PERIPHERAL ARTERIAL OCLUSIVE DISEASE

Sumary

Claudication, which is defined as reproducible ischemic muscle pain, is one of the most common manifestations of peripheral arterial occlusive disease (PAOD) caused by atherosclerosis. Claudication occurs during physical activity and is relieved after a short rest. Pain develops because of inadequate blood flow.

Angiography is the criterion standard arterial imaging study for the diagnosis of PAOD. The image below depicts a superficial femoral artery occlusion.

Signs and symptoms

Intermittent claudication typically causes pain that occurs with physical activity. Other signs and symptoms associated with peripheral arterial occlusive disease (PAOD) include the following:

- Pain is reproducible within same muscle groups; pain ceases with a resting period of 2-5 minutes

-The most common location of arterial lesions is the distal superficial femoral artery, which corresponds to claudication in the calf muscle area

-Thigh/buttock muscle claudication predominates, with atherosclerosis distributed throughout the aortoiliac area.

Diagnosis

Examination of a patient with claudication should include a complete lower-extremity evaluation and pulse examination, including measuring segmental pressures. Attempt to palpate pulses from the abdominal aorta to the foot, with auscultation for bruits in the abdominal and pelvic regions. When palpable pulses are not present, a handheld Doppler device may be used to assess circulation.

A useful tool in assessing a patient with claudication is the ankle-brachial index (ABI), which is a noninvasive way of establishing the presence of PAOD and is calculated as the ratio of systolic blood pressure at the ankle to that in the arm (normal range, 0.9-1.1; PAOD, < 0.9).

Laboratory testing

A laboratory workup is helpful only for identifying accompanying silent alterations in renal function and elevated lipid profiles.

Imaging studies

The following radiologic studies may be used to evaluate suspected PAOD:

- Angiography - The criterion standard for arterial imaging in the diagnosis of PAOD; usually reserved for when an intervention (either endovascular or traditional open surgery) is planned

- Magnetic resonance angiography (MRA) - Useful for imaging large and small vessels

- Computed tomography angiography (CTA) - Used to image arterial disease but requires large amount of contrast media and an upgraded CT scanner to reconstruct helpful images

- Duplex ultrasonography - Evaluates status of a patient’s vascular disease and provides information about hemodynamics; is noninvasive and requires no contrast media but is highly technician-dependent.

Management

Treatment of claudication is medical, with surgery reserved for severe cases. Medical management includes the following:

- Tobacco cessation in patients who smoke

-Regular exercise

-Control of lipid profile, diabetes, and hypertension

Pharmacotherapy

The following medications are used in the management of PAOD:

- Antiplatelet agents (eg, aspirin, clopidogrel, cilostazol, and pentoxifylline)

Antilipemic agents (eg, simvastatin)

Surgery For patients in whom medical and exercise therapy fail or those who have claudication symptoms that are lifestyle-limiting, surgical treatment includes either open bypass surgery or endovascular therapy (eg, stents, balloons, or atherectomy devices).

Background

Claudication, which is defined as reproducible ischemic muscle pain, is one of the most common manifestations of peripheral vascular disease caused by atherosclerosis (peripheral arterial occlusive disease [PAOD]). Claudication occurs during physical activity and is relieved after a short rest. Pain develops because of inadequate blood flow.

Pathophysiology

Single or multiple arterial stenoses produce impaired hemodynamics at the tissue level in patients with PAOD. Arterial stenoses lead to alterations in the distal perfusion pressures available to affected muscle groups.

Under resting conditions, normal blood flow to extremity muscle groups averages 300-400 mL/min. Once exercise begins, blood flow increases as much as 10-fold as a consequence of the increase in cardiac output and compensatory vasodilation at the tissue level. This allows the increase in oxygen demand to be met. When exercise ceases, blood flow returns to normal within minutes.

Resting blood flow in a person with PAOD is similar to that in a healthy person. In PAOD, however, blood flow cannot maximally increase in muscle tissue during exercise, because proximal arterial stenoses prevent compensatory vasodilation. When the metabolic demands of the muscle exceed blood flow, claudication symptoms ensue. At the same time, a longer recovery period is required for blood flow to return to baseline once exercise is terminated.

