⁹ Results from the Edinburgh Artery Study demonstrate that tobacco users have a 3.7 higher relative risk of intermittent claudication compared with 3.0 among individuals who have discontinued smoking for less than 5 years.²³ Smoking increases the risk of lower-extremity amputation, peripheral graft occlusion, and death in a dose-dependent fashion. The rate of progression and amputation in those who continue to smoke is more than twofold higher than the rate in those who quit, with 15% of those who continue smoking undergoing amputation within 5 years.⁴⁰

Diabetes

Diabetes mellitus increases the risk of PAD development by two- to fourfold. A 1% increase in hemoglobin A1C levels is associated with a 26% increased risk of PAD.⁴¹ Individuals who have insulin resistance demonstrate a higher prevalence of PAD.⁴² There is an association between a low ABI and mortality that is similar in those with and without diabetes, whereas the association with high ABI has only been observed in patients with diabetes.⁴³ In addition, individuals with longstanding diabetes tend to have more severe PAD and are more likely to suffer from claudication symptoms (albeit many are asymptomatic because of peripheral neuropathy). Diabetics have an amputation rate of 25% over 10 years, which has changed little over time.^44,45

Hypertension

Epidemiology studies demonstrate a strong association between increased systolic blood pressure and the development and progression of PAD.^46,47,48 Individuals with hypertension have a 2.5- to 4-fold increase of PAD compared to individuals with normal blood pressures.⁴⁹ Claudication is fourfold higher among those with hypertension and is proportional to the severity of hypertension.

Hyperlipidemia

The association between hyperlipidemia and PAD is inconsistent. Numerous studies show that increased total cholesterol is associated with an increased risk of PAD and claudication.^50,51 Each increase in total cholesterol of 10 mg/dL leads to a 5% to 10% increased risk in PAD.^49,50 Other studies demonstrate a protective effect against PAD among individuals with increased high-density lipoproteins (HDL).⁵² When non-HDL and a total-to-HDL cholesterol ratio are used, individuals in the highest quartile have nearly four times the claudication risk of those in the lowest quartile.⁵³ For those with isolated hypertriglyceridemia there appears to be a nonsignificant relationship between increased triglycerides and PAD.

Homocysteinemia

Homocysteinemia plays an independent role in development of PAD. The mechanism is partially related to an inborn genetic mutation affecting methylenetetrahydrofolate reductase (MTHFR), resulting in accelerated intimal damage and early atherosclerosis.^45,54

C-Reactive Protein

C-reactive protein (CRP), an inflammatory marker, increases among individuals with PAD.^55,56 CRP predicts PAD progression and severity.^57,58 In addition, CRP levels are higher in individuals with PAD than those with angiographically proven coronary artery disease.⁵⁹

Clinical Assessment of Arterial Disease

History

The differential diagnosis of claudication is broad; an abbreviated list is given in Table 96–2. Information regarding risk for atherosclerosis, current medical problems, prior lower-extremity and back trauma, and all vascular and orthopedic procedures should be obtained on all patients. The description of claudication symptoms is unique to each patient.^4,60 Symptom specifics, including onset, progression, and aggravating or alleviating factors, should be clarified. In some patients, different types of discomfort caused by different etiologies occur and may complicate the clinical picture.^61,62

Asymptomatic

Most individuals with PAD have no lower-extremity symptoms⁶⁰ and the diagnosis will be missed if ABI testing is reserved exclusively for individuals with classic claudication symptoms. Identifying PAD in those without classic intermittent claudication symptoms remains challenging.⁶³ Appropriate criteria for screening individuals for suspected PAD includes a history of walking impairment, claudication, ischemic rest pain, and/or nonhealing wounds; these criteria are recommended as a required component of a standard review of symptoms for adults 50 years and older who have atherosclerosis risk factors and for adults 70 years and older.⁶⁴ Screening patients for PAD should include those greater than 65 years old, individuals 50 years or older with history of diabetes mellitus or tobacco abuse, complaints of claudication, evidence of reduce pulses, or established atherosclerotic disease (renal, carotid, coronary, subclavian, etc.).⁶⁴

