Peripheral Arterial Occlusive Disease

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.

For patient education resources, see the Circulatory Problems Center and Cholesterol Center, as well as Peripheral Vascular Disease, High Cholesterol, and Cholesterol FAQs.

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.

The phenomenon of increased blood flow causing decreased pressure distally to an area of stenosis is a matter of physics. Poiseuille calculated energy losses across areas of resistance with varying flow rates by using the following equation:

• 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.

United States and international statistics

Atherosclerosis affects up to 10% of the Western population older than 65 years. With the elderly population expected to increase 22% by the year 2040, atherosclerosis is expected to have a huge financial impact on medicine.

Estimated PAOD prevalence in the general US population, based on National Health and Nutrition Examination Survey (NHANES) data, was 4.3%.[1] Thus in 2000, about 5 million people in the US were affected by PAOD. That number increases with age; therefore, as the population ages the number of people affected by PAOD increases.

Age-, sex-, and race-related demographics

When claudication is used as an indicator, it is estimated that 2% of the population aged 40-60 years and 6% of the population older than 70 years are affected. Intermittent claudication most commonly manifests in men older than 50 years. Although younger patients may present with symptoms consistent with intermittent claudication, other etiologies of leg pain and claudication (eg, popliteal entrapment syndrome) must be strongly considered. There seems to be a higher prevalence of PAOD in non-Hispanic blacks.

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).

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.

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.

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.

In the workup for peripheral arterial occlusive disease (PAOD), laboratory studies are helpful only for identifying accompanying silent alterations in renal function and elevated lipid profiles. Angiography is the recommended imaging study. Other studies that may be considered are computed tomography (CT) angiography (CTA), magnetic resonance angiography (MRA), and duplex ultrasonography.

Angiography is still the criterion standard arterial imaging study for the diagnosis of PAOD (see the image below). However, this test is usually reserved for when an intervention (either an endovascular procedure or a traditional open surgical procedure) is planned.

Patients undergoing vascular surgery are known to be at high risk for cardiovascular complications and mortality. In a study comparing systematic (routine) coronary angiography with selective coronary angiography in patients undergoing surgical treatment of PAOD, Monaco et al found that routine angiography had a positive impact.[9] Routine coronary angiography improved survival significantly, and no deaths or cardiovascular events were reported. Multicenter trials are needed to confirm this finding in a larger population.

MRA is useful for imaging large and small vessels. Although it was initially considered to provide inadequate images, this is no longer the case. With improved imaging capabilities, MRA can be used not only to diagnose but also to help plan the type of indicated intervention.

A study that compared MRA with conventional angiography in regard to quality of life and cost-effectiveness found that although MRA was nearly 20% cheaper, there was no difference in quality of life.[10]

CTA is another modality used to image arterial disease. Unfortunately, it still requires a large amount of contrast media, and an upgraded CT scanner is needed to reconstruct helpful images.

CTA is another modality used to image arterial disease. It does have some pitfalls, such as the requirement for large amounts of contrast media, the necessity of synchronizing the image acquisition with the media administration, and the need for an upgraded CT scanner with postprocessing techniques to reconstruct helpful images. However, advances in technology now allow three-dimensional (3D) and four-dimensional (4D) reconstructions providing temporal information.

A small study that evaluated the diagnostic accuracy of “dynamic CTA” for lower-extremity PAOD found the sensitivity and specificity to be 98% and 97.1%, respectively, for diagnosing vessel stenosis, and 95.4% and 99.3%, respectively, for diagnosing vessel occlusion.[11] These figures may be compared with the standard CTA sensitivities and specificities of 96.6% and 92.2%, respectively, for vessel stenosis and 94.4% and 94.4%, respectively, for occlusion. The investigators demonstrated a clear improvement in diagnostic accuracy for PAOD with dynamic CTA over standard CTA, without increased radiation or contrast administration.

Duplex ultrasonography is performed to evaluate the status of a patient’s vascular disease.[12] Duplex scanning has the advantage of being noninvasive and requiring no contrast media or radiation. Unfortunately, it is highly technician-dependent.

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]

Guidelines for the management of various aspects of PAOD have been published by the Society for Vascular Surgery (SVS)[15] ; the American Heart Association (AHA) and the American College of Cardiology (ACC)[16] ; the European Society of Cardiology (ESC), in collaboration with the European Society for Vascular Surgery (ESVS)[17] ; the SVS and the ESVS with the World Federation of Vascular Societies (WFVS)[18] ; the Canadian Cardiovascular Society (CCS)[19] ; and Diabetes Feet Australia (DFA).[20]  (See Guidelines.)

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.

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.

Daily aspirin has been 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.

As noted in SVS guidelines for management of claudication,[15] 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.

Several randomized studies have found cilostaxol to have a beneficial effect on walking distances,[15] 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.[21]

The investigators in this study measured arterial compliance, transcutaneous oxygenation, ankle-brachial index (ABI), and treadmill walking distance.[21] 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.

In 2009, Momsen et al evaluated the efficacy of drug therapy for improving walking distances in intermittent claudication.[22] Their study determined that statins seemed to be the best at improving maximal walking distance.

Evidence from the Heart Protection Study indicated that cholesterol-lowering statin agents (simvastatin), besides effectively lowering blood cholesterol profiles, reduced the rate of first major vascular events (myocardial infarction [MI], stroke, or limb revascularization), with the largest benefits seen in patients with peripheral vascular disease.[23] The benefits were demonstrated regardless of the baseline cholesterol profile.

These results suggest that cholesterol-lowering statin agents should be considered for medical treatment in patients with peripheral arterial disease. Such agents appear to provide substantial benefit for individuals with PAOD.[24]

Additional medical treatment may include control of diabetes as appropriate. For example, insulin-sensitizing medication may reduce PAOD in type 2 diabetics with coronary disease.[25]

In a secondary analysis of the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, of 303 patients with type 2 diabetes and stable coronary disease without peripheral arterial disease (PAD) at baseline, those treated with insulin-sensitizing therapy (16.9%) (ie, metformin or a glitazone) were less likely to develop any type of new PAD during 4.6 years of follow-up than were patients treated with insulin-providing therapy (24.1%).[25]

In the study, patients who received insulin-sensitizing therapy had lower frequencies of lower-extremity revascularization (1.1% vs 2.6%), low ankle-brachial index (16.5% vs 22.7%), and amputation (0.1% vs 1.6%) than patients who received insulin-providing therapy.[25] These findings suggest that progression of system-wide atherosclerosis, and thus development of PAD, in diabetic individuals with relatively advanced coronary disease may be slowed or reduced with insulin-sensitizing medication.