Similar abnormal alterations occur in distal perfusion pressure in affected extremities. In normal extremities, the mean blood pressure drop from the heart to the ankles is no more than a few millimeters of mercury. In fact, as pressure travels distally, the measured systolic pressure actually increases because of the higher resistance encountered in smaller-diameter vessels.

At baseline, a healthy person may have a higher measured ankle pressure than arm pressure. When exercise begins, no change in measured blood pressure occurs in the healthy extremity.

In the atherosclerotic limb, each stenotic segment acts to reduce the pressure head experienced by distal muscle groups. Correspondingly, at rest, the measured blood pressure at the ankle is less than that measured in a healthy person. Once physical activity starts, the reduction in pressure produced by the atherosclerotic lesion becomes more significant, and the distal pressure is greatly diminished.

- Pressure difference = 8QvL/πr4

where Q is flow, v is viscosity, L is the length of the stenotic area, and r is the radius of the open area within the stenosis. In this equation, the pressure gradient is directly proportional to the flow and the length of the stenosis and inversely proportional to the fourth power of the radius. Thus, although increasing the flow rate directly increases the pressure gradient at any given radius, these effects are much less marked than those due to changes in the radius of the stenosis.

Because the radius is raised to the fourth power, it is the factor that has the most dramatic impact on a pressure gradient across a lesion. This impact is additive when two or more occlusive lesions are located sequentially within the same artery.

Prognosis

Whether a patient progresses to limb amputation largely depends on the number and severity of cardiovascular risk factors (ie, smoking, hypertension, or diabetes). Continued smoking has been identified as the adverse risk factor most consistently associated with the progression of PAOD. Other factors are the severity of disease at the time of the initial patient encounter and, in some studies, the presence of diabetes.

In an effort to identify patients at highest risk for progression to critical limb ischemia (CLI), a simple risk score for PAOD was developed: the Graz CLI score.[2]Age and diabetes were among the most aggressive risk factors (respective odds ratios, 2.0 and 3.1).

As with most patients with vascular disease, survival is less than that of age-matched control groups. Coronary artery disease, with a subsequent myocardial event, is the major contributor to outcome. Predicted all-cause mortality for PAOD patients with claudication is approximately 30% at 5 years of follow-up, 50% at 10 years, and 70% at 15 years.[3]

In a double-blind trial (N = 6564), Bonaca et al randomly assigned patients with PAOD who had undergone revascularization to receive either rivaroxaban 2.5 mg bid plus aspirin (n = 3286) or placebo plus aspirin (n = 3278).[4]​ Compared with the patients in the aspirin-only group, those in the rivaroxaban-aspirin group had a significantly lower incidence of the composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes; however, they also had a significantly higher rate of major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH).

Clinical presentation

History

Intermittent claudication typically causes pain that occurs with physical activity. Determining how much physical activity is needed before the onset of pain is crucial. Typically, vascular surgeons relate the onset of pain to a particular walking distance expressed in terms of street blocks (eg, two-block claudication). Using some standard measure of walking distance helps quantify patients’ condition before and after therapy.

Other important aspects of claudication pain are that the pain is reproducible within the same muscle groups and that it ceases with a resting period of 2-5 minutes

The location of the pain in patients with peripheral arterial occlusive disease (PAOD) is determined by the anatomic location of the arterial lesions. PAOD is most common in the distal superficial femoral artery (located just above the knee joint), a location that corresponds to claudication in the calf muscle area (the muscle group just distal to the arterial disease). When atherosclerosis is distributed throughout the aortoiliac area, thigh and buttock muscle claudication predominates.

The perceived significance of claudication is variable. Most patients appear to accept a decrease in walking distance as a normal part of aging. Investigators report that 50-90% of patients with definite intermittent claudication do not report this symptom to their clinician.

