JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 67, NO. 11, 2016

2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jacc.2015.12.049

THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Peripheral Artery Disease

Evolving Role of Exercise, Medical Therapy, and
Endovascular Options
Jeffrey W. Olin, DO,a Christopher J. White, MD,b Ehrin J. Armstrong, MD, MSC,c Daniella Kadian-Dodov, MD,a
William R. Hiatt, MDd

JACC JOURNAL CME

This article has been selected as the months JACC Journal CME activity,

peripheral artery disease so as to decrease the likelihood of experiencing

available online at http://www.acc.org/jacc-journals-cme by selecting the

a myocardial infarction, stroke, and cardiovascular death; 2) for your

CME tab on the top navigation bar.

patients with claudication, counsel on lifestyle modications to improve

their quality of life; and 3) diagnose patients with critical limb ischemia so

Accreditation and Designation Statement

The American College of Cardiology Foundation (ACCF) is accredited by
the Accreditation Council for Continuing Medical Education (ACCME) to
provide continuing medical education for physicians.

that they may be referred for revascularization to prevent amputation.

CME Editor Disclosure: JACC CME Editor Ragavendra R. Baliga, MD, has
reported that he has no relationships to disclose.

The ACCF designates this Journal-based CME activity for a maximum

Author Disclosures: Dr. Olin serves on the steering committee and

of 1 AMA PRA Category 1 Credit(s). Physicians should only claim credit

scientic advisory board for Merck for the TRAP2 trial; serves on the

commensurate with the extent of their participation in the activity.

international steering committee for the EUCLID Trial; and is a site

investigator for AstraZeneca. Dr. White serves on the research advi-

Method of Participation and Receipt of CME Certicate

sory board for Lutonix and Surmodics. Dr. Armstrong is a consultant/

advisory board member for Abbott Vascular, Medtronic, Merck, Pzer,

To obtain credit for JACC CME, you must:

1. Be an ACC member or JACC subscriber.
2. Carefully read the CME-designated article available online and in this
issue of the journal.
3. Answer the post-test questions. At least 2 out of the 3 questions

and Spectranetics. Dr. Hiatt has received grant support for clinical
trial research from AstraZeneca, Bayer, Janssen, GlaxoSmithKline,
ReNeuron, and the National Institutes of Health. Dr. Kadian-Dodov
has no relationships relevant to the contents of this paper to
disclose.

provided must be answered correctly to obtain CME credit.

4. Complete a brief evaluation.

Medium of Participation: Print (article only); online (article and quiz).

5. Claim your CME credit and receive your certicate electronically by

following the instructions given at the conclusion of the activity.

CME Term of Approval

CME Objective for This Article: At the end of this activity the reader

Issue Date: March 22, 2016

should be able to: 1) evaluate medical treatment options for patients with

Expiration Date: March 21, 2017

From the aZena and Michael A. Wiener Cardiovascular Institute & Marie-Jose and Henry R. Kravis Center for Cardiovascular
Health, Icahn School of Medicine at Mount Sinai, New York, New York; bDepartment of Cardiology, Ochsner Clinical School, New
Orleans, Louisiana; cDepartment of Medicine, Division of Cardiology, University of Colorado School of Medicine, Denver, ColoListen to this manuscripts

rado, and Veterans Affairs Eastern Colorado Health Care System, Denver, Colorado; and the dDepartment of Medicine, Division of

audio summary by

Cardiology, University of Colorado School of Medicine, and CPC Clinical Research, Aurora, Colorado. Dr. Olin serves on the

JACC Editor-in-Chief

steering committee and scientic advisory board for Merck for the TRAP2 trial; serves on the international steering committee for

Dr. Valentin Fuster.

the EUCLID Trial; and is a site investigator for AstraZeneca. Dr. White serves on the research advisory board for Lutonix and
Surmodics. Dr. Armstrong is a consultant/advisory board member for Abbott Vascular, Medtronic, Merck, Pzer, and Spectranetics. Dr. Hiatt has received grant support for clinical trial research from AstraZeneca, Bayer, Janssen, GlaxoSmithKline,
ReNeuron, and the National Institutes of Health. Dr. Kadian-Dodov has no relationships relevant to the contents of this paper to
disclose. Michael Jaff, DO, served as Guest Editor for this paper.
Manuscript received October 8, 2015; revised manuscript received December 14, 2015, accepted December 15, 2015.