Claudication

Claudication, literally meaning limping (Latin), is a stereotypical, reproducible distress in single or multiple muscle groups of the lower extremity brought on by sustained exercise and relieved by rest. The distress is classically described as cramping, but numbness, weakness, giving way, aching, and dull pain are all common concerns.⁶⁵ The distress changes in character and/or location as the flow-limiting lesion(s) progress. When workload is increased by rapid pace, a burden, or walking uphill or over rough terrain, the distance or time to onset will shorten. When the distance to onset or severity abruptly changes, thrombosis in situ or an embolic event should be considered. In general, symptoms occur distal to the level of stenosis or occlusion. Claudication occurs in muscle groups rather than joints. Relief with rest is independent of position and is usually complete within 5 minutes. When specific positions are required for relief, musculoskeletal or neurologic disorders should be suspected. Claudication often worsens after a period of inactivity, such as hospitalization, but returns to baseline with reconditioning. Although lifestyle limitation and changes in quality of life are an integral part of the history, quantification of disease severity by history alone is unreliable.⁶⁶ Standardized treadmill testing using ABIs at rest and after completion of an exercise protocol confirms the diagnosis, determines the severity, documents claudication distance for future follow-up, and independently predicts mortality.^65,67,68,69

Acute Limb Ischemia

Acute limb ischemia may be defined as an abrupt event caused by arterial occlusion. It is important to inquire about sudden appearance of a cold, painful forefoot/toe, especially in the presence of skin color changes. Associated signs and symptoms include pain, paralysis, paresthesia, pulselessness, pallor, and “polar” changes (cold).⁷⁰ The pain typically lessens in the dependent position and often is localized. Common findings of early acute limb ischemia include the loss of light touch sensation, proprioception, and vibratory perception. There may be temperature or color change in the extremity where occlusion has occurred. Acute limb ischemia may be caused by in situ arterial thrombosis, embolization (from a cardiac or proximal aneurysmal source, or secondary to plaque disruption during trauma, angiography, intra-aortic balloon pump counterpulsation, or surgery), or other causes. Rates of death and complications among individuals who present with acute limb ischemia range from 15% to 20% within 1 year from presentation, while amputation occurs in 10% to 15% of individuals during hospitalization.^70,71

Critical Limb Ischemia

Critical limb ischemia may be defined as tissue loss or rest pain in a limb, usually at the distal portion and rarely in the entire limb. Small, localized areas of ischemic pain or ulceration are often caused by minor trauma to an area with poor perfusion rather than progression of disease.⁶⁵ Many individuals are asymptomatic prior to developing critical limb ischemia.⁷² It is important to inquire about new shoes, recent nail care, pets, and other potential sources of trauma. Rest pain is present when supine and is often relieved by dependency (such as hanging the limb off the bed or, paradoxically, by walking.) Pain may progress and become constant; this may interrupt sleep, suppress appetite, cause weight loss and delirium, or require large doses of analgesics for pain relief. Patients may sleep in a chair (with their legs dependent) to get better rest and often present with edema as a result.

Pseudoclaudication

Pseudoclaudication is typically of neurogenic origin. The patient with neurogenic claudication describes exercise-induced distress with a dysesthetic quality that clears slowly or requires a specific posture for relief, usually with the hips flexed.⁷³ Clumsiness may develop as walking continues. Symptoms also occur with prolonged standing or when supine. Compression of the distal spinal cord by hypertrophic bone, disk protrusion, or tumor may be present. A history of back injury is common. Arterial and pseudoclaudication often coexist. In this situation, the dominant lesion can often be clarified by observing and timing symptoms that occur with standing versus those produced by exercise, as well as by measuring the arterial indices before and after exercise.⁷⁴

Venous Claudication

Venous claudication is described as a congestive, often bursting, distress of thighs and calves induced by standing, walking, or running. Relief with rest is slow and notably accelerated when the patient elevates the legs. Venous claudication typically occurs in the setting of iliocaval obstruction. Signs of venous hypertension of the legs and lower abdomen are often noted during examination.⁷⁵

Arterial Examination

Inspection

A red or purplish color of the forefoot during dependency (dependent rubor) is common with severe ischemia. Rubor caused by ischemia will change to pallor with elevation; in contrast, rubor caused by cellulitis usually persists with elevation.⁷⁶ Timing the onset of pallor and venous refilling time can be performed in the examination room (Table 96–3). Loss of normal hair growth is also a marker of ischemia.