Atherosclerosis is a systemic disease process. Accordingly, patients who present with claudication due to PAOD can be expected to have atherosclerosis elsewhere. A full assessment of the patient’s risk factors for vascular disease should therefore be performed. The risk factors for PAOD are the same as those for coronary artery disease (CAD) or cerebrovascular disease and include the following:

- Diabetes

- Hypertension

- Hyperlipidemia

- Family history

- Sedentary lifestyle

- Tobacco use

- Chronic kidney disease

Smoking is the greatest of all the cardiovascular risk factors. The mechanism by which it causes or accentuates atherosclerosis is unknown. What is known is that the degree of damage is directly related to the amount of tobacco used. In a prospective cohort study of 39,825 women without cardiovascular disease, smoking was found to be a potent risk factor for symptomatic peripheral arterial disease, and cessation was found to reduce the risk.[5]Counseling patients on the importance of smoking cessation is paramount in PAOD management.

Low kidney function has been associated with the development of PAOD. In fact, a study conducted in Japan[6]found the prevalence of PAOD to be 17.2% among patients with estimated glomerular filtration rates (GFRs) lower than 60 mL/min/1.73 m2, compared with 7.0% in those with GFRs higher than 60 mL/min/1.73 m2. Advanced chronic kidney disease was found to be an independent risk factor for PAOD.

Physical Examination

Essential to the physical examination of a patient with claudication is a complete lower-extremity evaluation and pulse examination, including measurement of segmental pressures (see the image below). Atrophy of calf muscles, loss of extremity hair, and thickened toenails are clues to underlying PAOD.

Palpation of pulses should be attempted from the abdominal aorta to the foot, with auscultation for bruits in the abdominal and pelvic regions. This can be difficult with obese patients, in whom palpable pulses may be hidden under a deep subcutaneous layer.

The absence of a pulse signifies arterial obstruction proximal to the area palpated. For example, if no femoral artery pulse is palpated, significant PAOD is present in the aortoiliac distribution. Similarly, if no popliteal artery pulse can be palpated, significant superficial femoral artery occlusive disease exists. The exception is the rare case of a congenital absence of a pulse (eg, persistent sciatic artery).

Patients who report intermittent claudication and have palpable pulses can present a clinical dilemma. If the history is consistent with typical claudication symptoms, the clinician can have the patient walk around the office (or perform toe raises) until the symptoms are reproduced and then palpate for pulses. The exercise should cause the atherosclerotic lesion to become significant and should diminish the strength of the pulses distal to the lesion.

When palpable pulses are not present, further assessment of the circulation can be made with a handheld Doppler device. An audible Doppler signal assures the clinician that some blood flow is perfusing the extremity. If no Doppler signals can be heard, a vascular surgeon should be consulted immediately.

Pressure measurements can be performed to gain objective data on the circulatory status. An accurate pressure reading is obtained as follows:

- Place the pneumatic cuff around the ankle

- Position the Doppler probe over the dorsalis pedis or the posterior tibial artery

- Inflate the cuff to a reading above the systolic pressure and deflate; the systolic tone at the ankle vessel is the pressure recorded

A healthy person has no pressure drop from the heart to the ankle. In fact, the pressure at the ankle may be 10-20 mm Hg higher because of the augmentation of the pressure wave with travel distally. In a patient with claudication, however, the measured pressure at the ankle will be diminished to some extent, depending on the severity of PAOD.

A useful tool in assessing a patient with claudication is the ankle-brachial index (ABI), which is calculated as the ratio of systolic blood pressure at the ankle to systolic blood pressure in the arm. The ABI can help quantify the presence and severity of disease. A normal ABI is 0.9-1.1. By definition, any patient with an ABI lower than 0.9 has some degree of PAOD. As PAOD worsens, the ABI decreases further.

A 2011 study investigated whether subjects not considered to be at high risk for cardiovascular disease had abnormal ABIs.[7]Cardiovascular risk was determined on the basis of the Framingham Risk Score: 56.3% of the study subjects were at low risk for cardiovascular disease, 25.8% at intermediate risk, and 17.9% at high risk. Only a relatively low percentage (~12%) of participants had a low or intermediate Framingham Risk Score while still having an abnormal ABI. This study demonstrated the close association of cardiovascular disease with PAOD.

The ABI may be a less accurate assessment tool in patients with diabetes who have PAOD. Peripheral vessels in patients with diabetes may have extensive medial-layer calcinosis, which renders the vessel resistant to compression by the pneumatic cuff. These patients should be referred to a vascular laboratory for further evaluation. In this situation, the use of the toe-brachial index (TBI) may be helpful.