Olin et al.

JACC VOL. 67, NO. 11, 2016

MARCH 22, 2016:133857

Management of Patients With Peripheral Artery Disease

Peripheral Artery Disease

Evolving Role of Exercise, Medical Therapy, and
Endovascular Options
ABSTRACT
The prevalence of peripheral artery disease (PAD) continues to increase worldwide. It is important to identify patients
with PAD because of the increased risk of myocardial infarction, stroke, and cardiovascular death and impaired quality of
life because of a profound limitation in exercise performance and the potential to develop critical limb ischemia. Despite
effective therapies to lower the cardiovascular risk and prevent progression to critical limb ischemia, patients with PAD
continue to be under-recognized and undertreated. The management of PAD patients should include an exercise
program, guideline-based medical therapy to lower the cardiovascular risk, and, when revascularization is indicated,
an endovascular rst approach. The indications and strategic choices for endovascular revascularization will vary
depending on the clinical severity of the PAD and the anatomic distribution of the disease. In this review, we
discuss an evidence-based approach to the management of patients with PAD. (J Am Coll Cardiol 2016;67:133857)
2016 by the American College of Cardiology Foundation.

eripheral artery disease (PAD) refers to athero-

The risk factors for PAD mirror those of cerebrovas-

sclerosis involving the aorta, iliac, and lower-

cular and coronary atherosclerosis, including a posi-

extremity arteries and is associated with

tive family history, diabetes mellitus, smoking,

signicant morbidity and mortality (1,2). Since the

chronic kidney disease, hypertension, and hyperlip-

last iteration of the guidelines focused on PAD (24),

idemia (5,9,10,12,13). Smoking and diabetes are

published data have emerged that may alter the stan-

particularly virulent and are associated with worse

dard of care for this high-risk patient group. This re-

outcomes, independent of other risk factors (14).

view will delve in great detail into the management

Identication of patients with PAD is important

of PAD patients, highlighting the roles of exercise,

because there is a 3- to 4-fold increased risk of car-

optimal medical management, and endovascular

diovascular events, even in the setting of asymp-

therapy. Surgical revascularization will not be dis-

tomatic disease (15). At 5 years, approximately 1 of 5

cussed because current expert consensus documents

patients with PAD will experience a nonfatal cardio-

recommend an endovascular rst approach for the

vascular event, and 15% to 20% will die (most of

majority of PAD patients requiring revascularization

cardiovascular causes) (8,16).

(2,3).

Most patients with PAD fall into 1 of 3 groups:

Despite initiatives to improve on the identication

classic claudication (10% to 30%), atypical leg pain

and management of PAD (2,5), the number of people

(20% to 40%), or asymptomatic (nearly 50%). Formal

affected and disease morbidity continues to rise. As

testing to assess functional capacity and endurance

of 2010, more than 200 million people worldwide are

shows signicant impairment in patients with PAD,

living with PAD, which represents a 28.7% increased

even if asymptomatic. Although the majority of pa-

prevalence in low- and middle-income countries and

tients report leg symptoms other than classic claudi-

a 13.1% increase in high-income countries over a

cation, greater functional decline is associated with

10-year period (6,7). Prevalence studies in the United

greater severity of disease, lower baseline ankle-

States estimate that 5.9% of Americans over 40 years

brachial index (ABI), and increased numbers of

of age have PAD (8). When specic high-risk pop-

cardiovascular events (1720). In patients with CLI,

ulations are evaluated, estimates of PAD prevalence

outcomes are dire: at 1 year, 10% will experience a

are as high as 30% (9). The prevalence and severity of

fatal cardiovascular event, and 25% will undergo limb

PAD is increased in African Americans and Hispanics

amputation (2).

(10). A recent retrospective cohort study evaluating

Patient-reported symptoms underestimate PAD

nearly 12 million insured American adults reported

prevalence, and the physical examination is not a

mean annual incidence rates of PAD and critical limb

reliable tool for the identication of disease. Diag-

ischemia (CLI) of 2.35% and 0.35%, respectively (11).

nosis and prevention of adverse outcomes may

1339

1340

Olin et al.