Livedo reticularis is a transient, bluish discoloration with a lacy pattern found on the extremities and sometimes the trunk that is variable in its extent and intensity. It is most apparent after exposure to cold or emotion and fades with warming or exercise. It is more common in women and fair-skinned individuals. Livedo reticularis is common, and when mild it is often overlooked. It is postulated that spasm of the cutaneous arterioles (with secondary dilation of the capillaries and venules) causes slow flow, increased oxygen uptake, and reduced oxygenation of hemoglobin, producing the color change. Livido racemosa is a secondary livedo reticularis that is patchy, focal, and asymmetric in distribution and typically fixed. It may be complicated by local infarction or ulceration (Fig. 96–2).

Palpation

The aorta, radial, ulnar, subclavian, carotid, temporal, occipital, femoral, popliteal, posterior tibial, and dorsalis pedis arteries are accessible by palpation. Pulses are graded on a scale (Table 96–4).⁷⁷ If a pulse is not palpable, Doppler examination should be performed to establish whether flow is absent or below the level of detection by palpation. Surface temperature is reduced when perfusion is compromised. Temperature differences are best felt with the dorsum of the fingers; comparison to the contralateral limb or proximal ipsilateral limb should be made. The sizes of paired arteries are similar in magnitude. Ectasia or aneurysm is suspected when one side is larger or more forceful than the other. Tortuosity of the carotids, abdominal aorta, and subclavian arteries can mimic an aneurysm. Ultrasound or other imaging studies are needed to clarify the findings when the diagnosis of an aneurysm is entertained.

Auscultation

Blood pressures should be taken in both arms and should be similar (but rarely identical, even when measured simultaneously.). Respiratory variation, positioning of the arm, and atrial fibrillation are just a few reasons for pressure variation. If a large difference is noted between arms (> 14 mm Hg), blood pressures should be rechecked. If still discrepant, simultaneous pressures are done to confirm the finding. The femoral, iliac, aortic, carotid, and subclavian arteries should be auscultated routinely. Simultaneous palpation of a radial artery during auscultation will improve detection of subtle bruits (especially abdominal bruits when bowel sounds are vigorous) and allow accurate timing of bruits. An epigastric bruit that varies with respiration is most often due to compression of the celiac artery by the median arcuate ligament.

Laboratory Assessment of Arterial Disease

Objective testing of the arterial system is done for confirmation or clarification of the clinical findings, monitoring disease progression, or assessment of outcome after intervention.

Anatomic Studies

Conventional Angiography

Conventional angiography is the standard by which all other imaging techniques are judged.⁷⁷ It provides reproducible information with high resolution not yet matched by other modalities (Fig. 96–3A). Assessment of distal vessel fine structural detail and arteriovenous shunting are still best determined by angiography. Drawbacks include risk of distal embolization and arterial damage at the puncture site. Iodinated contrast is used and poses a small, but real, risk of anaphylactoid reaction and contrast nephropathy.

Computed Tomography Angiography

Computed tomography angiography (CTA) provides detailed anatomic information without need for arterial access.⁷⁸ Iodinated contrast is still required (Fig. 96–4). Three-dimensional (3D) reconstructions can include or exclude bony structures and other organs in the final images and also enable the image to be rotated on an axis. CTA is often used as an initial imaging modality when percutaneous intervention is unlikely.^79,80,81

Magnetic Resonance Angiography

Magnetic resonance angiography (MRA) provides information similar to CTA without the need for iodinated contrast. For those at risk of contrast nephropathy or anaphylactoid reaction, it is a safe and accurate alternative to CTA and conventional angiography.^79,82 However, most studies use gadolinium as a contrast agent, which puts patients with a low creatinine clearance at risk of gadolinium-induced nephrogenic fibrosing dermopathy, also known as nephrogenic systemic fibrosis.^79,83 Noncontrast techniques can be used in some instances to avoid this potential complication. MRA, like CTA, provides a 3D image and can include or exclude structures of interest. Patients with implantable devices such as pacemakers, automated defibrillators, recently placed vascular stents, and intracranial clips cannot be safely placed into the magnetic field, limiting availability to a small extent.

