Harrison's Practice: Peripheral Arteriosclerosis

Harrison's Practice

Peripheral Arteriosclerosis

Definition

A disease of the blood vessels characterized by narrowing, thickening, and loss of elasticity in peripheral arteries
- Also known as peripheral arterial disease (PAD)
Leads to decreased blood flow that can injure nerves and other tissues
Primary sites of involvement
- Abdominal aorta and iliac arteries (30% of symptomatic patients)
- Femoral and popliteal arteries (80–90% of patients)
- The more distal vessels, including the tibial and peroneal arteries (40–50% of patients)

Epidemiology

Prevalence
- Atherosclerosis is the leading cause of occlusive arterial disease of the extremities in patients > 40 years of age.
- ~12% of the adult population in U.S., approximately 10–12 million people, are affected in their lifetime.
Age
- Highest incidence occurs in the sixth and seventh decades of life.
Sex
- 2:1 male-to-female ratio

Risk Factors

Risk factors are similar to those for other forms of arteriosclerosis (coronary and cerebral vascular disease) and include:
- Cigarette smoking (especially important for PAD)
- Diabetes mellitus (especially important for PAD)
- Hypertension (blood pressure ≥ 140/90 mmHg or taking antihypertensive medication)
- Elevated low-density lipoprotein (LDL) cholesterol level
  - ≥4.1 mmol/L (≥160 mg/dL)
  - ≥3.4 mmol/L (≥130 mg/dL) in patients with ≥ 2 other risk factors
- Low high-density lipoprotein cholesterol level
  - < 1.0 mmol/L (< 40 mg/dL)
  - ≥1.6 mmol/L (≥60 mg/dL) counts as a "negative" risk factor; its presence removes 1 risk factor from the total count.
- Family history of premature arteriosclerotic vascular disease (ASVD)
- ASVD in male first-degree relative < 55 years
- ASVD in female first-degree relative < 65 years
- Age (men ≥ 45 years; women ≥ 55 years)
- Lifestyle risk factors
  - Obesity (body mass index ≥ 30 kg/m²)
  - Physical inactivity
  - Atherogenic diet
- Emerging risk factors
  - Lipoprotein(a)
  - Homocysteine
  - Prothrombotic factors
  - Proinflammatory factors
  - Impaired fasting glucose
  - Subclinical atherogenesis

Etiology

Causes of PAD
- Atherosclerosis is the leading cause of PAD in patients > 40 years old.
- Thrombosis
- Embolism
- Vasculitis
- Fibromuscular dysplasia
- Entrapment
- Cystic adventitial disease
- Trauma
Atherosclerotic lesions occur preferentially at:
- Arterial branch points
- Sites of increased turbulence
- Sites of altered shear stress
- Sites of intimal injury
Involvement of the distal vasculature is most common in elderly persons and in patients with diabetes mellitus.
The pathology of the lesions includes:
- Atherosclerotic plaques with calcium deposition
- Thinning of the media
- Patchy destruction of muscle and elastic fibers
- Fragmentation of the internal elastic lamina
- Thrombi composed of platelets and fibrin

Associated Conditions

Coronary artery disease (CAD)
- Approximately one-third to one-half of patients with symptomatic PAD have evidence of CAD based on clinical presentation and electrocardiogram, and over one-half have significant CAD on coronary angiography.

Symptoms & Signs

< 50% of patients with PAD are symptomatic.
Many have a slow or impaired gait.
Intermittent claudication is the most common symptom.
- Defined as a pain, ache, cramp, numbness, or a sense of fatigue in the muscles
- Occurs during exercise and is relieved by rest
- The site of claudication is distal to the location of the occlusive lesion.
Symptoms are far more common in the lower than in the upper extremities.
- Higher incidence of obstructive lesions
In severe arterial occlusive disease, critical limb ischemia may develop.
- Symptoms
  - Rest pain
  - Feeling of cold or numbness in the foot and toes
  - Frequently, these symptoms occur at night when the legs are horizontal.
  - Symptoms improve when the legs are in a dependent position.
  - Impotence in men
Physical findings
- Decreased or absent pulses distal to the obstruction
- Presence of bruits over the narrowed artery
- Muscle atrophy
- Elevation of the legs and repeated flexing of the calf muscles produce pallor of the soles of the feet.
- Rubor, secondary to reactive hyperemia, may develop when the legs are dependent.
  - Time required for rubor to develop or for veins in the foot to fill when legs are transferred from an elevated to a dependent position is related to the severity of ischemia and presence of collateral vessels.
- With more severe disease
  - Hair loss
  - Thickened nails
  - Smooth, shiny skin
  - Reduced skin temperature
  - Pallor or cyanosis
  - Ulcers or gangrene
  - Peripheral edema due to legs kept in a dependent position much of the time
- Ischemic neuritis can result in numbness and hyporeflexia.