JACC VOL. 67, NO. 11, 2016

MARCH 22, 2016:133857

Management of Patients With Peripheral Artery Disease

ABBREVIATIONS

therefore be elusive, unless patients are

are $50 years of age with a history of diabetes or

AND ACRONYMS

identied with targeted diagnostic testing

smoking (24,9,25). The goal is to identify and treat

BMS = bare-metal stent

CLI = critical limb ischemia
DAPT = dual-antiplatelet
therapy

DCB = drug-coated balloon

DES = drug-eluting stent
MACE = major adverse

patients with increased cardiovascular risk. Despite

these recommendations and the fact that nearly one-

factors results in reduced morbidity and

half of all PAD patients are asymptomatic, there is no

mortality for patients with PAD, although this

reimbursement for the performance of an ABI in the

population continues to be under-recognized

absence of clinical symptoms of PAD. Alternative

and undertreated for their cardiovascular risk

diagnostic methods for PAD are beyond the scope of

(2,8). Among 7,458 participants with PAD in

this review.

the 1999 to 2004 NHANES (National Health

Serum biomarkers have been used for risk predic-

and Nutrition Examination Survey) data, only

tion and the detection of PAD (26). A combined

30.5% of subjects were taking statins, 24.9%

biomarker prole that includes fasting glucose, high-

were taking angiotensin-converting enzyme

sensitivity C-reactive protein, b2-microglobulin, and

inhibitors (ACEI) or angiotensin receptor

cystatin C demonstrated efcacy in the identication

blockers,

administered

of PAD and reclassication of cardiovascular risk

aspirin. Among patients with PAD (and no

assessment by Framingham Risk Score in patients who

other clinical cardiovascular disease), use of

would have otherwise been misidentied (27). The

multiple preventive therapies was associated

BRAVO (Biomarker Risk Assessment in Vulnerable

with a 65% lower all-cause mortality (hazard ratio

Outcomes) study evaluated 595 patients with PAD and

[HR]: 0.35; p 0.02) (8).

followed them for 3 years. The primary outcome was

cardiovascular event

PAD = peripheral artery

disease

QOL = quality of life

SFA = supercial femoral
artery

TASC = Trans-Atlantic InterSociety Consensus

(i.e., ankle-brachial index [ABI]) (21). The

treatment of underlying cardiovascular risk

and

35.8%

were

The diagnosis of PAD can be made using the ABI.

ischemic heart disease events (myocardial infarction,

Using a handheld continuous-wave Doppler device,

unstable angina, or ischemic heart disease death). Of

the ABI can be measured by taking the higher of the

the 50 participants who had an event, the D-dimer was

2 systolic pressures in the dorsalis pedis and posterior

higher 2 months before the event than the values 10

tibial artery in each leg and dividing by the higher of

months, 12 months, 16 months 20 months, 26 months,

the brachial artery systolic blood pressures in each

and 32 months before the event. There was no change

arm. An abnormal ABI is diagnostic for PAD (21).

in the serum amyloid A or CRP 2 months before an

A normal ABI is between 1.00 and 1.40. An ABI #0.90

event (28). Although there is a clear association

demonstrates 90% sensitivity and 95% specicity for

between various biomarkers and PAD, the overall

PAD and is the accepted threshold for diagnosis (2,21).

clinical value related to patient outcomes remains

Values between 0.91 and 1.00 are considered border-

unclear, and thus, there is no clinical benet in

line; however, the cardiovascular event rate for an ABI

measuring biomarkers at this time.

in this range is increased by 10% to 20% (21). At levels

>1.40, the identication of PAD is not accurate

THE ROLE OF EXERCISE

because of the presence of arterial calcication and

noncompressibility of the blood vessels, a nding

Patients with PAD have a profound limitation in

frequently encountered in the very elderly and in

exercise performance that is related to a complex

those with diabetes and chronic kidney disease. In this

pathophysiology (29). Although reduced exercise

setting, the toe-brachial index is used and considered

performance is a hallmark of PAD, the symptomatic

abnormal when <0.70 (4,21). There is a strong and

manifestations are quite varied, as described previ-

consistent relationship between an abnormal ABI and

ously (30). Not surprisingly, patients with claudica-

the presence of coronary or cerebrovascular disease

tion slow their walking pace and often avoid walking

(5,16,22). In addition, the ABI is a predictor of cardio-

altogether. Thus, patients with PAD present with a

vascular morbidity and mortality independent of

complex array of symptoms, health beliefs, and

clinical risk prediction scores such as the Framingham

exercise limitations in their daily lives (31,32). These

Risk Score and other surrogate markers of systemic

perceptions and attitudes must be addressed if a

atherosclerosis such as the coronary calcium score and

treatment plan is to be successful.