Duplex Ultrasound

Duplex ultrasound (2D gray-scale imaging plus Doppler) assesses not only arterial anatomy, but also the hemodynamic effects of stenosis (see Fig. 96–3B). Contrast is not required and no ionizing radiation is used. Ultrasound is portable and captures images in real time, allowing both bedside and intraoperative monitoring of therapy (Fig. 96–5). Data acquisition may be limited by body habitus, overlying structures such as bowel gas, and other tissues that interfere with imaging. Surgical intervention using duplex as the sole imaging modality has proven effective in selected settings.⁸⁴

Hemodynamic Studies

The hemodynamic significance of a stenosis may be assessed by multiple methods. Direct catheter measurement of a pressure gradient across a stenosis is still considered the gold standard. Duplex scanning is widely used; spectral broadening, poststenotic velocity increase, and dampening of the waveform are seen as the degree of stenosis increases. Continuous-wave Doppler (CWD) is available as a portable, handheld device and provides valuable information at minimal cost; the normal triphasic waveform becomes monophasic or absent wave as the severity of a stenosis increases to occlusion.⁸⁵ Other noninvasive techniques include the assessment of segmental pressures (see “Segmental Pressures” in the next section).

Functional Studies

The information obtained by anatomic or hemodynamic testing at rest is often insufficient to explain symptoms or quantify the degree of impairment caused by the arterial lesion. Functional assessment, which usually involves some form of applied stress, such as walking on a treadmill, may be necessary.

Segmental Pressures

Segmental pressures and exercise testing provide a simple, reproducible, inexpensive, and accurate method of determining the presence, severity, and approximate location of stenotic lesions. Pneumatic cuffs are placed around the thigh, calf, ankle, upper or lower arm, or digits. A CWD probe is positioned over the artery at a site distal to the cuff, and the systolic pressure at which arterial flow ceases and resumes is recorded. Each segmental pressure is divided by a reference arterial pressure (usually the highest brachial artery pressure) to create an index. The most commonly reported segmental pressure is the ABI. An ABI ≥ 1.0 is considered normal in most laboratories. Severe disease is present when the ABI is < 0.50 (Table 96–5).

Segmental pressure measurement is unreliable in patients with noncompressible or poorly compressible vessels, seen most commonly in diabetes.^86,87 The stiff vessels are caused by calcium deposition in the media of the arteries (Mönckeberg calcification). Many groups use the great toe index in these patients.⁸⁶ A toe-brachial pressure index > 0.70 is considered normal. The great toe is most often used, with the second toe as an alternative.⁸⁸ Even when the large vessels of the limb are noncompressible, the digital vessels in the toes and fingers often remain noncalcified and can be used to estimate pressure with an appropriate-sized cuff. Pulse volume recording, laser Doppler fluximetry (LDF), and transcutaneous oximetry can be useful in these patients (see following sections).

Lower-Extremity Arterial Exercise Testing

Lower-extremity arterial exercise testing is performed by walking on a treadmill at a standardized protocol.⁸⁹ Protocols may be fixed (eg, 2 miles per hour at a 10% incline for a maximum of 5 minutes) or graded, (increasing speed and/or incline at set intervals, similar to those used in cardiac exercise studies.)⁹⁰ Select parts of the lower-extremity study (ie, ABIs or CWD at the common femoral level) are performed before and after exercise. With exercise, the systolic blood pressure increases as peripheral resistance decreases, resulting in a larger pressure gradient across the stenosis and lower ABI and abnormal Doppler signals distal to the stenosis. A decrease in ABI or a change in Doppler signal may be detected after exercise (Table 96–6). Even if the resting values are normal, a decreased ABI following exercise predicts an increase in mortality.^91,92,93 Exercise studies provide ancillary data such as the walking distance to onset of symptoms, absolute walking distance, and blood pressure response during exercise. They also correlate symptoms (which may be vague) with hemodynamic data, providing objective evidence of disease.⁹⁴ Toe tip exercise testing has good correlation to treadmill testing and is an excellent alternative in patients who are unable to walk safely on a treadmill, or when a treadmill is not available.⁹⁵

Pulse Volume Recording

Pulse volume recording assesses the magnitude of the arterial impulse entering a limb or segment of a limb. A pneumatic pressure cuff connected to a pressure transducer is placed around the limb and filled with air to a low pressure (typically 40 to 60 mm Hg). During systole, pulsatile inflow of the arterial system causes distension of the limb. This technique has the advantage of remaining accurate in the setting of poorly compressible vessels.^96,97