Differential Diagnosis

Fibromuscular dysplasia
- Distinguished angiographically by a "string of beads" appearance
Thromboangiitis obliterans (Buerger’s disease)
- Unlike peripheral arteriosclerosis, proximal atherosclerotic disease is usually absent.
Vasculitis
- May be distinguished by history, physical and angiographic findings
Muscle cramps, venous insufficiency, acute arterial occlusion
- Distinguished by history and physical findings

Diagnostic Approach

The history and physical examination are usually sufficient to establish the diagnosis of PAD.
An objective assessment of the severity of disease is obtained by noninvasive techniques.
- Ankle–brachial index (first test)
- Digital pulse volume recordings
- Stress testing with ankle brachial exercise during treadmill exercise
- Duplex ultrasonography (which combines B-mode imaging and pulse-wave Doppler examination)
- Treadmill exercise testing with ankle–brachial index
- Transcutaneous oximetry (when limb is threatened)

Laboratory Tests

Laboratory tests are not generally helpful in the work-up of peripheral arteriosclerosis, except for identification of atherosclerosis risk factors.
- Glucose measurement
- Lipid profile

Imaging

Doppler flow velocity waveform analysis
- In significant PAD, volume displacement in the leg is decreased with each pulse.
- Doppler velocity contour becomes progressively flatter.
Duplex ultrasonography (B-mode imaging and pulse-wave Doppler examination)
- Often useful in detecting stenotic lesions in native arteries and bypass grafts
Magnetic resonance angiography, computed tomographic angiography, and conventional contrast angiography
- Should not be used for routine diagnostic testing
- Performed before potential revascularization
- Each test is useful in defining anatomy to assist planning for catheter-based and surgical revascularization procedures.

Diagnostic Procedures

Digital pulse volume recordings
- Show pulsatile flow in the digits, and strain-gauge plethysmography establishes digital pressures
Segmental pressure measurements (ankle–brachial index)
- Arterial pressure can be recorded noninvasively along the legs.
  - Serial placement of sphygmomanometric cuffs
  - Use of a Doppler device to auscultate or record blood flow
- In the presence of hemodynamically significant stenoses, systolic blood pressure in the leg is decreased.
- Ankle–brachial index (the ratio of the ankle and brachial artery pressures)
  - ≥ 1.0 in normal persons
  - < 1.0 in patients with PAD
  - < 0.5 is consistent with severe ischemia.
Transcutaneous oximetry
- Uses differences in limb and trunk transcutaneous partial pressure of oxygen to assess the adequacy of local perfusion
Stress testing (usually treadmill exercise)
- Decline of the ankle–brachial systolic pressure ratio immediately after exercise may further support diagnosis of PAD in patients with equivocal symptoms and test results.
Tests for reactive hyperemia
- Standard blood pressure cuffs are placed around thighs and ankles.
- Thigh cuffs are inflated above normal systolic blood pressure for 3–5 minutes.
- Once the thigh cuffs are deflated, the ankle cuffs are inflated briefly above systolic blood pressure, then slowly deflated.
- Using a Doppler instrument, blood pressure measurements are immediately taken at both ankles.
- A significant (>50%) decrease in ankle blood pressure is considered diagnostic of PAD.

Treatment Approach

Patients with PAD should receive therapies to:
- Reduce the risk of associated cardiovascular events, such as myocardial infarction and death
- Improve limb symptoms
- Prevent progression to critical limb ischemia
- Preserve limb viability
Risk factor modification and antiplatelet therapy should be initiated to improve cardiovascular outcomes.
Therapeutic options include:
- Supportive measures
- Pharmacologic treatment
- Revascularization by nonoperative interventions or surgery

