Overview of lower extremity peripheral artery disease

Authors: Jeffrey S Berger, MD, MS, FAHA,

FACC Mark G Davies, MD, PhD, MBA, FACS,

FACC Section Editors: Denis L Clement, MD, PhD John F Eidt, MDJoseph L Mills, Sr, MDDeputy Editor:Kathryn A Collins,
MD, PhD, FACS

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Mar 2019. | This topic last updated: Nov 07, 2018.

INTRODUCTION

Atherosclerosis results in the accumulation of lipid and fibrous material between the layers of the arterial wall and
causes disease of the coronary, cerebral, and peripheral arteries. Atherosclerotic disease often involves the arteries
providing flow to the lower extremities, referred to as lower extremity peripheral artery disease (PAD). Atherosclerosis
can lead to acute or chronic symptoms due to embolism from more proximal disease, or due to thrombosis of an artery
that has been progressively narrowed.

Management of patients with lower extremity PAD should include medical therapies aimed at reducing the risk for
future cardiovascular events related to atherosclerosis, such as myocardial infarction, stroke, and peripheral arterial
events. These therapies are also particularly important for reducing the risk of events at the time of intervention
(surgical or endovascular), when indicated, and for improving long-term survival.

An overview of atherosclerotic occlusive disease affecting the lower extremities is provided here. Disease affecting the
upper extremity is reviewed separately. (See "Overview of upper extremity peripheral artery disease".)

ANATOMY AND PATHOPHYSIOLOGY

The subintimal accumulation of lipid and fibrous material can narrow the vessel lumen, or the plaque can rupture,
causing embolism. Multiple factors contribute to the pathogenesis of atherosclerosis, including endothelial dysfunction,
dyslipidemia, inflammatory and immunologic factors, plaque rupture, and tobacco use. (See "Pathogenesis of
atherosclerosis".)

The symptoms related to atherosclerotic narrowing of the aorta or lower extremity arteries depend upon the location
and severity of disease. Atherosclerotic disease tends to be well localized and usually occurs in the proximal or
midportions of a given arterial bed. Atherosclerotic disease follows anatomic patterns, which also have a bearing on the
natural history and progression of disease. Patients with diabetes or with end-stage renal disease generally present with
more distal disease.

Atherosclerosis in the aorta can be associated with aneurysm. The pathology of aneurysmal disease is felt to be distinct
from that of atherosclerosis; however, the clinical manifestations may overlap. The clinical features of aneurysmal
disease are reviewed separately. (See "Clinical features and diagnosis of abdominal aortic aneurysm" and "Iliac artery
aneurysm" and "Popliteal artery aneurysm".)

EPIDEMIOLOGY AND RISK FACTORS

The overall prevalence of lower extremity PAD varies widely depending upon the population studied but is estimated to
be approximately 10 percent of adults older than 55 years [1]. Data from the 2010 United States census suggested that
the overall burden of PAD among adults in the United States is greater for women compared with men [2]. Well-defined
risk factors are associated with the development of PAD and include older age, hypertension, tobacco use, diabetes, and
hypercholesterolemia, among others [3-5]. (See "Epidemiology, risk factors, and natural history of peripheral artery
disease".)

CLINICAL PRESENTATIONS

The clinical manifestations of PAD (claudication, rest pain, ulceration, and gangrene) are predominantly due to
progressive luminal narrowing (stenosis/occlusion), although thrombosis or embolism of unstable atherosclerotic plaque
or thrombotic material can also occur. The natural history of those who present with mild-to-moderate claudication is
generally benign, which contrasts with the more aggressive presentation seen in those who present with ischemic rest
pain or ulceration. (See "Clinical features and diagnosis of lower extremity peripheral artery disease".)

Single-level disease (ie, aortoiliac, superficial femoral) often manifests initially as claudication. Multilevel disease can
manifest as claudication, when collateral circulation is adequate (figure 1), but often manifests as ischemic rest pain or
lower extremity ulceration when a well-developed collateral circulation is absent. Severe manifestations can occur
without an intervening history of claudication, particularly in older patients with diabetes or chronic kidney disease.

●Asymptomatic – Evidence of underlying atherosclerotic occlusive disease may be present in the absence of symptoms.
It is estimated that there are three times as many asymptomatic patients with lower extremity PAD as symptomatic
patients [6]. Although those with asymptomatic PAD may not report exertional leg discomfort by definition (ie,
claudication), lower extremity physiological function may be impaired compared with matched controls without PAD [7].
(See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Asymptomatic patients
screened for PAD'.)
Among asymptomatic patients, atherosclerotic disease of the iliac and femoral arteries is most prevalent [8]. Due to the
fact that PAD may predict risk for future cardiovascular events, screening for PAD in asymptomatic high-risk individuals
using the ankle-brachial index (ABI) [9-11] is advocated by some, but not all, expert groups [12-14]. In the Viborg
Vascular (VIVA) screening trial, 50,156 men aged 65 to 74 years were randomly assigned to screening versus no
screening for hypertension, PAD, and abdominal aortic aneurysm. After a median 4.4 years of follow-up, there was a
small, but significant, mortality benefit likely due to adoption of preventive strategies in the screened group [9]. (See
"Screening for lower extremity peripheral artery disease" and "Epidemiology, risk factors, and natural history of
peripheral artery disease", section on 'Anatomic patterns of disease'.)

●Claudication – Exertional pain in patients with lower extremity PAD is termed "claudication," which is derived from the
Latin word "claudico" (to limp). Claudication is a reproducible discomfort of a defined group of muscles that is induced
by exercise and relieved with rest. Claudication can present unilaterally or bilaterally, as buttock and hip, thigh, calf, or
foot pain, singly or in combination. The severity of symptoms depends upon the number and degree of arterial
narrowing, the collateral circulation, and the vigor of extremity use. (See "Clinical features and diagnosis of lower
extremity peripheral artery disease", section on 'Intermittent claudication and atypical lower extremity pain'.)

●Limb-threatening ischemia – Limb-threatening ischemia presents as ischemic pain, tissue loss, or both. The nature of
these manifestations depends upon the time course over which arterial narrowing or occlusion occurs; this in turn
affects the extent to which the collateral circulation can develop (figure 1). Acute reductions in limb perfusion, which
may be due to atheroembolism, cholesterol embolism, or thrombotic occlusion of a stenotic vessel, cause diffuse limb
pain [1]. Chronic severe reductions in limb perfusion present as ischemic rest pain, typically localized to the forefoot and
toes, or as tissue loss (nonhealing ulcer, gangrene).

DIAGNOSIS

In patients with an appropriate history and physical examination, the diagnosis of PAD is established with the
measurement of an ankle-brachial index (ABI) ≤0.9. The ABI is a comparison of the resting systolic blood pressure at the
ankle to the higher systolic brachial pressure (algorithm 1A-B). For patients with appropriate symptoms, but a normal
ABI, we obtain an ABI following exercise testing. (See "Noninvasive diagnosis of arterial disease", section on 'Ankle-
brachial index' and "Noninvasive diagnosis of arterial disease", section on 'Exercise testing'.)