Surgical treatment options, typically reserved for patients with more severe disease or those in whom nonsurgical management fails, include the following:

• Open bypass surgery
• Endovascular therapy (eg, stenting, balloon angioplasty, or atherectomy)

Whereas open surgery dominated the treatment options two decades ago, endovascular management of PAOD has become exponentially more popular since then (see the image below).[26]

Along with the proliferation of endovascular procedures, a development of particular note has been the concurrent decrease in amputation rates for patients with PAOD. Unfortunately, factors directly contributing to lower amputation rates are difficult to delineate; they probably involve some combination of improved disease screening and patient awareness, better medical therapy, and evolving surgical device and technical modalities.

A few studies have directly compared endovascular and open surgical treatment options for patients with symptomatic PAOD. Unfortunately, a meta-analysis of four randomized control trials and six observational studies was unable to establish any well-defined superiority for either approach. Overall, recommendations for selecting a treatment modality may depend on the patient’s life expectancy and comorbid conditions, as well as on the extent of the occlusive disease.[27]

In October 2014, the US Food and Drug Administration (FDA) approved the first drug-coated balloon (DCB) for the treatment of peripheral arterial vascular disease, the Lutonix 035 Drug Coated Balloon Percutaneous Transluminal Angioplasty Catheter (Lutonix, New Hope, MN). The device is coated with paclitaxel and intended for use to treat stenotic or obstructive lesions in the femoropopliteal arteries to improve limb perfusion. Similar devices that have been developed include In.Pact Admiral (Medtronic Vascular, Santa Rosa, CA) and Stellarex (Spectranetics, Colorado Springs, CO).

In August 2019, the FDA issued an updated notification to healthcare providers regarding a potential association between treatment of peripheral arterial disease with paclitaxel-coated balloons or paclitaxel-eluting stents and increased late mortality.[28]  This notification was updated in December 2021 on an FDA Web page that listed paclitaxel-coated balloons and stents approved in the United States, provided recommendations for healthcare providers, and described the risks associated with these devices.[29]

Exercise plays a vital role in the treatment of claudication. Patients with PAOD reduce their daily walking because of the claudication pain they experience and their fear of causing further damage. Unfortunately, this leads to an increasingly sedentary lifestyle that is even more detrimental to their health.

In most patients with claudication, regular walking programs result in substantial improvement (80-234% in controlled studies). A daily walking program of 45-60 minutes is recommended. The patient walks until claudication pain occurs, rests until the pain subsides, and then repeats the cycle.

Although the exact mechanism by which exercise improves walking distance remains unknown, a meta-analysis found that the mechanism is most likely to be multifactorial, including changes in cardiorespiratory physiology, endothelial function, mitochondrial number and activity, and muscle conditioning.[30] Regular exercise is believed to condition muscles so that they work more efficiently (ie, extract more blood) and to increase collateral vessel formation.

Patients who are treated medically should be seen every 4-6 months to assess the effects of therapy. Any changes in walking distance, smoking habits, eating habits, or exercise performance should be reviewed. Hypertension and diabetes should be controlled if necessary. Finally, a repeat pulse examination should be performed and the ABI measured. If the patient’s symptoms are worsening, intervention and referral to a vascular surgeon may be warranted.

In July 2022, a guideline for diagnosis and management of peripheral arterial disease (PAD) in diabetes was published by the Australian Diabetes-Related Foot Disease Guidelines working group and an expert panel, with the authorization of Diabetes Feet Australia (DFA).[20] Guideline recommendations were adopted or adapted from International Working Group on the Diabetic Foot (IWGDF) guidelines.

Diagnosis

Clinically examine (eg, by relevant history and palpation of foot pulses) the feet of all diabetic patients annually for PAD, even in the absence of foot ulceration. Clinically examine all diabetic patients with foot ulceration for PAD.

Because clinical examination does not reliably exclude PAD in most diabetic persons with foot ulceration, evaluate pedal Doppler arterial waveforms, and measure ankle systolic pressure and systolic ankle-brachial index (ABI) or toe systolic pressure and toe-brachial index (TBI).

Prognosis

Perform at least one of the following bedside tests in a patient with a diabetes-related foot ulcer (DFU) and PAD: skin perfusion pressure (≥40 mm Hg), toe pressure (≥30 mm Hg), or transcutaneous oxygen pressure (TcPO2; ≥25 mm Hg).

Use the WIfI (Wound, Ischemia, foot Infection) classification to stratify amputation risk and revascularization benefit in a patient with a DFU and PAD.

Always consider urgent vascular imaging and revascularization in a patient with a DFU and ankle pressure <  50 mm Hg, ABI <  0.5, toe pressure <  30 mm Hg, or TcPO2 <  25 mm Hg.

Always consider vascular imaging in patients with a DFU, regardless of bedside test results, when the ulcer is not healing within 4-6 weeks despite good care.

Always consider revascularization in a patient with a DFU and PAD, regardless of bedside test results, when the ulcer is not healing within 4-6 weeks despite optimal management.

Do not assume diabetes-related microangiopathy, when present, to be the cause of poor healing in patients with a DFU; always consider other possible causes.

Treatment

When considering lower-extremity revascularization, obtain anatomic information with color duplex ultrasonography, computed tomography angiography, magnetic resonance angiography, or intra-arterial digital subtraction angiography. Evaluate the entire lower-extremity arterial circulation.

When performing revascularization in a patient with a DFU, aim to restore direct blood flow to at least one of the foot arteries (preferably the one supplying the anatomic region of the ulcer). After the procedure, objectively measure perfusion to evaluate its effectiveness.

Because it has not been established whether endovascular, open, or hybrid revascularization technique is superior, base the decision on individual factors (eg, morphologic distribution of PAD or availability of autogenous vein).

Any center treating patients with a DFU should have expertise in and/or rapid access to facilities necessary to diagnose and treat PAD (including both endovascular techniques and bypass surgery).

After revascularization in a patient with a DFU, ensure that the patient is treated by a multidisciplinary team as part of a comprehensive care plan.

Urgently assess and treat patients with signs or symptoms of PAD and a diabetes-related foot infection.

Avoid revascularization if, from the patient’s perspective, the risk-benefit ratio is unfavorable.

Provide intensive cardiovascular risk management for any patient with diabetes and an ischemic foot ulcer.

In May 2022, the Canadian Cardiovascular Society (CCS) published guidelines on the management of peripheral arterial disease (PAD).[19] Strong recommendations included the following.

Diagnosis and screening

Use an ankle-brachial index (ABI) and/or toe-brachial index (TBI) to confirm PAD in symptomatic patients.