Specific Treatments

Supportive measures

Meticulous care of the feet
- Clean and protected against excessive drying with moisturizing creams
Well-fitting and protective shoes to reduce trauma
- Sandals and shoes made of synthetic materials that do not "breathe" should be avoided.
Elastic support hose should be avoided, as they reduce blood flow to the skin.
In patients with ischemia at rest, shock blocks under the head of the bed together with a canopy over the feet may improve perfusion pressure and ameliorate rest pain.
Treatment of associated factors that contribute to the development of atherosclerosis should be initiated.
- Discontinuation of cigarette smoking (very important)
  - Counseling
  - Adjunctive drug therapy (increase smoking cessation rates and reduce recidivism)
    - Nicotine patch
    - Bupropion
    - Varenicline
- Control of blood pressure in hypertensive patients, avoiding hypotensive levels
  - Angiotensin-converting enzyme inhibitors
    - May reduce the risk of cardiovascular events in patients with symptomatic PAD
  - β-adrenergic blockers
    - Do not worsen claudication
    - May be used to treat hypertension, especially in patients with coexistent CAD
- Treatment of hypercholesterolemia to prevent or to slow progression of disease and to improve survival
  - The National Cholesterol Education Program Adult Treatment Panel considers PAD to be a coronary heart disease equivalent.
  - Recommends treatment to reduce LDL cholesterol to < 100 mg/dL
Patients with claudication should be encouraged to exercise regularly and at progressively strenuous levels.
- Supervised exercise training programs may improve muscle efficiency and prolong walking distance.
- Patients should be advised to walk for 30–45 minutes daily, 3–5 times per week for at least 12 weeks.
- Patients also should be advised to walk until near-maximum claudication discomfort occurs, then resting until the symptoms resolve before resuming ambulation.

Pharmacologic management

Pharmacologic treatment of PAD has not been as successful as medical treatment of CAD.
Vasodilators as a class have not proved to be beneficial.
Such drugs as α-adrenergic blockers, calcium-channel blockers, papaverine, and other vasodilators have not been shown to be effective in patients with PAD.
Platelet inhibitors, particularly aspirin (81–325 mg PO qd), reduce the risk of adverse cardiovascular events in patients with peripheral atherosclerosis.
Clopidogrel (75 mg PO qd) inhibits platelet aggregation via its effect on adenosine diphosphate–dependent platelet-fibrinogen binding.
- Appears to be more effective than aspirin in reducing cardiovascular morbidity and mortality in PAD
- There is insufficient evidence of efficacy to support the routine use of dual antiplatelet therapy with both aspirin and clopidogrel in patients with PAD.
Cilostazol (100 mg PO bid), a phosphodiesterase inhibitor with vasodilator and antiplatelet properties
- Increases claudication distance by 40–60%
- Improves measures of quality of life
Pentoxifylline (400 mg PO tid), a substituted xanthine derivative
- Reported to decrease blood viscosity and increase red cell flexibility, increasing blood flow to microcirculation and enhancing tissue oxygenation
- Several placebo-controlled studies have found that pentoxifylline increased duration of exercise in patients with claudication.
- Its efficacy has not been confirmed in all clinical trials.
Statins and propionyl-l-carnitine, a drug that affects skeletal muscle metabolic function, appear promising for treatment of intermittent claudication in initial clinical trials.
Several studies have suggested that long-term parenteral administration of vasodilator prostaglandins decreases pain and facilitates healing of ulcers in patients with severe limb ischemia.
Clinical trials with angiogenic growth factors, such as vascular endothelial growth factor and basic fibroblast growth factor, are underway.
Heparin and warfarin have not been shown to be effective in patients with chronic PAD.
- May be useful in acute arterial obstruction secondary to thrombosis or systemic embolism
- A recent study of patients with PAD showed: [1]
  - Combination of an oral anticoagulant and antiplatelet therapy was not more effective than antiplatelet therapy alone in preventing major cardiovascular complications and was associated with an increase in life-threatening bleeding.
Thrombolytic intervention using drugs such as streptokinase, urokinase, or recombinant tissue plasminogen activator (alteplase) may have a role in treatment of acute thrombotic arterial occlusion.
- Not effective in patients with chronic arterial occlusion secondary to atherosclerosis