Duplex ultrasonography is commonly used in conjunction with the ABI to identify the location and severity of arterial
obstruction [15]. Advanced vascular imaging (computed tomographic [CT] angiography, magnetic resonance [MR]
angiography, catheter-based arteriography) is usually reserved for patients in whom there remains uncertainty following
noninvasive testing, or in whom intervention is anticipated [16,17]. (See 'Revascularization' below.)
 CLASSIFICATION

Classification of lower extremity PAD, by grading symptoms and the anatomic lesions responsible for these symptoms,
provides an objective measure by which to follow patients clinically, and provides consistency when comparing medical
and interventional treatment strategies in clinical studies. The main classifications are listed below and reviewed in more
detail separately.

●Claudication is classified functionally by the initial and absolute walking distance and on the Society of Vascular Surgery
Rutherford scale graded from 1 to 3. (See "Classification of acute and chronic lower extremity ischemia", section on
'Rutherford'.)

●Atherosclerotic patterns of disease in the lower extremities are classified by TASC-II criteria according to their anatomic
distribution, multiplicity of lesions, and the nature of the lesion (stenosis or occlusion) [18]. (See "Classification of acute
and chronic lower extremity ischemia", section on 'TASC classification'.)

●The Society for Vascular Surgery (SVS) lower extremity threatened limb classification system, WIfI (Wound, Infection,
foot Infection), classifies the severity of limb threat in a manner that is intended to more accurately reflect important
clinical considerations that impact management and amputation risk (figure 2) [19]. (See "Classification of acute and
chronic lower extremity ischemia", section on 'WIfI (Wound, Ischemia, foot Infection)'.)

MANAGEMENT

The management of patients with lower extremity PAD is aimed at relieving symptoms and lowering the risk of
cardiovascular disease progression and complications. Patients with PAD exhibit a wide range of symptoms and
associated effects on daily function. The symptomatic treatment of lower extremity PAD is based on a careful
assessment of risk factors, medical comorbidities, compliance with pharmacologic treatments and follow-up care, and
the subjective values and goals of the patient. Patients with ischemic pain or ulceration may necessarily require early
intervention for limb salvage. (See 'Revascularization' below.)

Medical management involves cardiovascular risk factor reduction, lifestyle modification, and other pharmacologic
therapies to reduce the risk of atherosclerotic disease progression [6,20,21]. With aggressive medical management,
regression of noncalcified atherosclerotic lesions may be possible. Regular exercise and weight reduction are also
important. (See 'Risk factor modification' below and 'Claudication' below and 'Ischemic rest pain or tissue loss' below.)

Risk factor modification — PAD is regarded as a coronary heart disease risk equivalent. We agree with major
cardiovascular practice guidelines for the management of patients identified with PAD (asymptomatic or symptomatic)
that recommend secondary prevention measures to reduce the risk of future cardiovascular events and potentially limit
the progression of atherosclerosis [6,22-25]. Preventive strategies are appropriate for asymptomatic or symptomatic
patients with lower extremity PAD.
Preventive therapies include antiplatelet therapy, smoking cessation, lipid-lowering therapy, and treatment of diabetes
and hypertension. Prevention of cardiovascular disease events is reviewed separately. Some of these treatments can
also reduce the risk of periprocedural complications and also may improve symptoms or the patency of interventions.
Management of medications in the periprocedural period is reviewed separately. (See "Overview of the prevention of
cardiovascular disease events in those with established disease (secondary prevention) or at high risk" and
"Management of cardiac risk for noncardiac surgery" and 'Adjuncts to improve patency' below.)

Antithrombotic therapy — Based upon randomized trials showing a significantly reduced risk for future adverse
cardiovascular events, we agree with major cardiovascular consensus guidelines that recommend long-term antiplatelet
therapy (aspirin or clopidogrel) for patients identified with symptomatic lower extremity PAD [6,22,23]. For individuals
identified with PAD who are asymptomatic, treatment with aspirin is reasonable. We do not recommend dual
antiplatelet therapy in patients with PAD in the absence of other indications (eg, drug-eluting stent, prosthetic distal
lower extremity bypass) given the increased risk of bleeding in the absence of proven benefit. (See 'Asymptomatic PAD'
below and 'Adjuncts to improve patency' below.)

The effectiveness of antiplatelet therapy for the secondary prevention of adverse cardiovascular events (eg, myocardial
infarction [MI], stroke, vascular death) was demonstrated in the Antithrombotic Trialists' Collaboration [26-28]. (See
"Overview of the prevention of cardiovascular disease events in those with established disease (secondary prevention)
or at high risk" and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

Specifically among patients with PAD, in a meta-analysis that included 18 trials involving 5269 patients with PAD
(symptomatic and asymptomatic), aspirin therapy (alone or in combination with dipyridamole) was associated with a
nonsignificant reduction for the primary endpoint (composite endpoint of nonfatal MI, nonfatal stroke, and
cardiovascular death) but a significant reduction in the secondary outcome of nonfatal stroke (relative risk [RR] 0.66;
95% CI 0.47-0.94) [29]. There were no significant differences in other individual secondary outcomes (nonfatal MI, major
bleeding).

Other antiplatelet agents (clopidogrel, ticagrelor, vorapaxar) have been studied in the PAD patient population. Although
these may offer additional benefit, the excess risk of bleeding or other side effects provides the basis for our preference
for aspirin as a first-line agent [30-37].

●In the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, clopidogrel (75 mg/day) had a
modest, although significant, advantage over aspirin (325 mg/day) for reducing the risk for the combined outcome of
ischemic stroke, MI, or vascular death in 19,185 patients with a recent stroke, MI, or symptomatic PAD (relative risk
reduction 8.7 percent, 95% CI 0.3 to 16.5 percent) [38]. In a subgroup analysis, the benefit for clopidogrel over aspirin
was mainly driven by patients with PAD, for whom there was a 23.8 percent relative risk reduction (95% CI 8.9 to 36.2
percent).
●Some trials suggest that ticagrelor may provide additional benefit for preventing cardiovascular events [31-33]. Direct
comparisons between ticagrelor and clopidogrel in patients with symptomatic PAD have found no significant differences
[34, 36].

•In the PEGASUS-TIMI 54 trial, 21,162 patients with prior MI one to three years prior were randomly assigned to
ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo, all on a background of low-dose aspirin [31].
Among PAD patients with prior MI (1143 patients; 5 percent of the total), ticagrelor reduced the absolute rate of major
adverse cardiovascular event by 4.1 percent and significantly reduced the risk for peripheral revascularization (hazard
ratio [HR] 0.63, 95% CI 0.43-0.93). However, there was a 0.12 percent absolute excess of major bleeding.