carotid artery intimal-medial thickness (23). There is

The overall goal in treating the exercise limitation

also a higher cardiovascular event rate in patients with

from PAD is to improve exercise performance with a

PAD (even in asymptomatic patients) with known

corollary improvement in quality of life (QOL) and

coronary artery disease (CAD) (24).

functional status. In this regard, treatments that

Several consensus documents and practice guide-

improve

treadmill

exercise

performance,

6-min

lines recommend screening for the presence of PAD

walking distance, and patient-related QOL can serve

using the ABI in patients $65 years old or those who

as a basis for obtaining regulatory approval of a

Olin et al.

JACC VOL. 67, NO. 11, 2016

MARCH 22, 2016:133857

claudication therapy. In contrast, changes in limb

Management of Patients With Peripheral Artery Disease

and intensity of the walking exercise to inform the

hemodynamics, such as an improvement in the ABI or

research staff and patient as to the patients exercise

imaging after a successful revascularization, serve

prescription. One randomized trial combined the

only as surrogate measures of clinical benet.

activity monitor with a home-based program that

Exercise training has been a mainstay of treatment

used the principles of a hospital-based supervised

for symptomatic PAD, with a well-established benet

program (43). Adherence to the home program was

after a typical 12-week exercise training program

>80%, and the results on improvements in treadmill

(33,34). Exercise training directly modies several

exercise performance were comparable between

pathophysiological mechanisms in PAD, including

home and supervised programs. A follow-up study

improved skeletal muscle metabolism, endothelial

demonstrated similar results (44).

function, and gait biomechanics (35).

SUPERVISED EXERCISE TRAINING IMPROVES MORBIDITY
AND MORTALITY IN PAD. Individual single-site studies

and a meta-analysis of those studies demonstrate that

a 12-week intervention of supervised exercise (SE)
improves exercise performance and QOL in PAD (34).
Supervised exercise is also more effective than a
nonstructured community exercise program (36).
Physical activity in patients with PAD is associated
with decreased all-cause and cardiovascular mortality
(37,38). Standardized supervised training methods
have been published previously (39).
On the basis of current evidence, supervised
walking exercise gets a Class Ia recommendation and
unsupervised exercise a Class IIb recommendation
(2). Despite clear evidence of benet, SE programs
have not been accepted by payers, providers, or
patients for a variety of reasons, including questions
of long-term adherence and the benet of exercise as a
lifestyle intervention, coupled with the desire by most
patients and vascular physicians for a more immediate approach to relieving claudication with endovascular therapy (40). Therefore, SE training programs
for claudication are very limited and not reimbursed.

McDermott et al. (45) have developed a coordinated

exercise program (group-mediated cognitive behavioral therapy) that includes weekly group sessions run
by a trained facilitator. In a randomized controlled
trial of 194 patients, subjects in the intervention group
improved their 6-min walking distance, peak treadmill
exercise performance, and several measures of QOL
and accelerometer-measured physical activity (46).
In addition, after 6 months, the intervention group
gained self-efcacy, satisfaction with functioning,
pain acceptance, and social functioning, and these
benets were sustained at the 12-month endpoint (47).
At 12 months, fewer treated patients experienced
mobility loss, and treated patients also improved in
walking velocity and QOL (48).
It is apparent that many of the exercise methods
discussed are effective in improving walking distance
with less discomfort and improved QOL; however,
they all require resources that are not available in
many communities, especially those in the lowest
socioeconomic class. Although a simple recommendation between the physician and the patient to exercise is usually ineffective, the physician can provide
a comprehensive exercise prescription (Table 1) on
how to structure a home exercise program (50,51).

HOME-BASED EXERCISE DATA AND GENERALIZABILITY

This is not a 1-time recommendation but an ongoing

OF THE FINDINGS. The methodology to provide a

discussion between the physician and the patient

community (home)-based exercise intervention has

in an attempt to change patient behavior. Patients

improved considerably over the past decade, and

who are compliant with such a program often experi-

these exercise training methods have provided

ence considerable improvement in walking distance

encouraging results.

and QOL.