Revascularization

Revascularization procedures, including catheter-based and surgical interventions, are usually indicated for:
- Patients with disabling, progressive, or severe symptoms of intermittent claudication despite medical therapy
- Those with critical limb ischemia
Nonoperative interventions
- Percutaneous transluminal angioplasty (PTA)
  - PTA of the iliac artery is associated with a higher success rate than PTA of the femoral and popliteal arteries.
  - Approximately 90–95% of iliac PTAs are initially successful, with a 3-year patency rate > 75%.
  - Patency rates may be higher if a stent is placed in the iliac artery.
  - The initial success rate for femoral–popliteal PTA is approximately 80%, with a 60% 3-year patency rate.
  - Patency rates are influenced by the severity of pretreatment stenoses.
  - Prognosis of total occlusive lesions is worse than that of nonocclusive stenotic lesions.
- Stent placement
  - Role of drug-eluting stents in PAD is currently unclear.
- Atherectomy
Operative procedures
- For patients with aortoiliac and femoral–popliteal artery disease
- Preferred operative procedure depends on location and extent of obstruction(s) and general medical condition of the patient.
- Operative procedures for aortoiliac disease
  - Aortobifemoral bypass
  - Axillofemoral bypass
  - Femoral–femoral bypass
  - Aortoiliac endarterectomy
- Aortobifemoral bypass using knitted Dacron grafts
  - The most frequently used procedure
  - Immediate graft patency approaches 99%.
  - 5- and 10-year graft patency in survivors is >90% and 80%, respectively.
  - Operative complications
    - Myocardial infarction and stroke
    - Graft infection
    - Peripheral embolization
    - Sexual dysfunction from interruption of autonomic nerves in the pelvis
  - Operative mortality rate ranges from 1–3%, mostly due to ischemic heart disease.
- Operative therapy for femoral–popliteal artery disease
  - In situ and reverse autogenous saphenous vein bypass graft
  - Placement of polytetrafluoroethylene (PTFE) or other synthetic grafts
  - Thromboendarterectomy
- Operative mortality rate ranges from 1–3%.
- Long-term patency rate depends on the type of graft used, the location of the distal anastomosis, and the patency of run-off vessels beyond the anastomosis.
- Patency rates of femoral–popliteal saphenous vein bypass grafts approach 90% at 1 year and 70–80% at 5 years.
- 5-year patency rates of infrapopliteal saphenous vein bypass grafts are 60–70%.
- In contrast, 5-year patency rates of infrapopliteal PTFE grafts are < 30%.
Preoperative cardiac risk assessment may identify patients especially likely to experience adverse cardiac event perioperatively.
- Patients with angina, prior myocardial infarction, ventricular ectopy, heart failure, or diabetes are among those at increased risk.

Monitoring

Patients should be followed for response to treatment with supportive and pharmacologic measures.
Patients with poor response, disease progression, or rest pain should be referred for evaluation for revascularization.
Patients diagnosed with peripheral arteriosclerosis should also be evaluated for other coexisting vascular disease.

Complications

Complications of peripheral arteriosclerosis
- Acute plaque rupture and acute limb ischemia
- Progression of disease
- Complications related to coexisting coronary and cerebrovascular disease

Prognosis

The natural history of PAD is influenced primarily by the extent of coexisting CAD and cerebrovascular disease.
Patients with PAD have a 15–30% 5-year mortality rate.
Patients with PAD have a 2- to 6-fold increased risk of death from coronary heart disease.
Patients with claudication have a 70% 5-year survival rate and a 50% 10-year survival rate.
Most deaths are either sudden or secondary to myocardial infarction.
Mortality is highest in those with the most severe PAD.
The likelihood of symptomatic progression of PAD appears to be less than the chance of dying of CAD.
Approximately 75–80% of nondiabetic patients who present with mild to moderate claudication remain symptomatically stable.
- Deterioration is likely to occur in the remainder, with approximately 1–2% of the group ultimately developing critical limb ischemia.
- Approximately 25–30% of patients with critical limb ischemia survive and undergo amputation within 1 year.
Prognosis is worse in patients who continue to smoke cigarettes or who have diabetes mellitus.

Prevention

Screen patients for atherosclerotic risk factors (diabetes, hypertension, cigarette smoking, hyperlipidemia) during regular patient care.
Reduce LDL cholesterol level through diet or drug therapy as appropriate (see Atherosclerosis, Therapy and Prevention).
Counsel patients to maintain a healthy lifestyle.
- Smoking cessation
- Weight control
- Diet and exercise
Control hypertension.
Monitor patients with diabetes to ensure proper management of disease.

ICD-9-CM

440.20 Atherosclerosis of the extremities, unspecified (includes arteriosclerosis)