A broad, population-based PAD screening strategy is not recommended for individuals without claudication signs/symptoms.

Management

Smoking cessation is recommended to prevent PAD, as well as to prevent major adverse cardiovascular (CV) events (MACE) and major adverse limb events (MALE) in those with PAD. Recommended smoking cessation interventions include but are not limited to intensive counseling; pharmacotherapy (eg, nicotine replacement therapy [NRT], bupropion, varenicline); and, occasionally, nicotine-containing e-cigarettes.

Offer a sodium-glucose cotransporter 2 inhibitor (SGLT-2I) to diabetic patients with PAD rather than usual diabetic control for MACE reduction without a rise in amputation risk.

Administer lipid-modifying therapy to patients with PAD to lower death and CV death, nonfatal myocardial infarction (MI) and nonfatal stroke (MACE), and MALE. Use the maximally tolerated statin therapy. Use statin add-on therapies (ezetimibe and/or proprotein convertase subtilisin/kexin-9 inhibitors [PCSK-9Is]) if, while on maximally tolerated statin therapy, the level of low-density lipoprotein cholesterol (LDL-C) is ≥1.8 mmol/L, of non-high-density lipoprotein cholesterol (non-HDL-C) is ≥2.4 mmol/L, or of apolipoprotein B100 is ≥0.7 mg/dL.

For those who have PAD on maximally tolerated statin therapy but have a triglyceride level of 1.5-5.6 mmol/L, consider using icosapent ethyl to reduce CV death, nonfatal MI, and nonfatal stroke.

Unless there are contraindications, first-line treatment of hypertension in PAD consists of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs).

Routine antithrombotic therapy (antiplatelet or anticoagulant) is not recommended for those with isolated asymptomatic lower extremity (LE) PAD.

For patients with symptomatic LE PAD and who are:

• At high risk for ischemic events (high-risk comorbidities [eg, polyvascular disease, diabetes, heart failure history, renal insufficiency]) and/or high-risk limb presentation (following peripheral revascularization, limb amputation, rest pain, ischemic ulcers), and at low bleeding risk: Use rivaroxaban 2.5 mg twice daily (BID) with aspirin (80-100 mg daily)
• At low bleeding risk and without high-risk limb comorbidities or high-risk limb presentation: Use rivaroxaban 2.5 mg BID with aspirin or single antiplatelet therapy (SAPT)
• At high bleeding risk and still eligible for antithrombotic therapy: Consider SAPT with aspirin (75-325 mg) or clopidogrel (75 mg)

For those with stable LE PAD, additional full-dose anticoagulation with antiplatelet therapy is not recommended to reduce MACE and MALE events.

Administer rivaroxaban 2.5 mg BID daily with aspirin (80-100 mg daily) for patients with LE PAD after elective open revascularization, and with or without short-term clopidogrel for elective endovascular revascularization.

For those with PAD and intermittent claudication, supervised exercise programs are first-line therapy to improve maximal and pain-free walking distance and time, as well as quality of life (QoL); walking is the preferred form of exercise in exercise programs. When there are no available supervised exercise programs or when not desired by the patient, offer a structured home-based or community exercise program to improve leg symptoms and QoL.

Revascularization interventions

The Revised Cardiac Risk Index (RCRI) is not recommended for preoperative evaluation of cardiac risk and 30-day mortality in peripheral arterial surgery.

Revascularization is not recommended for those with asymptomatic PAD.

Selection of the revascularization procedure should be specific to the patient, expected to have low perioperative morbidity, and be reasonably likely to provide sustained symptomatic benefit. Selection of endovascular versus open revascularization strategies for PAD should take into account anatomic, patient, and procedural factors, as well as operator expertise and resource availability.

For patients with chronic limb-threatening ischemia (CLTI):

• Provide urgent referral to vascular specialists for consideration of revascularization
• Consider endovascular, open, or hybrid revascularization on the basis of the anatomic disease pattern, degree of ischemia, expected procedure durability, perioperative risk, and patient life expectancy
• Primary major amputation is recommended for those with nonreconstructible disease, nonsalvageable limb, nonambulatory status, severe sepsis, or for palliation for those with a short life expectancy and who are not suitable revascularization candidates

Depending on the severity of tissue loss, gangrene, and/or infection, wound debridement and/or minor amputation concurrent with revascularization or in a staged manner is recommended.

Endovascular therapy is recommended for appropriately selected patients with claudication or CLTI.

Endovascular therapy is not recommended in the common femoral or profunda femoris arteries; for lesions in asymptomatic patients; and for nonhemodynamically significant lesions.

Surgical revascularization

For intermittent claudication, perform surgical bypass to the popliteal artery (when indicated) with an autogenous vein preferred over prosthetic graft material. Femoral-tibial artery bypasses are not recommended.

For chronic limb-threatening ischemia, perform surgical bypass to the popliteal or infrapopliteal arteries with an autogenous vein. In those with CLTI for whom endovascular revascularization is not feasible and a suitable autogenous vein is not available, prosthetic material can be effective for bypass to the below-knee popliteal and tibial arteries as a last resort in cases of limb salvage.

Clinical guidelines on CLTI were released in June 2019 by the Society for Vascular Surgery (SVS), European Society for Vascular Surgery (ESVS), and World Federation of Vascular Societies (WFVS).[18]

Definitions and nomenclature

Evaluate for ischemia and determine its severity using objective hemodynamic tests in all patients with suspected CLTI.

Grade wound extent, degree of ischemia, and infection severity with a lower-extremity threatened-limb classification staging system to guide clinical treatment in all patients with suspected CLTI.

Diagnosis and limb staging

A detailed history should be performed in all patients with suspected CLTI to determine symptoms, cardiovascular risk factors, and medical history .

A complete cardiovascular physical examination should be performed in all patients with suspected CLTI.

A complete foot examination should be performed in all patients with pedal tissue loss and suspected CLTI, including a neuropathy assessment and a probe-to-bone test of any open ulcers.

Ankle pressure (AP) and ABI should be measured as first-line noninvasive testing in all patients with suspected CLTI.

Toe pressure (TP) and TBI should be measured in all patients with tissue loss and suspected CLTI.

High-quality angiographic imaging of the lower limb (including the ankle and foot) should be performed in all patients with suspected CLTI who may be candidates for revascularization.

Medical management

Cardiovascular risk factors should be evaluated in all patients with suspected CLTI.

Modifiable risk factors should be managed in all patients with suspected CLTI.

Antiplatelet therapy should be administered to all patients with CLTI.

Systemic vitamin K antagonists should be avoided in the treatment of lower-extremity atherosclerosis in patients with CLTI.