The least resource-intensive home-based program

STUDIES ON EXERCISE VERSUS ENDOVASCULAR

can employ education and behavioral interventions

THERAPY: ARE WE ASKING THE RIGHT QUESTIONS?

that prepare patients for exercise training (41).

Several studies have compared an SE program to

Notably, adherence to a community program may be

revascularization

poor without proper motivation and engagement.

exercise-limiting

in

patients

claudication

with
(52,53).

PAD

and

Given

the

There are a number of new devices that monitor

tremendous expansion and effectiveness of endovas-

the intensity and duration of an exercise session

cular treatments for symptomatic PAD, as well as

performed in the home environment. A pilot study

patient reluctance to enter an exercise-lifestyle treat-

that used a program of training, monitoring, and

ment program (as discussed previously), the most

coaching had encouraging results in a subgroup of

prudent approach would be to include both modalities

subjects but was too small to denitively establish the

in the treatment plan: exercise and revascularization.

benets of the interventions (42). Two larger trials

In fact, both exercise training and revascularization

used a step activity monitor to record the duration

can greatly improve patient exercise performance

1341

1342

Olin et al.

JACC VOL. 67, NO. 11, 2016

MARCH 22, 2016:133857

Management of Patients With Peripheral Artery Disease

T A B L E 1 A Practical Home Exercise Program for Patients

With PAD

Frequency
3-5 days per week
Modality
Treadmill (this program can be adapted for walking outside)
Method

therapy in both groups (52). At the initial 6-month

follow up, the primary endpoint of peak walking
time on a graded treadmill test was signicantly
improved in both the exercise and stent groups
compared with optimal medical management, but the
peak walking time was signicantly higher in the
exercise group than in the stent group (52). The sec-

1. Begin at 2 mph and a grade of 0 (at)

ondary endpoints were changes in responses to QOL

2. Try not to hold onto the treadmill. Use the side panels for balance
only.

questionnaires. Both of these patient-reported out-

3. Stop the treadmill completely when pain is 34 on claudication

discomfort scale*
4. When the discomfort has ceased, resume exercise at the same
intensity
5. Repeat rest/exercise cycles
6. Progress to a higher workload when you can walk for 8 min
without having to stop for leg symptoms

comes were improved with exercise or stenting over

optimal medical management; however, improvements tended to be greater in the stenting group. The
same endpoints were measured at 18 months of
follow-up (55). In 79 of 119 patients who completed
the study, improvements in treadmill peak walking

a) Increase speed by 0.2 mph each time you can walk for 8 min

time remained for both the exercise and stenting

b) Once you are able to walk at 3.4 mph, or reach a speed at which
you can no longer keep up, begin increasing the grade by 1%

groups over optimal medical therapy, but the differ-

Duration
The total exercise period, including rest periods, should equal
45 min per day
Tips for success
1. Do not continue walking past 34 on claudication pain/discomfort
scale. This way the pain/discomfort should go away in 25 min. If
you walk until you are in severe pain, you will build up lactic acid
in your muscles, and it will take much longer for the pain to go
away.
2. When at 34 on pain/discomfort scale, stop walking completely.
Do not slow down, but stop and stand on the treadmill until the
discomfort is gone.
This works if you do it! Not only will this improve your walking
performance, decrease your discomfort, and improve your
quality of life, this type of program is also benecial for your
heart, blood pressure, and lipid (cholesterol and triglyceride)
levels.
*Claudication pain scale: 1 no pain or discomfort; 2 onset of claudication;
3 mild pain or discomfort; 4 moderate pain or discomfort; 5 severe pain or
discomfort. Adapted from Weinberg et al. (49).
PAD peripheral artery disease.

ences in peak walking time between the exercise and

stenting groups were no longer statistically signicant. Improved patient-reported outcomes remained
for both the exercise and stent groups.
CLEVER clearly established the independent, longterm, and broad-based benets of both exercise
training and stent revascularization in symptomatic
PAD. Similar to many such trials, of the nearly 1,000
patients evaluated, only 11% were randomized, and
fewer were available for 18-month follow-up. Unfortunately, the arm of CLEVER that would have tested
the combination of exercise plus stenting was dropped because of poor enrollment.
In the recently published ERASE (Endovascular
Revascularization and Supervised Exercise) trial,
106 patients were randomized to both endovascular
therapy and SE and 106 patients to SE alone (56). After
1 year, the combination group had greater improve-

and QOL, but by very different mechanisms. Revascu-

ment in maximum walking distance (MWD) and

larization primarily improves exercise blood ow,

health-related QOL scores than the group randomized

whereas exercise training does not (29). In contrast,

to SE alone; however, both groups demonstrated

exercise training induces a variety of adaptive re-

dramatic improvement in MWD, pain-free walking

sponses, including improved skeletal muscle mito-

distance, and QOL. The supervised exercise group

chondrial oxidative metabolism, improved endothelial

increased MWD from 285 m to 1,240 m, for an

function, and more efcient biomechanics of walking.