Transcutaneous Oxygen

Transcutaneous oxygen pressure measurement (TCPO₂) assesses the microcirculation by quantifying the amount of oxygen that diffuses out of the skin.^98,99 It is dependent on a number of factors, including the arterial partial pressure of oxygen, cutaneous blood flow, and the rate of oxygen consumption by the skin. TCPO₂ can be used to monitor the effect of therapy such as bypass graft or stenting, sympathectomy, or spinal cord stimulation.¹⁰⁰ It may also predict whether the cutaneous perfusion is adequate for healing at a given amputation site.¹⁰¹ Values > 40 mm Hg are typically sufficient for healing, whereas those < 20 mm Hg are unlikely to heal.

Laser Doppler Fluximetry

LDF is increasing in popularity for determination of cutaneous perfusion. Frequently, LDF is used to image skin flaps and burns to determine viability of the tissue.¹⁰² Skin perfusion pressure may be assessed locally.¹⁰³

Treatment of Arterial Disease

Once the diagnosis of PAD has been made, aggressive risk factor modification is the cornerstone of therapy. The slow rate of progression and high incidence of cardiovascular comorbidities create the optimal situation for modifying the underlying atherosclerotic process.

Claudication Treatment

The American College of Cardiology/American Heart Association (ACC/AHA) Practice Guidelines on lower-extremity PAD nicely summarize the medical and interventional treatment options and level of evidence available¹⁰⁴ (Table 96–7). These guidelines were updated with new recommendations while outdated recommendations were removed in the 2011 American College of Cardiology Foundation (ACCF)/AHA Focused Update of the Guideline for the Management of Patients with Peripheral Artery Disease.⁶⁴

Behavioral Modification Therapy

Walking Programs

Walking programs should be initiated in all patients with claudication, both with typical and atypical symptoms.^105,106 Supervised exercise programs appear superior to stent revascularization, even for those with aortoiliac PAD.¹⁰⁷ However, exercise programs combined with endovascular revascularization have been shown to improve walking distances and health-related quality-of-life scores compared to supervised exercise alone.¹⁰⁸ Unfortunately, bicycling and other forms of exercise used for cardiovascular conditioning do not provide the same lower-extremity benefit as walking. The effectiveness of a supervised walking program is well-demonstrated, and supervised programs are more effective than non-supervised programs.^109,110,111 Community-based walking programs that implement structured training with monitoring and coaching commonly used in supervised exercise programs improve outcomes in PAD patients.^112,113,114 Exercise for 30 minutes on 4 to 5 days per week improves functional ability and exercise capacity; total and absolute walking distances increase from 50% to 300%.¹¹⁵ Patients should walk until they near their maximal pain threshold, then rest for relief before walking until they reach their pain threshold again.¹¹⁶ The mechanism of improvement is unclear, but increased collateral formation or recruitment, muscle training, improved oxygen uptake, and improved mechanics of walking may be involved.^117,118 Diligent foot care and protection must be emphasized, particularly in diabetics and those with severe reductions in ABI or TCPO₂ values. Footwear must be supportive and protective, and nail care should be performed regularly by professionals.¹¹⁹

Smoking Cessation

Smoking cessation is important for the treatment of PAD. The increase in progression to amputation with tobacco use should be emphasized with the patient.⁸ In a study of patients with intermittent claudication, the 10-year survival rate in tobacco users compared to former tobacco users was 46% and 82%, respectively. Recent study has demonstrated an independent association between active smoking and early graft failure.¹²⁰ Clinicians should advise smoking cessation programs and pharmacological treatment, such as varenicline or bupropion, if indicated.^121,122

Pharmacologic Therapy

Antiplatelet agents including aspirin and clopidogrel have historically been considered first-line agent for patients with PAD.¹²³ However, a meta-analysis by Berger et al¹²⁴ showed no significant benefit of antiplatelet therapy, including aspirin or dipyridamole, on either all-cause or cardiovascular mortality, but did show a reduction in nonfatal stroke. The Aspirin for Prevention of Cardiovascular Events in a General Population Screened for a Low Ankle Brachial Index (AAA) trial further evaluated the role of aspirin in patients with PAD and showed no benefit on cardiovascular death, myocardial infarction, stroke, or revascularization, but aspirin was associated with increased bleeding.¹²⁵ The Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial showed a benefit of clopidogrel over aspirin in all-cause cardiovascular mortality, with PAD patients having the most significant improvement.¹²⁶ In a subgroup analysis of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) study in patients with PAD, it was shown that a combination of clopidogrel and aspirin is more effective than aspirin alone in prevention of myocardial infarction, although with an increase in minor bleeding.^127,128 Based on the current data, it is appropriate to consider dual-antiplatelet therapy of clopidogrel 75 mg daily and aspirin 75 to 162 mg daily, or clopidogrel 75 mg daily alone, unless there are contraindications to antiplatelet therapy (such as a high risk of bleeding complications).