Statin therapy (moderate- or high-intensity) should be administered to patients with CLTI to reduce the likelihood of all-cause and cardiovascular mortality.

Hypertension should be modified to target levels of < 140 mm Hg systolic and < 90 mm Hg diastolic in patients with CLTI.

Metformin is the primary hypoglycemic agent in patients with type 2 diabetes mellitus (DM) and CLTI.

Smoking-cessation interventions should be offered to all patients with CLTI who use tobacco products.

Smokers or former smokers with CLTI should be inquired about the status of tobacco use at every visit.

Analgesics should be prescribed to patients with CLTI who have ischemic rest pain of the lower extremity and foot until pain resolves following revascularization.

Chronic severe pain should be treated with acetaminophen in combination with opioids in patients with CLTI.

Global Limb Anatomic Staging System

An integrated limb-based anatomic staging system (eg, Global Limb Anatomic Staging System [GLASS]) should be used to define the complexity of a preferred target artery path (TAP) and to aid in revascularization (EBR) in patients with CLTI.

Strategies for evidence-based revascularization

A vascular specialist should be consulted in all cases of suspected CLTI to consider limb salvage except when major amputation is considered medically urgent.

Patients with a limited life expectancy, unsalvageable limb, or poor functional status should be offered primary amputation or palliation after shared decision-making.

The periprocedural risk should be assessed and life expectancy estimated in patients with CLTI who are candidates for revascularization.

All patients with CLTI who are candidates for limb salvage should be staged with an integrated threatened limb classification system.

Urgent surgical drainage and debridement (including minor amputation, if needed) should be performed and antibiotic therapy initiated in all patients with suspected CLTI who have wet gangrene or deep-space foot infection.

Limb staging should be repeated following surgical drainage, debridement, minor amputation, or correction of inflow disease (aortoiliac [AI], common and deep femoral artery disease) and before subsequent major treatment decisions.

Revascularization should not be performed in patients without significant ischemia (Wound, Ischemia, and foot Infection [WIfI] ischemia grade 0) unless an isolated region of poor perfusion in conjunction with major tissue loss (eg, WIfI wound grade 2 or 3) can be effectively targeted and the wound progresses or fails to decrease in size by 50% or more within 4 weeks despite appropriate infection control, wound care, and offloading.

Revascularization should be offered to all average-risk patients with advanced limb-threatening conditions (eg, WIfI stage 4) and significant perfusion deficits (eg, WIfI ischemia grades 2 and 3).

High-quality angiographic imaging with dedicated views of foot and ankle arteries should be performed for anatomic staging and procedural planning in all patients with CLTI who are candidates for revascularization.

The anatomic pattern of disease and preferred TAP should be defined with an integrated lib-based staging system in all patients with CLTI who are candidates for revascularization.

When available, ultrasonographic vein mapping should be performed in all patients with CLTI who are candidates for surgical bypass.

The ipsilateral great saphenous vein (GSV) and small saphenous vein (SSV) should be mapped to plan the surgical bypass.

Veins in the contralateral leg and both arms should be mapped if the ipsilateral vein is insufficient.

A patient with CLTI should not be considered as unsuitable for revascularization until imaging studies are reviewed and the patient is clinically evaluated by a qualified vascular specialist.

Inflow disease should be corrected first in patients with CLTI who have both inflow and outflow disease.

The decision for staged versus combined inflow and outflow revascularization should be based on risk and limb threat.

Inflow disease alone should be corrected in patients with CLTI who have multilevel disease and low-grade ischemia (eg, WIfI ischemia grade 1) or limited tissue loss (eg, WIfI wound grade 0 or 1) and whenever the risk-benefit of additional outflow reconstruction is high or initially unclear.

The limb should be restaged and hemodynamic assessment repeated following inflow correction in patients with CLTI who have both inflow and outflow disease.

An endovascular-first approach should be used to treat patients with CLTI who have moderate to severe (eg, GLASS stage IA) aortoiliac (AI) disease.

Open common femoral artery (CFA) endarterectomy with patch angioplasty should be performed, with or without extension into the profunda femoris artery (PFA), in patients with CLTI who have hemodynamically significant disease of the common and deep femoral arteries (>50% stenosis).

Endovascular treatment should be considered for significant CFA disease in patients who are deemed to be at high surgical risk or to have a hostile groin.

Stents should be avoided in the CFA, and they should not be placed across the origin of a patent deep femoral artery.

Hemodynamically significant disease of the proximal deep femoral artery should be corrected, when technically feasible.

Decisions concerning endovascular intervention versus open surgical bypass should be based on the severity of the limb threat (eg, WIfI grade), the anatomic disease pattern (eg, GLASS), and the availability of autologous vein in average-risk patients with CLTI.

The preferred conduit for infrainguinal bypass surgery is autologous vein in patients with CLTI.

Intraoperative imaging (angiography, duplex ultrasonography, or both) should be performed upon completion of open bypass surgery for CLTI and significant technical defects corrected, if feasible, during the index operation.

Nonrevascularization treatments

Vasoactive drugs and defibrinating agents (ancrod) should not be offered to patients in whom revascularization is not possible.

Hyperbaric oxygen therapy (HBOT) should not be offered to improve limb salvage in patients with CLTI who have severe uncorrected ischemia (eg, WIfI ischemia grade 2 or 3).

Optimal wound care should be continued until the lower extremity wound has completely healed or amputation is performed.

Biologic and regenerative medicine approaches

Therapeutic angiogenesis should be restricted for patients with CLTI who are enrolled in a registered clinical trial.

Minor and major amputations

After shared decision-making, primary amputation should be offered to patients with CLTI who have an unsalvageable or pre-existing dysfunctional limb, a short life expectancy, or poor functional status.

A multidisciplinary rehabilitation team should be involved from the time of decision to amputate through successful completion of rehabilitation.

Patients with CLTI who have undergone amputation should be monitored at least yearly to track disease progression in the contralateral limb, to maintain optimal medical therapy, and to manage risk factors.

Postprocedural care and surveillance following infrainguinal revascularization

Following lower-extremity revascularization, optimal medical therapy for PAD, including long-term antiplatelet and statin therapies, should be continued.

Smoking cessation should be promoted to all patients with CLTI who have undergone lower-extremity revascularization.

Patients who have undergone lower-extremity vein bypass for CLTI should be observed regularly for at least 2 years. The clinical surveillance program should include interval history, pulse examination, and assessment of resting APs and TPs. Duplex ultrasonography (DUS) should also be considered.

Patients who have undergone lower-extremity prosthetic bypass for CLTI should be observed regularly for at least 2 years, with interval history, pulse examination, and measurement of resting APs and TPs.