•In the EUCLID trial, 13,885 patients with predominantly symptomatic PAD were randomly assigned to single-agent
therapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily) [35,36]. The rate of ischemic stroke was
significantly reduced for clopidogrel compared with ticagrelor (1.9 versus 2.4 percent; HR 0.78, 95% CI 0.62-0.98), but
there were no significant differences between the groups for the composite primary outcome (cardiovascular death, MI,
or ischemic stroke; 10.8 versus 10.6 percent) or other outcomes (death, MI, acute limb ischemia, the need for
revascularization, major bleeding). More patients receiving ticagrelor discontinued treatment due to dyspnea or minor
bleeding. In a subgroup analysis, patients enrolled based on prior revascularization had similar rates for the primary
composite outcome compared with those enrolled based upon ankle-brachial index values but significantly higher rates
of MI (HR 1.29, 95% CI 1.08-1.55) and acute limb ischemia (HR 4.23, 95% CI 2.86-6.25) [39].

●Vorapaxar is a novel antagonist of protease-activated receptor (PAR-1), which is located on platelets, vascular
endothelium, and smooth muscle and is the primary receptor for thrombin on human platelets [40]. In the Trial to
Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis in
Myocardial Infarction 50 (TRA2°P-TIMI 50), among patients with symptomatic lower extremity PAD, vorapaxar reduced
the rate of first acute limb ischemia events, particularly among those who had undergone revascularization [41-44]. (See
"Surgical management of claudication", section on 'Antithrombotic therapy' and "Percutaneous interventional
procedures in the patient with lower extremity claudication", section on 'Antiplatelet therapy' and 'Adjuncts to improve
patency' below.)

No benefit over aspirin has been established for anticoagulation for reducing mortality in those with PAD. A systematic
review that identified nine small trials involving 4889 patients noted no significant difference in mortality for
anticoagulation versus control or versus aspirin following lower extremity bypass procedures, and the rate of major
bleeding events was increased [45]. Similarly, in the later Warfarin and Antiplatelet Vascular Evaluation (WAVE) trial, a
combination of warfarin (target international normalized ratio [INR] 2 to 3) plus antiplatelet therapy was not more
effective compared with aspirin alone for preventing cardiovascular morbidity in patients with PAD [46].

Recent data suggest the benefit of combined antithrombotic therapy in PAD [47-49]. A multicenter trial (COMPASS)
randomly assigned over 27,000 patients with stable coronary or peripheral artery disease to a low dose of rivaroxaban
(2.5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban (5 mg twice daily) plus placebo, or aspirin (100 mg
once a day) plus placebo [47]. At a mean follow-up of 23 months, rivaroxaban plus aspirin significantly reduced
cardiovascular mortality and ischemic stroke compared with aspirin alone. In a prespecified subgroup analysis among
7470 subjects with PAD, rivaroxaban plus aspirin reduced the composite endpoint of cardiovascular death, myocardial
infarction, or stroke compared with aspirin alone (5 versus 7 percent; HR 0.72, 95% CI 0.57-0.90), and major adverse
limb events (1 versus 2 percent; HR 0.54, 95% CI 0.35-0.82) [48]. Rivaroxaban alone compared with aspirin alone did not
significantly reduce the composite endpoint, but there was a trend toward reduced major adverse limb events.
Rivaroxaban increased the risk of major bleeding (3 versus 2 percent) whether used alone or in combination. A direct
comparison between low-dose rivaroxaban and clopidogrel would be useful before rivaroxaban could be considered an
alternative to clopidogrel, which has previously shown in the CAPRIE trial to have provided an additional benefit over
aspirin alone in reducing adverse limb events. An essential question is whether the observed improvements in limb
outcomes outweigh the risk of bleeding, and if so, for which PAD patients.

The role of oral anticoagulation for preventing graft thrombosis is discussed below. (See 'Adjuncts to improve patency'
below.)

Smoking cessation — numerous epidemiological and observational studies show that smoking cessation reduces adverse
cardiovascular events and the risk for limb loss in patients with PAD, but smoking cessation may be difficult to
accomplish. We agree with consensus guidelines that recommend smoking cessation for all patients with PAD. The
patient should be assessed for willingness to quit smoking and assisted in finding resources (eg, behavioral modification)
to help with this goal. Follow-up for smoking cessation therapy should also be arranged. Nicotine replacement therapy
and use of other pharmacologic adjuncts (varenicline or bupropion) should be considered. Nicotine replacement therapy
does not appear to be associated with any increase in adverse cardiovascular events. (See "Cardiovascular risk of
smoking and benefits of smoking cessation" and "Overview of smoking cessation management in adults" and
"Cardiovascular effects of nicotine".)

Lipid-lowering therapy — Lipid-lowering therapy with at least a moderate dose of a statin, irrespective of the baseline
LDL cholesterol, is recommended for all patients with atherosclerotic cardiovascular disease. The evidence for benefit
and the appropriate goals for cholesterol lowering in patients with all forms of cardiovascular disease are discussed in
more detail elsewhere. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of
cardiovascular disease".)

Examples of outcomes with the use of statin therapy among patients with PAD include the following [50-52]:

●In the Heart Protection Study, among 6748 patients who had PAD, there was a 22 percent relative risk reduction in the
first major vascular event for those randomized to simvastatin (40 mg) compared with placebo [50]. The absolute
reduction in first major vascular event was 63 (standard error [SE] 11) per 1000 patients with PAD and 50 (SE 7) per 1000
without preexisting PAD.

●In a five-year prospective study, patients undergoing major lower extremity amputations and who were on medium-
intensity and high-intensity statin therapy had improved survival at one year compared with those who were not on
similar statin therapy [51].

●The effect of statin therapy in patients with chronic limb-threatening ischemia was evaluated in a retrospective study
of 931 patients (1019 affected limbs) who underwent first-time revascularization (endovascular or surgical) over a nine-
year period (2005 to 2014) [52]. Discharge on the recommended intensity of statin therapy was associated with lower
mortality (HR 0.73; 95% CI 0.60-0.99) and lower major adverse limb event rate (HR 0.71; 95% CI 0.51-0.97) over a
median follow-up of 380 days.

●The effect of PCSK9 inhibition with evolocumab was evaluated in 3642 patients with PAD from the FOURIER trial [53].
The primary composite endpoint (cardiovascular death, myocardial infarction, stroke, hospital admission for unstable
angina, coronary revascularization) was significantly reduced for those with PAD randomized to evolocumab compared
with placebo (HR 0.79; 95% CI 0.66-0.94). Evolocumab also reduced the risk of major adverse limb events in all patients
(HR 0.58; 95% CI 0.38-0.88) with consistent effects among those with and without known PAD.

Glycemic control — although it is unknown whether aggressive serum glucose control decreases the likelihood of
adverse cardiovascular events in patients with lower extremity PAD, treatment of diabetes can be effective for reducing
complications. We agree with recommendations for control of blood glucose levels with an A1C goal of <7.0 percent.
Less stringent goals may be appropriate for some patients (eg, older patients and those with comorbid conditions). (See
"Glycemic control and vascular complications in type 1 diabetes mellitus", section on 'Summary and recommendations'
and "Glycemic control and vascular complications in type 2 diabetes mellitus".)