Lipid lowering has a beneficial role in patients with PAD, and targets are identical to those for patients with CAD. Statins are beneficial: they lower mortality and increase amputation-free survival in critical limb ischemia patients,¹²⁹ improve survival in critical limb ischemia patients 1 year after surgical revascularization,¹³⁰ and improve outcome in patients with peripheral artery disease.¹³¹ Lipid lowering in PAD decreases progression of claudication symptoms.¹³² It is appropriate to consider high-intensity statin therapy for individuals with PAD (for secondary cardiac prevention) unless they are unable to tolerate high-intensity statin therapy; if so, they may be treated with moderate-intensity statin therapy.^64,133 For individuals who are unable to tolerate any statin therapy, a nonstatin cholesterol-lowering drug may be considered.¹³³

Hypertension control should be optimized to reduce adverse cardiovascular outcomes.¹³⁴ Angiotensin-converting enzyme inhibitors (ACEIs) and β-blockers were effective in reducing cardiovascular mortality in a longitudinal study.¹³² Angiotensin receptor blocker is as effective as ACEI at reducing cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure in those with PAD.¹³⁵ A small study suggests that ramipril improves pain-free and maximal walking time.¹³⁶ The use of ACEI or angiotensin receptor blocker therapy in patients with vascular disease is appropriate, whereas the combination should not be used. β-Blockade was once contraindicated for patients with arteriosclerosis obliterans (ASO), but studies have refuted this idea.¹³⁷ Given the beneficial effects of β-blockade in patients with CAD, these agents should be used in patients with peripheral ASO.¹³⁸ In general, patients with established cardiovascular disease, including symptomatic PAD, should have optimization of their blood pressure.¹³⁹

Cilostazol, a phosphodiesterase type 3 inhibitor, induces vasodilatation and inhibits platelet aggregation. Cilostazol is effective in increasing walking distance and quality of life when used in conjunction with a walking program.^140,141 The effect is lost when the drug is stopped.¹⁴² Although effective, cilostazol should always be used as part of a comprehensive program including exercise and risk-factor reduction.¹⁴³ Cilostazol has side effects such as diarrhea, headache, and dizziness, which may limit its tolerability.¹⁴⁴ The long-term adherence of cilostazol is poor, with more than 60% of individuals discontinuing therapy by 36 months.¹⁴⁵

Vorapaxar, an oral protease-activated receptor [PAR]-1 antagonist, inhibits thrombin-induced platelet aggregation. The Thrombin Receptor Antagonist for Secondary Prevention-TIMI Study Group (TRA2P-TIMI) trial showed a benefit of vorapaxar on cardiovascular risk in stable patients with atherosclerotic vascular disease.¹⁴⁶ In a subgroup of the TRA2P-TIMI study in patients with PAD, vorapaxar reduced the occurrence of acute limb ischemia and peripheral revascularization.¹⁴⁷ However, in the recent Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial, no benefit was seen in lower rates of ischemic end points, peripheral revascularization, and amputation among non–ST-segment elevation acute coronary syndrome with PAD who were treated with vorapaxar.¹⁴⁷

Homocysteinemia may play an independent role in development of PAD. Treatment with folic acid and vitamins B₁₂ and B₆ is appropriate when > 14 μmol/L.¹⁴⁸ While elevated homocysteine may contribute to development of PAD and B₆/B₁₂/folate can lower homocysteine, this combination has not been shown to reduce the risk of developing PAD.