Patients who have undergone infrainguinal endovascular interventions for CLTI should be observed in a surveillance program that includes clinical visits, pulse examination, and noninvasive testing (resting APs and TPs).

Additional imaging should be considered in patients with lower-extremity vein grafts whose ABI has decreased ≥0.15 and whose symptoms have recurred or pulse status changed to evaluate for vein graft stenosis.

Intervention should be offered if vein graft lesions are detected on duplex US in patients with an associated peak systolic velocity (PSV) of >300 cm/s and a PSV ratio >3.5 or grafts with low velocity (midgraft PSV < 45 cm/s) to maintain patency.

Long-term surveillance, including DUS graft scanning, should be maintained following surgical or catheter-based revision of a vein graft to evaluate for recurrent graft-threatening lesions.

Mechanical offloading should be provided as a primary component of care in all patients with CLTI who have pedal wounds.

Counseling on protection of the healed wound and foot should be provided, including appropriate shoes, insoles, and monitoring of inflammation.

In August 2017, the European Society for Cardiology (ESC), in collaboration with the ESVS, issued updated guidelines on the diagnosis and treatment of PAD[17] ; these guidelines were also endorsed by the European Stroke Organisation (ESO).

Recommendations regarding best medical therapy for PAD include the following:

• Smoking cessation is recommended in all patients with PAD (class I recommendation; evidence level B)
• Healthy diet and physical activity are recommended for all patients with PAD (class I recommendation; evidence level C)
• Statins are recommended in all patients with PAD (class I recommendation; evidence level A)
• In patients with PAD, it is recommended to reduce LDL-C to < 1.8 mmol/L (70 mg/dL) or decrease it by ≥50% if baseline values are 1.8-3.5 mmol/L (70-135 mg/dL) (class I recommendation; evidence level C)
• In diabetic patients with PAD, strict glycemic control is recommended (class I recommendation; evidence level C)
• Antiplatelet therapy is recommended in patients with symptomatic PAD (class I recommendation; evidence level C)
• In patients with PAD and hypertension, it is recommended to control blood pressure at < 140/90 mm Hg (class I recommendation; evidence level A)
• ACEIs or ARBs should be considered as first-line therapy in patients with PAD and hypertension (class I recommendation; evidence level B)

Recommendations related to screening and diagnosis of lower-extremity arterial disease (LEAD) include the following:

• ABI is indicated as a first-line noninvasive test for screening and diagnosis of lower-extremity arterial disease (LEAD) (class I recommendation; evidence level C)
• If ankle arteries are not compressible or ABI >1.40, alternative methods (eg, TBI, Doppler waveform analysis, or pulse volume recording) are indicated (class I recommendation; evidence level C)
• DUS is a first-line imaging modality for confirming LEAD (class I recommendation; evidence level C)
• DUS and/or computed tomography angiography (CTA) and/or magnetic resonance angiography (MRA) are indicated for characterizing anatomy in LEAD and guiding optimal revascularization (class I recommendation; evidence level C)
• Anatomic imaging data should always be analyzed in conjunction with symptoms and hemodynamic data for treatment is decided on (class I recommendation; evidence level C)
• DUS screening for abdominal aortic aneurysm (AAA) should be considered (class IIa recommendation; evidence level C)

Recommendations for patients with IC are as follows:

• On top of general prevention, statins are indicated to improve walking distance (class I recommendation; evidence level A)
• In patients with intermittent claudication, supervised exercise training is recommended (class I recommendation; evidence level A); unsupervised exercise training is recommended when supervised training is not feasible or available (class I recommendation; evidence level C)
• If daily life activities are compromised despite exercise therapy, revascularization should be considered (class IIa recommendation; evidence level C)
• If daily life activities are severely compromised, revascularization should be considered in association with exercise therapy (class IIa recommendation; evidence level B)

Recommendations for revascularization of aortoiliac occlusive lesions in patients with intermittent claudication and severe chronic limb ischemia are as follows:

• Endovascular-first strategy is recommended for short (< 5 cm) occlusive lesions (class I recommendation; evidence level C)
• In patients fit for surgery, aorto(bi)femoral bypass should be considered (class IIa recommendation; evidence level B)
• Endovascular-first strategy should be considered in long and/or bilateral lesions in patients with severe comorbidities (class IIa recommendation; evidence level B)
• Endovascular-first strategy may be considered for aortoiliac occlusive lesions if it is done by an experienced team and does not compromise subsequent surgical options (class IIb recommendation; evidence level B)
• Primary stent implantation rather than provisional stenting should be considered (class IIa recommendation; evidence level B)
• Open surgery should be considered in fit patients with an aortic occlusion extending up to the renal arteries (class IIa recommendation; evidence level C)
• For iliofemoral occlusive lesions, a hybrid procedure combining iliac stenting and femoral endarterectomy or bypass should be considered (class IIa recommendation; evidence level C)
• Extra-anatomic bypass may be indicated for patients with no other alternatives (class IIb recommendation; evidence level C)

Recommendations for revascularization of femoropopliteal occlusive lesions in patients with intermittent claudication and severe chronic limb ischemia are as follows:

• Endovascular-first strategy is recommended in short (< 25 cm) lesions (class I recommendation; evidence level C)
• Primary stent implantation should be considered in short (< 25 cm) lesions (class IIa recommendation; evidence level A)
• Drug-eluting balloons may be considered in short (< 25 cm) lesions (class IIb recommendation; evidence level A)
• Drug-eluting stents may be considered for short (< 25 cm) lesions (class IIb recommendation; evidence level B)
• Drug-eluting balloons may be considered for treatment of in-stent restenosis (class IIb recommendation; evidence level B)
• In patients not at high risk for surgery, bypass surgery is indicated for long (≥25 cm) superficial femoral artery (SFA) lesions when an autologous vein is available and life expectancy is >2 years (class I recommendation; evidence level B)
• The autologous saphenous vein is the conduit of choice for femoropopliteal bypass (class I recommendation; evidence level A)
• When above-the-knee bypass is indicated, the use of a prosthetic conduit should be considered in the absence of any autologous saphenous vein (class IIa recommendation; evidence level A)
• In patients unfit for surgery, endovascular therapy may be considered in long (≥25 cm) femoropopliteal lesions (class IIb recommendation; evidence level C)

Recommendations for revascularization of infrapopliteal occlusive lesions are as follows:

• In the case of CLTI, infrapopliteal revascularization is indicated for limb salvage (class I recommendation; evidence level C)
• For revascularization of infrapopliteal arteries, bypass using the GSV is indicated (class I recommendation; evidence level A); endovascular therapy should be considered (class IIa recommendation; evidence level B)