Complications

The most feared consequence of PAOD is severe limb-threatening ischemia leading to amputation. However, studies of large patient groups with claudication reveal that amputation is uncommon. Boyd prospectively followed 1440 patients with intermittent claudication for as long as 10 years and reported that only 12.2% required amputation.[8]In the Framingham study, only 1.6% of patients with claudication reached the amputation stage after 8.3 years of follow-up.

Differential diagnoses

Diagnostic Considerations

Various disease processes mimic claudication symptoms and must be excluded before a diagnosis of peripheral arterial occlusive disease (PAOD) can be made. Such processes include the following:

- Osteoarthritis - This is associated with arthritic pain that is variable from day to day and may be aggravated by certain weather patterns or movements; rest does not relieve pain

Venous disease - This is described as a dull, aching pain that typically occurs at the end of the day or after prolonged standing; it is not exacerbated by exercise

Neurospinal disease - The pain occurs in the morning and is not relieved by short resting periods; neurospinal pain is frequently relieved by leaning forward against a solid surface or by sitting

Chronic compartment syndrome - This rare condition is usually observed in runners and other athletes with large, developed calf muscles; muscles swell during activity, leading to increased compartment pressure and decreased venous return; although, as with claudication, the pain occurs with exercise and is relieved with rest, the exercise is at a more strenuous level and the recovery period longer

Popliteal entrapment syndrome - This syndrome, similar to intermittent claudication but usually observed in active young people, is caused by various abnormal anatomic configurations of the insertion of the medial gastrocnemius muscle head, which cause compression of the popliteal artery; upon physical examination, tibial pulses may disappear when the knee is at full extension; pain is aggravated with walking but not with running, because knee extension is not as severe with running

Reflex sympathetic dystrophy or minor causalgia - This is characteristically described as a burning pain; the superficial pain is often distributed along a somatic nerve and is often related to a past trauma in the extremity

Diabetic neuropathy - The pain is due to a peripheral neuritis; differentiation from intermittent claudication can be difficult because of accompanying skin discoloration and diminished pulses; extensive neurologic evaluation is essential

Venous thrombosis - Swelling and leg pain occur with walking; pain is relieved by extremity elevation, a finding that distinguishes this entity from arterial insufficiency

Chronic Exertional Compartment Syndrome

Chronic Venous Insufficiency

Degenerative Disk Disease

Osteoarthritis

Spinal Stenosis

Thromboangiitis Obliterans

Varicose Vein Surgery

Treatment

Treatment of claudication is medical,[13]except in severe cases. The goal of medical management of peripheral arterial occlusive disease (PAOD) is to impede the progression of the disease. This may include both pharmacologic and nonpharmacologic measures. For patients in whom medical and exercise therapy fail or those who have lifestyle-limiting claudication symptoms, surgical treatment options are the next line of therapy.

In July 2014, the Society for Cardiac Angiography and Interventions (SCAI) issued a consensus statement on the treatment of infrapopliteal arterial disease. The statement indicated the following[14]:

Endovascular intervention is not appropriate for most single-vessel, mildly symptomatic, or asymptomatic blockages of infrapopliteal vessels

It is not appropriate to treat most cases of moderate-to-severe claudication or major tissue loss in one-vessel disease and mild claudication in one-, two-, or three-vessel disease

Primary amputation should be the preferred intervention in nonambulatory patients with a limited life expectancy and extensive necrosis or gangrene

Consider surgical bypass and evaluate its associated risks for ambulatory patients with a patent infrapopliteal artery that has direct flow to the foot and an adequate autologous venous conduit

Use balloon angioplasty for clinically significant infrapopliteal arterial disease; consider bailout bare-metal and drug-elutive stents for tibial arterial disease that is refractory to treatment with balloon angioplasty

Moreover, the SCAI indicated that intervention for infrapopliteal disease is appropriate in patients with two- or three-vessel disease and (1) moderate-to-severe claudication with a focal arterial lesion; (2) ischemic foot pain during rest (Rutherford classification 4); or (3) minor and major (skin necrosis, gangrene) tissue loss.[14]