Antihypertensive therapy — Hypertension is a major risk factor for PAD. However, there are no data evaluating whether
antihypertensive therapy alters the progression of PAD. Nevertheless, hypertension should be controlled to reduce
morbidity from cardiovascular and cerebrovascular disease [18]. Goals for blood pressure lowering therapy and choice
of antihypertensive therapy are discussed in detail separately. In the Heart Outcomes Prevention Evaluation (HOPE)
study, ramipril (10 mg per day) significantly reduced the rates of death, MI, and stroke in a broad range of patients,
including those with asymptomatic or symptomatic PAD [54]. In a follow-up study looking at the PAD patients, the
relative benefit of ramipril was similar in patients subdivided by levels of ABI [55]. Given that event rates were higher in
those with an ABI <0.9, the absolute benefits are approximately twice as large in this group (50 per 1000 events
prevented) compared with those with an ABI >0.9 (24 per 1000 events prevented). (See "Management of claudication
due to peripheral artery disease", section on 'Cardiovascular risk modification' and "Goal blood pressure in adults with
hypertension".)

Diet and exercise — Healthy diets are associated with lower cardiovascular disease events. Guidelines from the
American Heart Association/American College of Cardiology (AHA/ACC) and European Society of Cardiology (ESC) on
lifestyle management are discussed separately. (See "Overview of the prevention of cardiovascular disease events in
those with established disease (secondary prevention) or at high risk", section on 'Diet'.)

Asymptomatic PAD — Although those with asymptomatic PAD (defined as an abnormal ABI) may not report exertional
pain, lower extremity function may nonetheless be impaired as evidenced by slow walking speed or poor balance.
Whether those with asymptomatic PAD should undergo repeat ABI testing and with what frequency has not been
established, but repeat testing may be useful in higher-risk patients. It is also important to note that some asymptomatic
PAD patients, particularly those with diabetes, can develop limb-threatening ischemia without an antecedent history of
claudication.

It is unknown if specific therapies, in addition to risk factor modification, can improve functional abilities or quality of
life. As an example, it is unclear if antiplatelet therapy is beneficial for these patients. In trials of patients with
asymptomatic PAD, aspirin compared with placebo did not significantly reduce the incidence of cardiovascular events
[56-58]. Nevertheless, given the systemic nature of atherosclerotic disease, it is reasonable to treat patients with PAD
who do not exhibit symptoms. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

Claudication — The initial treatment for exertional pain (ie, claudication) is a supervised exercise program (algorithm 2)
[59,60]. Patients must be screened for sufficient cardiopulmonary reserve and other medical comorbidities for their
ability to tolerate an exercise program. The addition of the phosphodiesterase inhibitor, cilostazol, may also improve
symptoms. Statin therapy may also improve pain-free walking time in patients with claudication, but the evidence for
this is conflicting. There is no evidence that beta blocker therapy for treatment of high blood pressure worsens
claudication. (See "Management of claudication due to peripheral artery disease".)

Without treatment, the natural history of claudication is a slow progressive decline in the distance the individual is able
to walk before the onset of pain. However, with intensive medical management (risk factor reduction, exercise therapy,
pharmacologic therapy), among patients with claudication and no diabetes or renal dysfunction, less than 5 percent will
develop any signs of limb-threatening ischemia, and the risk of major amputation is exceedingly low (<1 percent per
year). The risk for other adverse cardiovascular events (eg, stroke, heart attack) is greater than the risk for adverse limb
outcomes [61-63].

Symptoms should be reevaluated after conservative treatments (risk factor reduction, exercise therapy, pharmacologic
therapy) have been instituted and allowed to have an effect. If claudication symptoms persist and the patient has been
responsive to adjusting his/her lifestyle, the patient may be a candidate for an endovascular or open intervention
depending on the location and severity of lesions and medical risk. Some patients with severe symptoms, particularly
those with more proximal disease (aortoiliac) may benefit more from earlier, rather than later, intervention [64]. (See
'Revascularization' below.)

Patients with symptomatic PAD are at risk for developing new or recurrent lesions in the same or other vascular beds,
which underscores the need for ongoing follow-up.

Ischemic rest pain or tissue loss — once a patient develops ischemic rest pain or tissue loss, the natural history often
involves an inexorable progression to amputation unless there is some form of intervention to improve arterial
perfusion. (See 'Revascularization' below.)

In the interim prior to intervention, and for those who are not candidates for intervention, it is appropriate to
aggressively manage the patient's pain. (See "Overview of the treatment of chronic non-cancer pain".)

Many patients are poor candidates for any type of revascularization procedure (endovascular, surgical) because of
concomitant diseases or unfavorable anatomy. Medical therapies would be desirable in such patients. Therapies that
have been investigated include prostaglandins, therapeutic angiogenesis, stem cell therapy, and spinal cord stimulation;
however, none of these are recommended. (See "Investigational therapies for treating symptoms of lower extremity
peripheral artery disease".)

The presence of ischemic ulcers/gangrene influences the timing of debridement, revascularization, and definitive
coverage/closure. (See "Basic principles of wound management" and "Overview of treatment of chronic wounds".)

In general:
●For patients with wet gangrene or abscess, the wound should be debrided or drained immediately regardless of the
anticipated need for revascularization. The dressing choice depends upon the level of anticipated drainage and the size
of the wound. Dead space is usually managed with gauze packing. The extremity should be revascularized as soon as
safely possible, if needed, after drainage/debridement and control of the infection.

●For patients with dry gangrene without cellulitis, the limb should be revascularized first. The wound dressing is
protective, reducing the risk for trauma or infection. The wound should be lightly wrapped with a bulky dry gauze
bandage, avoiding excess pressure that could aggravate ischemia. Following revascularization, the wound should be
monitored closely for signs of healing, or for tissue necrosis/drainage that may indicate a need for further debridement.

REVASCULARIZATION

Indications

●For those with significant or disabling symptoms unresponsive to lifestyle adjustment and pharmacologic therapy,
intervention (percutaneous, surgical) may be reasonable. In the absence of limb-threatening ischemia, symptoms of PAD
tend to remain stable with medical therapy. Performing prophylactic intervention, whether percutaneous or surgical, in
patients with minimal claudication provides little benefit, may cause harm, and is not indicated. (See "Management of
claudication due to peripheral artery disease".)

●For patients with limb-threatening ischemia (eg, rest pain, ulceration), revascularization is a priority to establish arterial
blood flow [18]. Some patients with acute thrombosis superimposed on chronic stenosis or occlusion may benefit from
thrombolytic therapy. The role of thrombolytic therapy in such patients is discussed separately. (See "Treatment of
chronic limb-threatening ischemia".)

Once the decision has been made for interventional treatment, the patient should undergo vascular imaging to
determine the arterial anatomy and extent of disease, and comprehensive medical assessment.

For patients over 65 years of age, comprehensive geriatric assessment may improve outcomes following elective lower
extremity bypass. In a trial that included 176 patients undergoing lower extremity bypass surgery or abdominal aortic
aneurysm (AAA) repair, length of stay was reduced for those randomly assigned to comprehensive geriatric assessment
and optimization versus standard preoperative assessment (3.32 versus 5.53 days) [65]. Although the outcomes were
not stratified by the type of surgery, the major benefit shown is more likely to have occurred in the bypass group. The
comprehensive assessment increased the number of new diagnoses (eg, pulmonary disease, chronic kidney disease,
cognitive impairment) and influenced the number of patients who did not undergo surgery. There was a lower incidence
of complications, including cardiac complications (8 versus 27 percent), bladder/bowel complications (33 versus 55
percent), and delirium (11 versus 24 percent). Patients in the comprehensive assessment group were also less likely to
require discharge to a higher level of dependency. This trial underscores the need to accurately assess medical risk prior
to undertaking elective vascular surgery in older adults.