Recommendations for management of CLTI are as follows:

• Early recognition of tissue loss or infection and referral to the vascular team is mandatory to improve limb salvage (class I recommendation; evidence level C)
• Assessment of the risk of amputation is indicated (class I recommendation; evidence level C)
• In patients with CLTI and diabetes, optimal glycemic control is recommended (class I recommendation; evidence level C)
• For limb salvage, revascularization is indicated whenever feasible (class I recommendation; evidence level B)
• In CLTI patients with below-the-knee lesions, angiography (including foot runoff) should be considered before revascularization (class IIa recommendation; evidence level C)
• Stem cell or gene therapy is not indicated for CLTI (class III recommendation; evidence level B)

Recommendations for management of acute limb ischemia are as follows:

• In the case of neurologic deficit, urgent revascularization is indicated; imaging should not delay intervention (class I recommendation; evidence level C)
• In the absence of neurologic deficit, revascularization is indicated within hours after initial imaging on a case-by-case basis (class I recommendation; evidence level C)
• Heparin and analgesics are indicated as soon as possible (class I recommendation; evidence level C)

In November 2016, the American Heart Association (AHA) and the American College of Cardiology (ACC) published the following recommendations regarding lower-extremity PAD[16] :

• The vascular examination for PAD includes pulse palpation, auscultation for femoral bruits, and inspection of the legs and feet. Lower extremity pulses are assessed and rated as follows: 0, absent; 1, diminished; 2, normal; or 3, bounding
• To confirm the diagnosis of PAD, abnormal physical examination findings must be confirmed with diagnostic testing, generally with the ABI as the initial test
• Patients with a confirmed diagnosis of PAD are at increased risk for subclavian artery stenosis; an interarm blood pressure difference of >15 to 20 mm Hg is abnormal and suggestive of subclavian (or innominate) artery stenosis; measuring blood pressure in both arms identifies the arm with the highest systolic pressure, a requirement for accurate measurement of the ABI
• Resting ABI results should be reported as abnormal (ABI ≤ 0.90), borderline (ABI 0.91-0.99), normal (1.00-1.40), or noncompressible (ABI >1.40)
• ABI is not recommended in patients who are not at increased risk of PAD and who do not have a  history or physical examination findings suggestive of PAD
• TBI should be measured to diagnose patients with suspected PAD when the ABI is >1.40
• Patients with exertional non-joint-related leg symptoms and normal or borderline resting ABI (>0.90 and ≤ 1.40) should undergo exercise treadmill ABI testing to evaluate for PAD
• Patients with PAD should receive a comprehensive program of guideline-directed medical therapy, including structured exercise and lifestyle modification, to reduce cardiovascular ischemic events and improve functional status
• Antiplatelet therapy with aspirin alone (range, 75-325 mg/day) or clopidogrel alone (75 mg/day) is recommended to reduce myocardial infarction (MI), stroke, and vascular death in patients with symptomatic PAD
• Treatment with a statin medication is indicated for all patients with PAD
• Patients with PAD who smoke cigarettes or use other forms of tobacco should be advised at every visit to quit
• Cilostazol is an effective therapy to improve symptoms and increase walking distance in patients with claudication
• Endovascular procedures are effective as a revascularization option for patients with lifestyle-limiting claudication and hemodynamically significant aortoiliac occlusive disease
• When surgical revascularization is performed, bypass to the popliteal artery with autogenous vein is recommended in preference to prosthetic graft material 

In 2015, the SVS issued practice guidelines for management of atherosclerotic disease of the lower extremities.[15]

Recommendations for diagnosis of PAD include the following:

• ABI is recommended as the first-line noninvasive test to establish a diagnosis of PAD in individuals with symptoms or signs suggestive of disease. If the ABI is borderline or normal (>0.9) and symptoms of claudication are suggestive, an exercise ABI is recommended (grade 1 recommendation; evidence level A).
• Routine screening is not suggested for lower-extremity PAD in the absence of risk factors, history, signs, or symptoms of PAD (grade 2 recommendation; evidence level C).
• For asymptomatic individuals at elevated risk (eg, those aged >70 years, smokers, diabetic patients, those with an abnormal pulse examination, and those with other established cardiovascular disease), screening for lower-extremity PAD is reasonable if used to improve risk stratification, preventive care, and medical management (grade 2 recommendation; evidence level C).
• In symptomatic patients being considered for revascularization, physiologic noninvasive studies (eg, segmental pressures and pulse volume recordings) are suggested to aid in quantification of arterial insufficiency and help localize the level of obstruction (grade 2 recommendation; evidence level C).
• In symptomatic patients being considered for revascularization treatment, anatomic imaging studies (eg, arterial DUS, CTA, MRA, and contrast arteriography) are recommended (grade 1 recommendation; evidence level B).

Recommendations for management of asymptomatic PAD include the following:

• Multidisciplinary comprehensive smoking cessation interventions are recommended for patients with asymptomatic PAD who use tobacco (repeatedly until tobacco use has stopped) (grade 1 recommendation; evidence level A).
• Provision of education about the signs and symptoms of PAD progression to asymptomatic patients with PAD is recommended (grade 1 recommendation; evidence ungraded).
• Invasive treatments for PAD are not recommended in the absence of symptoms, regardless of hemodynamic measures or imaging findings demonstrating PAD (grade 1 recommendation; evidence level B).

Recommendations for medical treatment of intermittent claudication (IC) include the following:

• Multidisciplinary comprehensive smoking cessation interventions are recommended for patients with IC (repeatedly until tobacco use has stopped) (grade 1 recommendation; evidence level A).
• Statin therapy is recommended for symptomatic PAD (grade 1 recommendation; evidence level A).
• Optimized diabetes control (hemoglobin A1c goal of < 7.0%) is recommended in patients with IC if this goal can be achieved without hypoglycemia (grade 1 recommendation; evidence level B).
• Indicated beta blockers (eg, for hypertension, cardiac indications) are recommended in patients with IC; no evidence supports concerns about worsening claudication (grade 1 recommendation; evidence level B).
• In patients with IC due to atherosclerosis, antiplatelet therapy with aspirin (75-325 mg daily) is recommended (grade 1 recommendation; evidence level A).
• Clopidogrel 75 mg/day is recommended as an effective alternative to aspirin for antiplatelet therapy in patients with IC (grade 1 recommendation; evidence level B).
• In patients with IC due to atherosclerosis, it is suggested that warfarin not be used solely to reduce the risk of adverse cardiovascular events or vascular occlusions (grade 1 recommendation; evidence level C).
• It is suggested that folic acid and vitamin B12 supplements not be used to treat IC (grade 2 recommendation; evidence level C).
• In patients with IC who do not have congestive heart failure (CHF), a 3-month trial of cilostazol (100 mg bid) is suggested to improve pain-free walking (grade 2 recommendation; evidence level A).
• In patients with IC who cannot tolerate or have contraindications for cilostazol, a trial of pentoxifylline (400 mg tid) is suggested to improve pain-free walking (grade 2 recommendation; evidence level B).