In January 2015, the Society for Vascular Surgery (SVS) issued guidelines for the management of atherosclerotic occlusive disease of the lower extremities.[15]In November 2016, the American Heart Association (AHA) and the American College of Cardiology (ACC) issued a guideline on the management of lower-extremity peripheral artery disease.[16] In August 2017, the European Society of cardiology (ESC), in collaboration with the European Society for Vascular Surgery (ESVS), issued guidelines for the management of peripheral arterial disease

Misdiagnosis for intermittent claudication rarely leads directly to limb loss. However, it is advisable to make early referrals to a vascular surgeon so as to reduce the likelihood of any legal action.

Smoking Cessation

In patients who smoke, the most expedient way of impeding the progression of PAOD is to stop tobacco use. Extensive evidence indicates that smoking cessation improves the prognosis. In addition, improved walking distance and ankle pressure have been attributed to smoking cessation.

Pharmacologic Therapy

Daily aspirin is recommended for overall cardiovascular care. Standard dosages range from 81 to 325 mg/day, but no consensus has been reached on the most effective dose.

Pentoxifylline shows promise. Numerous randomized trials have documented modest improvements in walking distance in pentoxifylline treatment groups as compared with placebo treatment groups. Treatment may take as long as 2-3 months to produce noticeable results.

The use of clopidogrel bisulfate and enoxaparin sodium in the treatment of PAOD is increasing; however, further research is needed to establish clinical efficacy.

Cilostazol has shown increasing promise in the treatment of intermittent claudication. Several randomized studies have found it to have a beneficial effect on walking distances, increasing both the distance before the onset of claudication pain and the distance before exercise-limiting symptoms become intolerable (ie, the maximal walking distance).

In a randomized, double-blind, placebo-controlled trial, O’Donnell et al assessed the vascular and biochemical effects of cilostazol therapy on 80 patients with peripheral arterial disease, finding that this agent to be an efficacious treatment that, besides improving patients’ symptoms and quality of life, appeared to have beneficial effects on arterial compliance.[18]

The investigators in this study measured arterial compliance, transcutaneous oxygenation, ankle-brachial index (ABI), and treadmill walking distance.[18]As compared with the placebo group, the cilostazol group had significant reduction in the augmentation index and also showed reduction in transcutaneous oxygenation levels. The mean percentage change in walking distance from baseline was greater in the cilostazol group than in the placebo group. Lipid profiles were also improved in the cilostazol group.

References

1. Selvin E, Erlinger TP. Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999-2000. Circulation. 2004 Aug 10. 110 (6):738-43. [Medline].

2. Gary T, Belaj K, Hafner F, Eller P, Rief P, Hackl G, et al. Graz Critical Limb Ischemia Score: A Risk Score for Critical Limb Ischemia in Peripheral Arterial Occlusive Disease. Medicine (Baltimore). 2015 Jul. 94 (27):e1054. [Medline].

3. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg. 2007 Jan. 45 Suppl S:S5-67. [Medline]. [Full Text].

4. Bonaca MP, Bauersachs RM, Anand SS, Debus ES, Nehler MR, Patel MR, et al. Rivaroxaban in Peripheral Artery Disease after Revascularization. N Engl J Med. 2020 May 21. 382 (21):1994-2004. [Medline].

5. Conen D, Everett BM, Kurth T, Creager MA, Buring JE, Ridker PM, et al. Smoking, smoking cessation, [corrected] and risk for symptomatic peripheral artery disease in women: a cohort study. Ann Intern Med. 2011 Jun 7. 154 (11):719-26. [Medline]. [Full Text].

6. Yamasaki S, Izawa A, Koshikawa M, Saigusa T, Ebisawa S, Miura T, et al. Association between estimated glomerular filtration rate and peripheral arterial disease. J Cardiol. 2015 Nov. 66 (5):430-4. [Medline].

7. Dhangana R, Murphy TP, Coll JR, Ahn SH, Zafar AM, Qadeer FF, et al. Prevalence of abnormal ankle-brachial index among individuals with low or intermediate Framingham Risk Scores. J Vasc Interv Radiol. 2011 Aug. 22 (8):1077-82. [Medline].