Choice of intervention — Among those with appropriate indications for intervention, determining whether
percutaneous or surgical revascularization is the more appropriate initial treatment depends upon a myriad of factors,
including location and extent of disease, patient's comorbidities and risk for the intervention, and patient preference.

Endovascular interventions have a lower periprocedural risk in the short term, but durability has not been comparable
to surgical revascularization. For patients with claudication, the Society for Vascular Surgery suggests that a minimal
effectiveness threshold for invasive therapy should be a >50 percent likelihood of sustained clinical improvement for at
least two years [6]. Freedom from hemodynamically significant restenosis in the treated limb is considered a
prerequisite for this goal. The majority of patients presenting with limb-threatening ischemia can be offered a
reasonable attempt at limb salvage. Freedom from pain or sustained healing of areas of tissue loss may be acceptable
goals even in the absence of sustained patency of the treated lesion, particularly among patients who are poor
candidates for surgical revascularization. Overall, only approximately 25 percent of patients with critical limb ischemia
require amputation within one year. However, for some patients, primary amputation may be the best course of
therapy.

Given the widespread availability of percutaneous procedures, major cardiovascular society guidelines recommend
initial percutaneous revascularization. Surgery is reserved for those with arterial anatomy for which a percutaneous
approach is not likely to provide a durable clinical success, provided the patient has an acceptable risk for surgery [1,15-
17]. Lesions that display unfavorable anatomy for a percutaneous approach have one or more of the following features,
which reflect more extensive disease and are typically associated with more severe symptoms:

●Long-segment stenosis

●Multifocal stenoses

●Eccentric, calcified stenosis

●Long segment occlusions

The issues regarding the choice of intervention differ depending upon clinical manifestations, goals of care, and the
affected vascular bed.
Perioperative medication management — Following percutaneous or surgical intervention, we generally maintain
patients on prescribed antiplatelet therapies.

Whether to continue or discontinue antiplatelet agents prior to vascular surgical intervention is controversial [66,67].
Few studies have focused specifically on vascular surgery patients who should be taking aspirin (or clopidogrel) as a
recommended strategy for long-term cardiovascular risk reduction. (See 'Antithrombotic therapy' above.)

In the PeriOperative ISchemic Evaluation 2 (POISE-2) trial, perioperative aspirin use increased the risk of bleeding but
had no effect on perioperative (30 day) mortality. Whether these results apply to vascular surgery patients was
addressed in a subgroup analysis of POISE-2 that included 603 patients [68]. Among these were 272 patients undergoing
surgery for peripheral occlusive disease. Excluded from the POISE-2 trial were patients with carotid occlusive disease and
patients with bare metal coronary stents placed fewer than six weeks before the surgery or drug-eluting coronary stents
less than one year before surgery. As with the overall results, there was no significant difference for the primary
outcome (composite of death or myocardial infarction at 30 days) for those allocated to aspirin compared with placebo
(15.8 versus 13.6 percent; hazard ratio [HR] 1.16, 95% CI 0.62-2.17). Perioperative withdrawal of chronic aspirin therapy
did not appear to increase vascular occlusive complications. However, while there was an increased risk of major or life-
threatening bleeding, the difference was not statistically significant among vascular surgery patients taking aspirin. The
results of this study (positive and negative) need to be viewed with caution as the number of events was small and the
subgroup analysis was underpowered.

Adjuncts to improve patency — Definitive data to support the use of antithrombotic therapy (antiplatelet therapy,
anticoagulation) to improve the patency of lower extremity revascularization are overall lacking.

Antiplatelet therapy may benefit those undergoing prosthetic bypass, and although anticoagulation with vitamin K
antagonists is not routinely used following surgical revascularization, it may be useful in the following situations:
following vein bypass for those with either a suboptimal conduit or compromised distal runoff, or following prosthetic
graft bypass to reduce the ischemic consequences of graft thrombosis. (See "Surgical management of claudication" and
"Percutaneous interventional procedures in the patient with lower extremity claudication".)

Whether the addition of another antiplatelet agent to aspirin (ie, dual antiplatelet therapy) offers any additional benefit
for those who have undergone lower extremity percutaneous revascularization remains debated. (See "Percutaneous
interventional procedures in the patient with lower extremity claudication", section on 'Antiplatelet therapy'.)

A new protease-activated receptor (PAR-1) antagonist, vorapaxar, may offer benefit, but further studies are needed to
identify its role following revascularization. In the Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and
Stroke in Patients With Atherosclerosis-Thrombolysis in Myocardial Infarction 50 (TRA2°P-TIMI 50) trial discussed above,
3787 patients with symptomatic lower extremity PAD were included [42,43]. In a follow-up analysis [44], vorapaxar
significantly reduced the risk of first acute limb ischemia (ALI) event compared with placebo (HR 0.58; 95% CI 0.39-0.86)
and also significantly reduced total ALI events (94 versus 56 events). The majority of first and recurrent ALI events
occurred in those with symptomatic PAD. The causes of the 150 critical limb ischemia events in the PAD group were
surgical graft thrombosis in 93 (62 percent), native vessel in-situ thromboses in 37 (25 percent), stent thromboses in 14
(9 percent), and thromboembolism in 6 (4 percent). (See "Surgical management of claudication", section on
'Antithrombotic therapy' and "Treatment of chronic limb-threatening ischemia", section on 'Antithrombotic therapy'.)

Outcome measures — Outcomes of revascularization may be measured anatomically, hemodynamically, and

The Society for Vascular Surgery (SVS) has adopted objective performance goals to assess cross-platform interventions in
a patient-centric manner [69,70].

●Major adverse cardiovascular events (MACE)

●30-day major adverse limb events (MALE)

●30-day amputation rate

●Amputation-free survival

●Freedom from MALE

Anatomically, the patency of the intervention, as defined by the SVS reporting standards, allows one to assess the time
to primary failure (ie, occlusion or need for intervention) and the time to final failure after multiple interventions and
revisions.

●Primary patency – Refers to patency that is obtained without the need for an additional or secondary surgical or
endovascular procedure.

●Assisted primary patency – Refers to patency achieved with the use of an additional or secondary endovascular
procedure as long as occlusion of the primary treated site has not occurred.

●Secondary patency – Refers to patency obtained with the use of an additional or secondary surgical procedure once
occlusion occurs.
Hemodynamic success is defined as an increase in ankle brachial index (ABI) of 0.15. Immediate and long-term
hemodynamic success (ABI >0.15) after percutaneous procedures is directly related to tibial runoff [71]. Most studies
have shown an appropriate increase in ABI after intervention. The magnitude of change may or may not correlate with
symptomatic improvement.