improvement of 955 m. The combination group

Thus, the obvious best treatment strategy would

increased MWD from 264 m to 1,501 m, for an

appear to be the combined program, utilizing endo-

improvement of 1,237 m. This study illustrates

vascular revascularization and an optimal home-based

2 important points: 1) the combination of endovascular

and long-term exercise program. This hypothesis

therapy and SE is the most effective therapy for many

was initially tested more than 25 years ago, and the

patients with claudication; and 2) even the group

combination of bypass surgery and exercise training

randomized to SE alone showed marked improvement

was superior to either treatment alone (54).

in MWD, pain-free walking distance, and QOL (56).

The CLEVER (Claudication: Exercise Versus Endo-

The cost of therapy must also be considered when

luminal Revascularization) study was an important

planning a particular strategy to treat symptomatic

and well-designed comparative effectiveness trial

PAD. In a single-center Dutch randomized trial,

that compared the outcomes for stenting of aortoiliac

endovascular revascularization had similar benet

disease with SE on a background of optimal medical

but higher total mean cumulative costs per patient

Olin et al.

JACC VOL. 67, NO. 11, 2016

MARCH 22, 2016:133857

CENTRAL I LLU ST RAT ION

Management of Patients With Peripheral Artery Disease

The Peripheral Artery Disease Prescription

Decrease the Risk of MI, Stroke,

and CV Death

Improve Symptoms, Quality of Life,

and Prevent Amputation

Discontinue Tobacco Use

Discontinue Tobacco Use

Walking Program

Walking Program

Control Blood Pressure to Goal

Cilostazol

-ACE Inhibitor

High-Dose Statin Therapy

Good Foot Care

-Moisturizing cream, nail care, treat
and prevent tinea, orthotics to
prevent abnormal pressure points

Antiplatelet Therapy

Revascularization

Olin, J.W. et al. J Am Coll Cardiol. 2016; 67(11):133857.

Management of patients with peripheral artery disease: recommendations for improving outcomes and quality of life. ACE angiotensin-converting
enzyme; CV cardiovascular; MI myocardial infarction.

compared with a hospital-based exercise program

compared with patients with CAD (8,59). Adherence

(57). Another study from a Dutch health-care database

to these guidelines in real-world practice is associated

of 4,954 patients demonstrated that a stepped

with improved outcomes (Figure 1), which empha-

approach of exercise therapy followed by endovas-

sizes the benet of multifactorial risk reduction in

cular revascularization was more cost-effective than

this high-risk population (12). Performance measures

revascularization only (58).

for PAD will help improve quality of care and may be

Thus, future studies should address not only the

clinical benets but also the effectiveness of the
combination of an exercise program and limb revascularization. In this context, effectiveness pertains to
the ability of a treatment program to be utilized by a
majority of appropriate patients in a community and
to achieve high adherence to the program, as well as
that the desired improvements in functional outcomes are obtained.

incorporated into future quality metrics (60).

SMOKING CESSATION
Smoking is a major risk factor for the development and
progression of PAD. A multidisciplinary approach to
smoking cessation should be used, including groupbased programs and cognitive behavioral therapy.
A recent study evaluated the association between
successful quitting after endovascular intervention

OPTIMAL MEDICAL THERAPY FOR

and long-term outcomes (61). Among 739 patients

PATIENTS WITH PAD

undergoing lower-extremity angiography, 28% were

active smokers at the time of endovascular interven-

Medical therapy for PAD should address treatment for

tion. In the subsequent year, 30% of active smokers

limb-related outcomes (improve claudication symp-

successfully quit. Those who remained off tobacco

toms and prevent CLI and amputation) and treatment

had signicantly lower 5-year mortality (14% vs. 31%)

to prevent major adverse cardiovascular events

and improved amputation-free survival (81% vs.