Revascularization

The indication for revascularization is based on a number of factors, including comorbidities, functional status, and severity of symptoms.¹⁴⁹ Surgical and endovascular treatment strategies are addressed in adjacent chapters. In general, proximal (iliac) stenosis and short segment occlusion are best treated endovascularly, with long lesions and occlusions best treated surgically. Outcomes for endovascular treatment of the femoral to popliteal segment are improving, and this treatment should be considered by experienced operators for patients with good lesion characteristics.^150,151

Critical Limb Ischemia

Revascularization is an option for patients with rest pain, tissue loss, or lifestyle-limiting symptoms.¹⁵⁰ Surgical revascularization is effective, durable, and has a good outcome with regard to limb salvage.¹⁵² Percutaneous transluminal angioplasty (PTA), with or without stent placement, is useful and durable for lesions of the iliac and proximal superficial femoral arteries. Distal PTA has been less durable, but for patients at high risk for limb loss who are also poor surgical candidates (or technically unfeasible for surgical revascularization), it is reasonable to consider distal PTA for limb salvage.¹⁵⁰ Medical treatment for critical limb ischemia is challenging.¹⁵³ Intermittent pneumatic compression and angiogenesis with growth factors are emerging therapies.¹⁵⁴

Presentation

Acute arterial ischemia is a particularly ominous event, with a 20-day mortality of 25%.^155,156 It presents suddenly as a painful, cold pale, pulseless limb that progress to paresthesia and paralysis. Limb viability is at risk if flow is not restored quickly. Distal changes of livedo caused by microembolization may be present. Severe ischemia is suggested by pallor at rest, profound coolness, tender or hard muscles, and loss of motor and/or sensory functions. If caused by arterial dissection, variability in the pulse deficit and affected area over a short time (migratory signs and symptoms) will cause discrepancy between examiners, thus providing a valuable clue to the diagnosis.

Etiology

The etiology of acute arterial occlusions may be trauma, dissection, thrombosis in situ, or embolism from a proximal source. Aneurysms, clotting disorders, atherosclerosis, and recent arterial manipulation may precipitate acute occlusion by mechanical disruption of plaque. Cardiac thrombus is the most common source for large embolism. Both the left ventricle and atrium may harbor thrombus and should be interrogated with transesophageal echocardiography.¹⁵⁷ Paradoxical emboli from the right heart or limbs pass across cardiac septal defects or a patent foramen ovale and cause cerebrovascular events. Interrogation of the venous system should be done when paradoxical emboli are suspected.

Treatment

Immediate measures are needed to protect the limb and restore blood flow. Heparin should be started to prevent clot propagation and to stabilize the embolic source(s). Angiography (conventional or other) may be required to plan repair when there is preexisting occlusive or aneurysmal disease or when the etiology is unclear. Ideally, all occlusions should be considered for reestablishment of flow, but urgency is governed by the degree of ischemia. If the affected limb is not viable, amputation should be performed as quickly as possible to avoid further complications. Additional time may be taken to address ancillary problems in lesser degrees of ischemia. When critical ischemia is present, repair must occur within hours to salvage the limb, provided risks to the patient are acceptable.¹⁵⁸ When indicated, thrombolysis of acute thrombus can be effective, although the risks of bleeding and stroke must be considered.^159,160

Thromboangiitis Obliterans

Thromboangiitis obliterans (TAO), or Buerger disease, is an inflammatory vasculopathy affecting small and medium-sized arteries and veins caused by an inflammatory, highly cellular intraluminal thrombus.¹⁶¹ TAO was thought to be exclusively associated with tobacco use, but cannabis, either on its own or because of contamination with tobacco, causes a similar entity, and its use should also be addressed.¹⁶² Historically, TAO was seen in males in the second through fifth decades. Currently, the incidence in women has risen, reflecting the changing demographics of tobacco use. Clinically, TAO differs from atherosclerosis in that involvement of the upper extremity is common and usually present. The initial involvement is often in digital, pedal, and hand vessels; patients may present with ulceration of one or more digits. Rare manifestations include coronary, cerebral, and mesenteric artery lesions.¹⁶³ Episodes of recurrent superficial phlebitis are common. Biopsy of acute lesions, particularly superficial veins, is diagnostic, whereas angiographic features are characteristic, but not diagnostic.