Postprocedure surveillance — Following vascular interventions, angioplasty sites, stents, and vascular bypass grafts are
carefully monitored using duplex ultrasonography. The surveillance schedule depends on the nature of the intervention.
At a minimum, patients should be evaluated twice a year for any new symptoms. The main complications are graft or
stent thrombosis, vein graft stenosis, in-stent stenosis, and new native vessel stenotic lesions. There are three major
time periods for failure after intervention.

●Failure in the immediate or early postoperative period (<30 days) is most often due to technical complications or
judgmental error. Other causes include inadequate outflow, infection, and an unrecognized hypercoagulable state.

●Failure between 30 days and two years is most often the result of myointimal hyperplasia within the endovascular
treated areas, within the vein graft or at anastomotic sites.

●Late endovascular and late graft failure is usually due to the natural progression of atherosclerotic disease.

OUTCOMES

The overall prognosis of the patient with PAD depends on the specific risk factors for PAD, the specific vascular beds that
are more predominantly affected, and the presence of coronary heart disease and other comorbidities [62,72,73].

●Claudication – Estimates for limb and cardiovascular outcomes at five years in patients with claudication are as follows
[20]:

•For limb morbidity – Stable claudication in 70 to 80 percent, worsening claudication in 10 to 20 percent, and limb-
threatening ischemia (ie, critical limb ischemia) in 1 to 2 percent.

•For cardiovascular morbidity and mortality – Nonfatal myocardial infarction or stroke in 20 percent, and death in 15 to
30 percent (three quarters due to cardiovascular causes); an association between cardiovascular disease and PAD has
been noted in multiple studies [62,74]. The importance of PAD as a marker for coexistent coronary artery disease cannot
be understated.

●Limb-threatening critical ischemia – Among the 1 to 2 percent of patients who develop critical limb ischemia, outcomes
have improved over time, related to improved medical management [75,76], and possibly the more liberal use of
endovascular intervention [77]. Even among those without a revascularization option, amputation-free survival has
improved [78]. Overall (all comers), at one year, 45 percent of patients will be alive with both limbs, 30 percent will have
undergone amputation, and 25 percent will have died. At five years, more than 60 percent of patients with critical limb
ischemia will have died. For patients with nonreconstructible disease at one year, approximately 55 percent will be alive
without amputation (range 40 to 69 percent); 20 percent of patients will have died (range: 12 to 32 percent), and 34
percent will have undergone major amputation (range: 25 to 45 percent) [78].

These general estimates do not apply equally to all patients. Atherosclerotic vascular disease tends to be more
aggressive in patients with diabetes and lower extremity PAD with amputation rates that are five to 10 times higher
compared with nondiabetic patients with PAD. Sensory neuropathy and increased susceptibility to infection contribute
to the increased amputation rate. The prognosis for both limb loss and survival is significantly worse in patients with
diabetes and end-stage renal disease, and those who continue to smoke [79]. (See "Overview of peripheral artery
disease in patients with diabetes mellitus" and "Lower extremity peripheral artery disease in patients with chronic
kidney disease", section on 'Introduction'.)

SUMMARY AND RECOMMENDATIONS

●Peripheral artery disease (PAD) is growing as a clinical problem due to the aging population in the United States and
other developed countries. Risk factors for PAD are similar to those that promote the development of coronary
atherosclerosis (ie, smoking, hypertension, hyperlipidemia, diabetes, and metabolic syndrome). The natural history of
PAD in patients who present initially as asymptomatic or with mild-to-moderate exertional pain (claudication) is
relatively benign, which contrasts with the more rapid deterioration often seen in those who initially present with
ischemic rest pain or extremity ulceration. (See 'Clinical presentations' above.)

●Noninvasive vascular testing is an extension of the vascular history and physical examination and is used to confirm a
diagnosis of arterial disease and determine the level and extent of disease. (See 'Diagnosis' above.)

●The management of patients with PAD is aimed at lowering the risk of cardiovascular disease progression and
complications and improving symptoms. We recommend initiation of cardiovascular risk reduction strategies for all
patients identified with PAD to reduce the risk of future cardiovascular events and to potentially limit the progression of
atherosclerosis. This includes patients identified on screening studies to have PAD but who remain asymptomatic. As
with other patients with cardiovascular disease, for patients with PAD, we recommend long-term antithrombotic
therapy with aspirin or clopidogrel (Grade 1A). Smoking cessation, lipid-lowering therapy, and treatment of diabetes and
hypertension are also recommended. (See 'Risk factor modification' above and "Overview of the prevention of
cardiovascular disease events in those with established disease (secondary prevention) or at high risk", section on
'Summary and recommendations' and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

●For most patients with lower extremity PAD, in addition to cardiovascular risk reduction strategies, we recommend
exercise therapy (for those who can participate), and possibly pharmacologic therapy, rather than initial vascular
intervention (Grade 1B). For patients who can participate in exercise therapy, we suggest supervised rather than
unsupervised exercise therapy, where available (Grade 2B). For patients who have been compliant with risk reduction
strategies, yet six months to one year of exercise therapy and adjunctive pharmacotherapy have failed to provide
satisfactory improvement, referral for possible revascularization is appropriate. (See 'Management' above and
'Revascularization' above and "Management of claudication due to peripheral artery disease", section on 'Exercise
therapy'.)

●For patients with limb-threatening critical ischemia (ischemic rest pain or ulceration), where the limb is at risk of
amputation, revascularization is a priority to restore perfusion and limit tissue loss. Some patients with acute thrombosis
superimposed on chronic stenosis or occlusion may benefit from thrombolytic therapy. The role of thrombolytic therapy
in such patients is discussed separately.

●Among patients with indications for revascularization, options include percutaneous intervention, surgical bypass, or a
combination of these. The choice depends upon the level of obstruction (aortoiliac, femoropopliteal), severity of
disease, the patient's risk for the intervention, and the goals for care. For patients with lesions that have anatomic
features associated with durable clinical success with a percutaneous approach (single, short segment, uniform), we
agree with guidelines that suggest an initial attempt at percutaneous revascularization rather than initial surgical
revascularization.

REFERENCES

1. Pande RL, Perlstein TS, Beckman JA, Creager MA. Secondary prevention and mortality in peripheral artery
disease: National Health and Nutrition Examination Study, 1999 to 2004. Circulation 2011; 124:17.

2. Hirsch AT, Allison MA, Gomes AS, et al. A call to action: women and peripheral artery disease: a scientific
statement from the American Heart Association. Circulation 2012; 125:1449.

3. Gallino A, Aboyans V, Diehm C, et al. Non-coronary atherosclerosis. Eur Heart J 2014; 35:1112.
4. Berger JS, Hochman J, Lobach I, et al. Modifiable risk factor burden and the prevalence of peripheral artery
disease in different vascular territories. J Vasc Surg 2013; 58:673.

5. Joosten MM, Pai JK, Bertoia ML, et al. Associations between conventional cardiovascular risk factors and risk of
peripheral artery disease in men. JAMA 2012; 308:1660.