(MACE; myocardial infarction, stroke, and cardio-

60%). Discontinuation of smoking is the most

important lifestyle modication in preventing CLI,

vascular death) (Central Illustration).

societal

amputation, and MACE in patients with PAD. This

guidelines on the management of patients with PAD

needs to be conveyed to the patient in an empathetic

(2), these patients continue to be undertreated

and nonjudgmental way during every ofce visit. The

Despite

the

recommendations

from

1343

Olin et al.

1344

JACC VOL. 67, NO. 11, 2016

MARCH 22, 2016:133857

Management of Patients With Peripheral Artery Disease

which cilostazol improves claudication is not known

F I G U R E 1 Adherence to Guideline-Recommended Medical Therapies and

(63). A pooled analysis of all of the randomized

Outcomes in PAD

40

tion distance of approximately 50% compared with

Hazard ratio, 0.64; 95% CI, 0.45-0.89; P=0.009

placebo (64). Although cilostazol appears to be safe

for long-term administration, adherence is low (>60%

30

discontinuation at 3 years) because of adverse effects

including headache, palpitations, and diarrhea (65).

20

Because of its mechanistic similarity to other type III

phosphodiesterase inhibitors, such as milrinone, cilostazol is contraindicated in patients with a history of
10

heart failure. The optimal dose of cilostazol is 100 mg

twice daily, and it may take up to 4 months to derive
maximum benet from this drug (63).
<4 Guideline Therapies

Major Adverse Cardiovascular Events, %

trials shows an improvement in absolute claudica-

Number at risk
<4 Guideline 502
4 Guideline 237

450
222

4 Guideline Therapies

12
18
24
Follow-Up (Months)
391
207

355
180

322
156

30

36

288
143

256
123

Pentoxifylline is rarely used today to treat claudication because of a lack of efcacy compared with
cilostazol. Naftidrofuryl is a 5-HT2 antagonist that is
approved in Europe. In a pooled analysis involving
888 patients randomized to naftidrofuryl, there was a
26% increase in pain-free walking compared with
placebo (66). It is not available for use in the United

Hazard ratio, 0.55; 95% CI, 0.37-0.83; P=0.005

States.

30

ACEIs

20

ACEIs are associated with a signicant reduction in

MACE among patients with PAD. These data are
derived primarily from the HOPE (Heart Outcomes
Prevention Evaluation) trial, which randomized 9,297

10

Major Adverse Limb Events, %

40

high-risk patients with vascular disease or diabetes

plus 1 other risk factor to ramipril 10 mg daily

<4 Guideline Therapies

0

Number at risk
<4 Guideline 502
4 Guideline 237

306
155

4 Guideline Therapies

12
18
24
Follow-Up (Months)
240
133

201
102

175
94

30

36

142
76

125
64

or placebo. Among these, 1,966 patients with PAD

(42.3%) were randomized to ramipril and 2,085
(44.8%) to placebo. The primary outcome (myocardial
infarction, stroke, cardiovascular death) occurred in
14.3% of those without PAD versus 22.0% of those
with PAD (67). In the 5,231 patients without PAD, the

Among patients with symptomatic peripheral artery disease (PAD) undergoing

primary outcome was observed in 12.6% in the ram-

lower-extremity angiography, adherence to the guideline-recommended therapies of an

ipril group and 14.9% in the placebo arm. In those with

antiplatelet agent, statin, angiotensin-converting enzyme inhibitor, and abstention from

an ABI <0.6, the primary outcome occurred in 16.4% in

smoking is associated with a signicant reduction in (A) major adverse cardiovascular

the ramipril arm versus 22% in the placebo arm. The

events and (B) major adverse limb events. Reproduced with permission from Armstrong
et al. (12). CI condence interval; PAD peripheral artery disease.

cardiovascular benet of ramipril applies to patients

with both asymptomatic and symptomatic PAD across
a broad range of ABI values (68). Similar results have

VAPOR (Vascular Physician Offer and Report) trial is

currently evaluating methods to improve physicianpatient interactions to encourage patients with PAD
to abstain from smoking (62).

also been observed with telmisartan, which suggests a

possible class effect of ACEI/angiotensin receptor
blockade among patients with PAD (69,70).