Recommendations for exercise therapy for IC include the following:

• A supervised exercise program consisting of walking a minimum of three times per week (30-60 min/session) for at least 12 weeks is recommended as first-line therapy for all suitable patients with IC (grade 1 recommendation; evidence level A).
• Home-based exercise is recommended, with a goal of at least 30 minutes of walking three to five times per week when a supervised exercise program is unavailable or for long-term benefit after a supervised program is completed (grade 1 recommendation; evidence level B).
• After revascularization therapy for IC, exercise (either supervised or home-based) is recommended for adjunctive functional benefits (grade 1 recommendation; evidence level B).
• Patients with IC should be be followed up annually to assess compliance with lifestyle measures (smoking cessation, exercise) and medical therapies and to look for evidence of progression in symptoms or signs of PAD. Yearly ABI testing may be of value to provide objective evidence of disease progression (grade 1 recommendation; evidence level C).

General recommendations for interventions for IC include the following:

• Endovascular therapy (EVT) or surgical treatment of IC is recommended for patients with significant functional or lifestyle-limiting disability when it is reasonably likely to yield symptomatic improvement, when pharmacologic or exercise therapy or both have failed, and when the benefits outweigh the potential risks (grade 1 recommendation; evidence level B).
• Selection of an invasive treatment for IC should be individualized. The modality offered should provide a reasonable likelihood of sustained benefit to the patient (>50% likelihood of clinical efficacy for at least 2 years). For revascularization, anatomic patency (freedom from hemodynamically significant restenosis) is considered a prerequisite for sustained efficacy (grade 1 recommendation; evidence level C).

Recommendations for interventions for aortoiliac occlusive disease (AIOD) in IC include the following:

• EVT is preferred to open surgery for focal AIOD causing IC (grade 1 recommendation; evidence level B).
• EVT is recommended as first-line revascularization therapy for most patients with common iliac artery or external iliac artery occlusive disease causing IC (grade 1 recommendation; evidence level B).
• Selective use of bare-metal stents or covered stents for aortoiliac angioplasty is recommended for common iliac artery or external iliac artery occlusive disease, because of improved technical success and patency (grade 1 recommendation; evidence level B).
• Covered stents are recommended for AIOD in the presence of severe calcification or aneurysmal changes where the risk of rupture may be increased after unprotected dilation (grade 1 recommendation; evidence level C).
• For patients with diffuse AIOD undergoing revascularization, either EVT or surgical intervention is suggested as first-line therapy. Endovascular interventions that may impair the potential for subsequent aortofemoral bypass AFB in surgical candidates should be avoided (grade 2 recommendation; evidence level B).
• EVT for AIOD in the presence of aneurysmal disease should be undertaken cautiously. The modality used either should achieve concomitant aneurysm exclusion or should not jeopardize the conduct of any future open or endovascular aneurysm repair (grade 1 recommendation; evidence level C).
• In all patients undergoing revascularization for AIOD, the common femoral artery (CFA) should be assessed. If hemodynamically significant CFA disease is present, surgery (endarterectomy) is recommended as first-line treatment (grade 1 recommendation; evidence level B).
• In patients with iliac artery disease and CFA involvement, hybrid procedures combining femoral endarterectomy with iliac inflow correction are recommended (grade 1 recommendation; evidence level B).
• Direct surgical reconstruction (bypass, endarterectomy) is recommended in patients with reasonable surgical risk and diffuse AIOD not amenable to EVT, after one or more failed attempts at EVT, or in patients with combined occlusive and aneurysmal disease (grade 1 recommendation; evidence level B).
• In younger patients (< 50 years) with IC, a shared decision-making approach is recommended to engage patients and inform them of the possibility of inferior outcomes with either EVT or surgery (grade 2 recommendation; evidence level C).
• Either axial imaging (eg, CT or magnetic resonance imaging [MRI]) or catheter-based angiography is recommended for evaluation and planning of surgical revascularization for AIOD (grade 1 recommendation; evidence ungraded).
• When surgical bypass is performed for AIOD, concomitant aneurysmal disease of the aorta or iliac arteries should be treated as appropriate (exclusion) and is a contraindication for end-to-side proximal anastomoses (grade 1 recommendation; evidence ungraded).
• For any bypass graft originating from the CFA, the donor iliac artery must be free of hemodynamically significant disease or any preexisting disease should be corrected before the bypass procedure is performed (grade 1 recommendation; evidence ungraded).

Recommendations for interventions for femoropopliteal occlusive disease (FPOD) in IC include the following:

• EVT is preferred to open surgery for focal occlusive disease of the SFA that does not involve the origin at the femoral bifurcation (grade 1 recommendation; evidence level C).
• Selective stenting is suggested for focal lesions (< 5 cm) in the SFA that have unsatisfactory technical results with balloon angioplasty (grade 2 recommendation; evidence level C).
• Adjunctive use of self-expanding nitinol stents (with or without paclitaxel) is recommended for intermediate-length (5-15 cm) SFA lesions to improve the midterm patency of angioplasty (grade 1 recommendation; evidence level B).
• Preoperative ultrasonographic vein mapping is suggested to establish the availability and quality of autogenous vein conduit in patients being considered for infrainguinal bypass to treat IC (grade 2 recommendation; evidence level C).
• EVT is not recommended for isolated infrapopliteal disease in IC, because it is of unproven benefit and may be harmful (grade 1 recommendation; evidence level C).
• Surgical bypass is recommended as an initial revascularization strategy for patients with diffuse FPOD, small vessel caliber (< 5 mm), or extensive SFA calcification if their anatomy is favorable for bypass (popliteal artery target, good runoff) and their operative risk is average or low (grade 1 recommendation; evidence level B).
• The saphenous vein is the preferred conduit for infrainguinal bypass grafts (grade 1 recommendation; evidence level A).
• In the absence of suitable vein, a prosthetic conduit is suggested for femoropopliteal bypass in claudicant patients if the above-knee popliteal artery is the target vessel and good runoff is present (grade 2 recommendation; evidence level C).