6. Society for Vascular Surgery Lower Extremity Guidelines Writing Group, Conte MS, Pomposelli FB, et al. Society
for Vascular Surgery practice guidelines for atherosclerotic occlusive disease of the lower extremities:
management of asymptomatic disease and claudication. J Vasc Surg 2015; 61:2S.

7. McDermott MM, Fried L, Simonsick E, et al. Asymptomatic peripheral arterial disease is independently
associated with impaired lower extremity functioning: the women's health and aging study. Circulation 2000;
101:1007.

8. Fernández-Friera L, Peñalvo JL, Fernández-Ortiz A, et al. Prevalence, Vascular Distribution, and Multiterritorial
Extent of Subclinical Atherosclerosis in a Middle-Aged Cohort: The PESA (Progression of Early Subclinical
Atherosclerosis) Study. Circulation 2015; 131:2104.

9. Lindholt JS, Søgaard R. Population screening and intervention for vascular disease in Danish men (VIVA): a
randomised controlled trial. Lancet 2017; 390:2256.

10. Guirguis-Blake JM, Evans CV, Redmond N, Lin JS. Screening for Peripheral Artery Disease Using the Ankle-
Brachial Index: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.
JAMA 2018; 320:184.

11. McDermott MM, Criqui MH. Ankle-Brachial Index Screening and Improving Peripheral Artery Disease Detection
and Outcomes. JAMA 2018; 320:143.

12. Alahdab F, Wang AT, Elraiyah TA, et al. A systematic review for the screening for peripheral arterial disease in
asymptomatic patients. J Vasc Surg 2015; 61:42S.

13. Golomb BA, Dang TT, Criqui MH. Peripheral arterial disease: morbidity and mortality implications. Circulation
2006; 114:688.

14. Mohty D, Magne J, Deltreuil M, et al. Outcome and impact of surgery in paradoxical low-flow, low-gradient
severe aortic stenosis and preserved left ventricular ejection fraction: a cardiac catheterization study. Circulation
2013; 128:S235.

15. Koelemay MJ, den Hartog D, Prins MH, et al. Diagnosis of arterial disease of the lower extremities with duplex
ultrasonography. Br J Surg 1996; 83:404.
16. Romano M, Mainenti PP, Imbriaco M, et al. Multidetector row CT angiography of the abdominal aorta and lower
extremities in patients with peripheral arterial occlusive disease: diagnostic accuracy and interobserver
agreement. Eur J Radiol 2004; 50:303.

17. Menke J, Larsen J. Meta-analysis: Accuracy of contrast-enhanced magnetic resonance angiography for assessing
steno-occlusions in peripheral arterial disease. Ann Intern Med 2010; 153:325.

18. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus for the Management of Peripheral Arterial
Disease (TASC II). J Vasc Surg 2007; 45 Suppl S:S5.

19. Mills JL Sr, Conte MS, Armstrong DG, et al. The Society for Vascular Surgery Lower Extremity Threatened Limb
Classification System: risk stratification based on wound, ischemia, and foot infection (WIfI). J Vasc Surg 2014;
59:220.

20. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 Practice Guidelines for the management of patients with
peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report
from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular
Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology,
and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the
Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of
Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular
Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006; 113:e463.

21. Rooke TW, Hirsch AT, Misra S, et al. 2011 ACCF/AHA focused update of the guideline for the management of
patients with peripheral artery disease (updating the 2005 guideline): a report of the American College of
Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in
collaboration with the Society for Cardiovascular Angiography and Interventions, Society of Interventional
Radiology, Society for Vascular Medicine, and Society for Vascular Surgery. J Vasc Surg 2011; 54:e32.

22. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC Guideline on the Management of Patients With
Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart
Association Task Force on Clinical Practice Guidelines. Circulation 2017; 135:e726.

23. Alonso-Coello P, Bellmunt S, McGorrian C, et al. Antithrombotic therapy in peripheral artery disease:
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-
Based Clinical Practice Guidelines. Chest 2012; 141:e669S.

24. European Stroke Organisation, Tendera M, Aboyans V, et al. ESC Guidelines on the diagnosis and treatment of
peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral,
 mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of
Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J 2011; 32:2851.

25. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular
risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice
Guidelines. Circulation 2014; 129:S76.

26. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy
for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324:71.

27. Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial
infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists'
Collaboration. BMJ 1994; 308:81.

28. Antithrombotic Trialists' (ATT) Collaboration, Baigent C, Blackwell L, et al. Aspirin in the primary and secondary
prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
Lancet 2009; 373:1849.

29. Berger JS, Krantz MJ, Kittelson JM, Hiatt WR. Aspirin for the prevention of cardiovascular events in patients with
peripheral artery disease: a meta-analysis of randomized trials. JAMA 2009; 301:1909.

30. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of
atherothrombotic events. N Engl J Med 2006; 354:1706.

31. Bonaca MP, Bhatt DL, Storey RF, et al. Ticagrelor for Prevention of Ischemic Events After Myocardial Infarction in
Patients With Peripheral Artery Disease. J Am Coll Cardiol 2016; 67:2719.

32. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N
Engl J Med 2009; 361:1045.

33. Bonaca MP, Braunwald E, Sabatine MS. Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction.
N Engl J Med 2015; 373:1274.

34. Patel MR, Becker RC, Wojdyla DM, et al. Cardiovascular events in acute coronary syndrome patients with
peripheral arterial disease treated with ticagrelor compared with clopidogrel: Data from the PLATO Trial. Eur J
Prev Cardiol 2015; 22:734.

35. Hiatt WR, Fowkes FG, Heizer G, et al. Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease. N
Engl J Med 2017; 376:32.

36. Berger JS, Katona BG, Jones WS, et al. Design and rationale for the Effects of Ticagrelor and Clopidogrel in
Patients with Peripheral Artery Disease (EUCLID) trial. Am Heart J 2016; 175:86.
37. Cacoub PP, Bhatt DL, Steg PG, et al. Patients with peripheral arterial disease in the CHARISMA trial. Eur Heart J
2009; 30:192.

38. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of
ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996; 348:1329.

39. Jones WS, Baumgartner I, Hiatt WR, et al. Ticagrelor Compared With Clopidogrel in Patients With Prior Lower
Extremity Revascularization for Peripheral Artery Disease. Circulation 2017; 135:241.

40. Vorapaxar. Am J Cardiovasc Drugs 2010; 10:413.

41. Bonaca MP, Creager MA, Olin J, et al. Peripheral Revascularization in Patients With  Peripheral Artery Disease
With Vorapaxar: Insights From the TRA 2°P-TIMI 50 Trial. JACC Cardiovasc Interv 2016; 9:2157.

42. Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the secondary prevention of atherothrombotic events.
N Engl J Med 2012; 366:1404.

43. Bonaca MP, Scirica BM, Creager MA, et al. Vorapaxar in patients with peripheral artery disease: results from
TRA2{degrees}P-TIMI 50. Circulation 2013; 127:1522.