Improvement is possible only after all exposure to tobacco ceases, but the improvement remains variable.^164,165 Amputation of ulcerated digits and limbs is often required.^166,167 Progressive tissue loss is inevitable until tobacco exposure is stopped, with amputation rates approaching 50% in those who continue to use tobacco.^161,168

Giant Cell and Takayasu Arteritis

Takayasu arteritis (TA) and giant cell (temporal) arteritis (GCA) are similar in pathologic process, but affect different age groups. TA occurs in those younger than 40 years of age, and GCA usually affects those older than 50 years.^169,170 TA generally involves arteries below the neck and GCA generally involves arteries above the diaphragm, but involvement of the aorta and subclavian, axillary, renal, iliac, femoral, and superficial femoral arteries is described in both. Disease is usually bilateral and presents with rapidly progressive symptoms in the setting of a nonspecific systemic illness. Limb-threatening ischemia is rare, but may occur when diagnosed late. Both GCA and TA have characteristic clinical and laboratory findings including an elevated sedimentation rate (> 90%, but not in all patients) and typical angiographic features of smooth, tapered narrowing in large and medium-sized arteries (Fig. 96–6).¹⁷⁰

For GCA, confirmatory biopsy of the temporal artery within 3 days of steroid initiation is the gold standard.¹⁷¹ A preceding history of polymyalgia rheumatica is present in > 50% of patients.¹⁷² Visual changes in the setting of an elevated sedimentation rate, jaw claudication, or a pulse deficit should be treated as medical emergency with parenteral corticosteroids.¹⁷³ TA may also present as a medical emergency. The coronary arteries can be involved, resulting in unstable angina.¹⁷⁴ It may also affect the aortic root, causing acute aortic insufficiency with pulmonary edema.¹⁷⁵ This should be considered in a young person with absent pulse(s), dyspnea, and a diastolic murmur.

These diseases are unique among arteriopathies in that the acutely stenotic lesions improve rapidly with steroid therapy. Alternative immunosuppressive agents are often used, but corticosteroids remain the mainstay of treatment.¹⁷⁰ When required, revascularization is best performed when the inflammatory process is quiet or burned out and steroids have been discontinued or tapered to a maintenance dose.¹⁷⁶

Fibromuscular Dysplasia

Fibromuscular dysplasia (FMD) most commonly affects women and has been described in almost all arteries.¹⁷⁷ The renal artery is most often involved; it occurs in approximately 75% of patients with FMD and is bilateral in approximately > 35% of cases.¹⁷⁸ Although early reports described the renal arteries as being affected most often, more recent data from the US FMD registry suggest that FMD was found equally in the renal and carotid/vertebral arteries.¹⁷⁹ Treatment with angioplasty has generally good outcomes, with stent use reserved for complications such as angioplasty-associated dissection. Surgical repair is reserved for refractory cases or when distal renal disease is present.¹⁷⁹

Raynaud Phenomenon

Raynaud phenomenon is diagnosed by history, with the examination and laboratory findings playing a secondary role. The syndrome is classically defined as discoloration episodes of white ischemia, then blue stasis, and then red hyperemia during the recovery phase. In practice, most patients do not describe all three phases.¹⁸⁰ Fingers are involved more often than toes. The fingertips are affected more commonly than the palm or dorsum of the hand, as shown in Fig. 96–7. Prevalence was estimated at slightly less than 10% of the population in the Framingham study.¹⁸¹

Allen and Brown¹⁸² defined primary Raynaud phenomenon as episodes of bilateral color changes induced by cold or emotion without evidence of ischemia or other disease occurring for 2 years. This represents most cases and, in some sense, can be considered simply the exaggerated response of a normal reflex. The pathophysiology of exaggerated vasoconstriction is complex, but appears to involve both local and systemic pathways.¹⁸⁰ Most patients with primary Raynaud phenomenon require no therapy and quickly learn to keep not only hands, but the whole body, warm. For those with severe symptoms, treatment options are similar to secondary Raynaud.

Secondary Raynaud phenomenon is caused by a specific etiology and is present in approximately 10% of patients at initial evaluation. For those without a secondary cause at presentation, one is identified at a rate of 2% per year over a 10-year interval.¹⁸³ Causes of secondary Raynaud phenomenon are diverse (see Table 96–6). Treatment of secondary Raynaud is directed at the underlying cause when feasible. Calcium channel blockers and α-blockers, either as monotherapy or in combination, can blunt the episodes in many patients, but may have little impact on ischemic complications. ACEI, angiotensin II receptor inhibition, and endothelin receptor inhibition are promising in the setting of scleroderma.¹⁸⁴