Recommendations for postinvervention therapy in IC include the following:

• After EVT or open surgical intervention for claudication, optimal medical therapy (antiplatelet agents, statins, antihypertensives, control of glycemia, smoking cessation) is recommended for all patients (grade 1 recommendation; evidence level A).
• After lower-extremity bypass (venous or prosthetic), antiplatelet therapy (aspirin, clopidogrel, or aspirin plus clopidogrel) is suggested (grade 2 recommendation; evidence level B).
• After infrainguinal endovascular intervention for claudication, treatment with aspirin and clopidogrel for at least 30 days is suggested (grade 2 recommendation; evidence level B).

Recommendations for surveillance after intervention for IC include the following:

• Patients treated with open surgery or EVT for IC should be monitored with a clinical surveillance program that consists of an interval history to detect new symptoms, ensure compliance with medical therapies, and record subjective functional improvements; pulse examination; and measurement of resting and, if possible, postexercise ABIs (grade 2 recommendation; evidence level C).
• Patients treated with lower-extremity vein grafts for IC should be monitored with a surveillance program consisting of clinical follow-up and DUS (grade 2 recommendation; evidence level C).
• Patients who have previously undergone vein bypass surgery for IC and have developed a significant graft stenosis on DUS should be considered for prophylactic reintervention (open or endovascular) to promote long-term bypass graft patency (grade 1 recommendation; evidence level C).

Daily aspirin is recommended for overall cardiovascular care. In addition, the following agents have shown promise in the management of peripheral arterial occlusive disease (PAOD) and may be considered:

• Pentoxifylline

• Clopidogrel

• Enoxaparin

• Cilostazol

• Simvastatin

Class Summary

Antiplatelet agents decrease the overall risk of cardiovascular disease from myocardial infarction (MI) and stroke. They also improve walking distance by enhancing circulation.

Aspirin (Ascriptin, Bayer aspirin, Aspirtab, Ecotrin, Halfprin)

Aspirin inhibits prostaglandin synthesis, thereby preventing formation of platelet-aggregating thromboxane A2.

Clopidogrel (Plavix)

Clopidogrel selectively inhibits binding of adenosine diphosphate (ADP) to platelet receptors and subsequent ADP-mediated activation of glycoprotein IIb/IIIa complex, thereby inhibiting platelet aggregation. It is indicated for reduction of atherosclerotic events.

Cilostazol (Pletal)

The mechanism by which cilostazol affects symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are phosphodiesterase (PDE) subtype 3 (PDE3) inhibitors, inhibiting PDE activity and suppressing degradation of cyclic adenosine monophosphate (cAMP); the resultant increase in cAMP in platelets and blood vessels leads to inhibition of platelet aggregation and vasodilation, respectively.

Cilostazol reversibly inhibits platelet aggregation induced by various stimuli, including thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress.

Pentoxifylline

Pentoxifylline is indicated for treatment of patients with intermittent claudication due to atherosclerosis or other obstructive arteriopathies. It improves blood flow by increasing red blood cell deformability, thereby decreasing blood viscosity.

Class Summary

Antilipemic agents are beneficial in lowering blood cholesterol profiles, thereby possibly reducing the rate of first major vascular events.

Simvastatin (Zocor)

Simvastatin reduces cardiovascular heart disease mortality and morbidity (eg, nonfatal MI or stroke and revascularization procedures) in high-risk patients (ie, those with existing coronary heart disease, diabetes, peripheral vessel disease, or a history of stroke or other cerebrovascular disease). Simvastatin competitively inhibits HMG-CoA, which catalyzes the rate-limiting step in cholesterol synthesis. Patients should be placed on a cholesterol-lowering diet; the diet should be continued indefinitely.

Pravastatin (Pravachol)

Pravastatin is a lipid-lowering HMG-CoA reductase inhibitor. This agent reduces cholesterol biosynthesis and is orally administered in its active form. Pravastatin is rapidly absorbed (peak plasma 1-1.5 h), with a therapeutic response usually seen in 1 week. This agent is highly effective in reducing total cholesterol, LDL cholesterol, and triglyceride levels in patients with heterozygous familial hypercholesterolemia, presumed familiar forms of primary hypercholesterolemia, and mixed dyslipidemia.

Lovastatin (Mevacor, Altoprev)

Lovastatin is a cholesterol-lowering agent that is isolated from a strain of Aspergillus terreus. This HMG-CoA reductase inhibitor catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol. Lovastatin is available in immediate-release (Mevacor) and sustained-release (Altocor) dosage forms.

Rosuvastatin (Crestor)

Rosuvastatin is also an HMG-CoA reductase inhibitor that decreases cholesterol synthesis and increases cholesterol metabolism. This agent reduces total cholesterol, LDL cholesterol, and triglyceride levels but increases HDL cholesterol levels. Rosuvastatin is used adjunctively with diet and exercise to treat hypercholesterolemia.

Atorvastatin (Lipitor)

Atorvastatin competitively inhibits HMG-CoA reductase, which is responsible for the rate-limiting step in cholesterol synthesis. Before initiating therapy, place patients on a cholesterol-lowering diet for 3-6 months, and continue the diet indefinitely. Dosing usually starts with 10 mg/day orally once daily; titrate to a maximum of 80 mg/day as necessary.

Fluvastatin (Lescol)

Fluvastatin competitively inhibits HMG-CoA reductase, which is responsible for the rate-limiting step in cholesterol synthesis. Before initiating therapy, place patients on a cholesterol-lowering diet for 3-6 months, and continue the diet indefinitely. Immediate-release capsules (Lescol) and extended-release tablets (Lescol XL) are available. Dose at 20-80 mg/day orally once daily or divided twice daily.

Class Summary

Anticoagulants decrease microthrombus formation. Reversible elevation of hepatic transaminase levels occurs occasionally. Heparin-associated thrombocytopenia has been observed with low-molecular-weight heparin (LMWH).

Enoxaparin (Lovenox)

Enoxaparin enhances the inhibition of factor Xa and thrombin by increasing antithrombin III activity. It also slightly affects thrombin and clotting time and preferentially increases the inhibition of factor Xa.

This agent has a wide therapeutic window; the prophylactic dose is not adjusted based on the patient's weight. Enoxaparin is safer and more effective than unfractionated heparin for prophylaxis of venous thromboembolism. The average duration of treatment is 7-14 days.

Dalteparin (Fragmin)

Dalteparin is an LMWH with antithrombotic properties. It enhances the inhibition of factor Xa and thrombin by increasing antithrombin. It has a minimal effect on activated partial thromboplastin time (aPTT).

Tinzaparin

Tinzaparin is an LMWH with antithrombotic properties. It enhances the inhibition of factor Xa and thrombin by increasing antithrombin. It has a minimal effect on aPTT.