44. Bonaca MP, Gutierrez JA, Creager MA, et al. Acute Limb Ischemia and Outcomes With Vorapaxar in Patients
With Peripheral Artery Disease: Results From the Trial to Assess the Effects of Vorapaxar in Preventing Heart
Attack and Stroke in Patients With Atherosclerosis-Thrombolysis in Myocardial Infarction 50 (TRA2°P-TIMI 50).
Circulation 2016; 133:997.

45. WAVE Investigators. The effects of oral anticoagulants in patients with peripheral arterial disease: rationale,
design, and baseline characteristics of the Warfarin and Antiplatelet Vascular Evaluation (WAVE) trial, including a
meta-analysis of trials. Am Heart J 2006; 151:1.

46. Warfarin Antiplatelet Vascular Evaluation Trial Investigators, Anand S, Yusuf S, et al. Oral anticoagulant and
antiplatelet therapy and peripheral arterial disease. N Engl J Med 2007; 357:217.

47. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease.
N Engl J Med 2017; 377:1319.

48. Anand SS, Bosch J, Eikelboom JW, et al. Rivaroxaban with or without aspirin in patients with stable peripheral or
carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018;
391:219.

49. Anand SS, Caron F, Eikelboom JW, et al. Major Adverse Limb Events and Mortality in Patients With Peripheral
Artery Disease: The COMPASS Trial. J Am Coll Cardiol 2018; 71:2306.
50. Heart Protection Study Collaborative Group. Randomized trial of the effects of cholesterol-lowering with
simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial
disease and other high-risk conditions. J Vasc Surg 2007; 45:645.

51. DeCarlo C, Scher L, Shariff S, et al. Statin use and other factors associated with mortality after major lower
extremity amputation. J Vasc Surg 2017; 66:216.

52. O'Donnell TFX, Deery SE, Darling JD, et al. Adherence to lipid management guidelines is associated with lower
mortality and major adverse limb events in patients undergoing revascularization for chronic limb-threatening
ischemia. J Vasc Surg 2017; 66:572.

53. Bonaca MP, Nault P, Giugliano RP, et al. Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and
Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular
Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation 2018; 137:338.

54. Heart Outcomes Prevention Evaluation Study Investigators, Yusuf S, Sleight P, et al. Effects of an angiotensin-
converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;
342:145.

55. Ostergren J, Sleight P, Dagenais G, et al. Impact of ramipril in patients with evidence of clinical or subclinical
peripheral arterial disease. Eur Heart J 2004; 25:17.

56. Fowkes FG, Price JF, Stewart MC, et al. Aspirin for prevention of cardiovascular events in a general population
screened for a low ankle brachial index: a randomized controlled trial. JAMA 2010; 303:841.

57. Critical Leg Ischaemia Prevention Study (CLIPS) Group, Catalano M, Born G, Peto R. Prevention of serious
vascular events by aspirin amongst patients with peripheral arterial disease: randomized, double-blind trial. J
Intern Med 2007; 261:276.

58. Belch J, MacCuish A, Campbell I, et al. The prevention of progression of arterial disease and diabetes (POPADAD)
trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and
asymptomatic peripheral arterial disease. BMJ 2008; 337:a1840.

59. Anderson JL, Halperin JL, Albert NM, et al. Management of patients with peripheral artery disease (compilation
of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013; 127:1425.

60. Clever YP, Cremers B, Speck U, et al. Influence of a paclitaxel coated balloon in combination with a bare metal
stent on restenosis and endothelial function: comparison with a drug eluting stent and a bare metal stent.
Catheter Cardiovasc Interv 2014; 84:323.
61. Leng GC, Lee AJ, Fowkes FG, et al. Incidence, natural history and cardiovascular events in symptomatic and
asymptomatic peripheral arterial disease in the general population. Int J Epidemiol 1996; 25:1172.

62. Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial
disease. N Engl J Med 1992; 326:381.

63. Smith GD, Shipley MJ, Rose G. Intermittent claudication, heart disease risk factors, and mortality. The Whitehall
Study. Circulation 1990; 82:1925.

64. Murphy TP, Cutlip DE, Regensteiner JG, et al. Supervised exercise, stent revascularization, or medical therapy for
claudication due to aortoiliac peripheral artery disease: the CLEVER study. J Am Coll Cardiol 2015; 65:999.

65. Partridge JS, Harari D, Martin FC, et al. Randomized clinical trial of comprehensive geriatric assessment and
optimization in vascular surgery. Br J Surg 2017; 104:679.

66. Lewis SR, Pritchard MW, Schofield-Robinson OJ, et al. Continuation versus discontinuation of antiplatelet
therapy for bleeding and ischaemic events in adults undergoing non-cardiac surgery. Cochrane Database Syst
Rev 2018; 7:CD012584.

67. Devereaux PJ, Mrkobrada M, Sessler DI, et al. Aspirin in patients undergoing noncardiac surgery. N Engl J Med
2014; 370:1494.

68. Biccard BM, Sigamani A, Chan MTV, et al. Effect of aspirin in vascular surgery in patients from a randomized
clinical trial (POISE-2). Br J Surg 2018; 105:1591.

69. Goodney PP, Schanzer A, Demartino RR, et al. Validation of the Society for Vascular Surgery's objective
performance goals for critical limb ischemia in everyday vascular surgery practice. J Vasc Surg 2011; 54:100.

70. Stoner MC, Calligaro KD, Chaer RA, et al. Reporting standards of the Society for Vascular Surgery for
endovascular treatment of chronic lower extremity peripheral artery disease. J Vasc Surg 2016; 64:e1.

71. Albäck A, Biancari F, Schmidt S, et al. Haemodynamic results of femoropopliteal percutaneous transluminal
angioplasty. Eur J Vasc Endovasc Surg 1998; 16:7.

72. Teraa M, Conte MS, Moll FL, Verhaar MC. Critical Limb Ischemia: Current Trends and Future Directions. J Am
Heart Assoc 2016; 5.

73. Welten GM, Schouten O, Hoeks SE, et al. Long-term prognosis of patients with peripheral arterial disease: a
comparison in patients with coronary artery disease. J Am Coll Cardiol 2008; 51:1588.

74. Leng GC, Fowkes FG, Lee AJ, et al. Use of ankle brachial pressure index to predict cardiovascular events and
death: a cohort study. BMJ 1996; 313:1440.
75. Chung J, Timaran DA, Modrall JG, et al. Optimal medical therapy predicts amputation-free survival in chronic
critical limb ischemia. J Vasc Surg 2013; 58:972.

76. Suzuki H, Maeda A, Maezawa H, et al. The efficacy of a multidisciplinary team approach in critical limb ischemia.
Heart Vessels 2017; 32:55.

77. Goodney PP, Beck AW, Nagle J, et al. National trends in lower extremity bypass surgery, endovascular
interventions, and major amputations. J Vasc Surg 2009; 50:54.

78. Benoit E, O'Donnell TF Jr, Kitsios GD, Iafrati MD. Improved amputation-free survival in unreconstructable critical
limb ischemia and its implications for clinical trial design and quality measurement. J Vasc Surg 2012; 55:781.

79. Ouriel K. Peripheral arterial disease. Lancet 2001; 358:1257