STATINS

PHARMACOTHERAPY TO IMPROVE
CLAUDICATION SYMPTOMS

High-intensity statin medications are recommended

for all patients with PAD on the basis of the

Cilostazol is a type III phosphodiesterase inhibitor

most recent American College of Cardiology (ACC)/

with a number of properties, but the mechanism by

American Heart Association (AHA) guidelines, which

Olin et al.

JACC VOL. 67, NO. 11, 2016

MARCH 22, 2016:133857

Management of Patients With Peripheral Artery Disease

emphasize cardiovascular risk over low-density lipo-

trial compared low-dose aspirin with placebo in

protein targets (71). The majority of the data in sup-

patients with a low ABI. Neither study demonstrated

port of statin use in patients with PAD are derived

a reduction in fatal and nonfatal cardiovascular

from subset analysis of larger clinical trials. The

events or revascularization with aspirin mono-

Medical Research Council/British Heart Foundations

therapy, although both notably included low-risk

Heart Protection Study randomized 20,536 high-risk

patients with borderline ABI (#0.99 in POPADAD

patients to simvastatin 40 mg daily or placebo (72).

and #0.95 in AAA) (77,78).

All-cause mortality occurred in 12.9% of patients

Consistent with these results, a meta-analysis

randomized to simvastatin and 14.7% randomized to

specically examined aspirin for PAD in 18 trials

placebo (22% relative risk reduction; p 0.0003).

involving 5,269 patients. In patients taking aspirin

Observational studies have also conrmed the car-

monotherapy, there was a nonsignicant reduction

diovascular and overall mortality benet of statins

in cardiovascular events (absolute event rate 8.2%

among patients with more advanced PAD, including

vs. 9.6%; relative risk: 0.75; 95% condence inter-

CLI (73).

val [CI]: 0.48 to 1.18); however, there was a sig-

Recent data suggest that statin use is also associ-

nicant reduction in nonfatal stroke (HR: 0.64; 95%

ated with a reduction in adverse limb outcomes,

CI: 0.42 to 0.99; p 0.04) (76). In the last iteration

including amputation. In the REACH (Reduction of

of the PAD guidelines (2), aspirin was a Class I,

Atherothrombosis for Continued Health) registry,

Level of Evidence A recommendation among pa-

statin therapy was associated with a signicant

tients with symptomatic PAD, a Class IIa recom-

reduction in the combined endpoint of worsening

mendation among patients with asymptomatic PAD

claudication, new CLI, new revascularization, or

and an ABI <0.90, and a Class IIb indication among

amputation (74). The absolute 4-year event rates were

asymptomatic patients with an ABI of 0.90 to 0.99

22.0% versus 26.2%, which emphasizes the high rate of

(2). Some of these recommendations may change in

adverse limb events among patients with symptom-

the upcoming revision of the ACC/AHA PAD prac-

atic PAD. Importantly, statin therapy was also associ-

tice guidelines.

ated with a signicant reduction in 4-year rates of

ischemic amputation (3.8% vs. 5.6%). In an analysis of
Medicare claims data of patients undergoing lowerextremity revascularization, statin use was associated with lower rates of amputation at 30 days,
90 days, and 1 year (75). Single-center observational
data among patients with CLI suggest that statin
therapy is also associated with improved 1-year rates
of primary patency, secondary patency, and improved
limb salvage after endovascular intervention (73).
Patients with PAD should be prescribed a highintensity statin to reduce the risk of cardiovascular
events. In most studies, the rates of statin prescription were <75%, which emphasizes the importance of
maximizing medical therapy among this high-risk
group of patients with advanced atherosclerotic
disease (59).

ANTIPLATELET THERAPY

CLOPIDOGREL AND
DUAL-ANTIPLATELET THERAPY
Clopidogrel is indicated as an alternative to aspirin
for antiplatelet monotherapy among patients with
PAD, although recent studies suggest that <20% of
patients with PAD are prescribed clopidogrel in clinical practice (79). The data supporting clopidogrel use
are primarily based on the CAPRIE (Clopidogrel
Versus Aspirin in Patients at Risk of Ischaemic
Events) study, in which clopidogrel monotherapy was
associated with a small benet compared with aspirin
325 mg daily in the overall population, but there was a
23.8% relative risk reduction among the subgroup of
patients with symptomatic PAD (n 6,452; absolute
event rate 3.7% vs. 4.9% per year) (80).
Dual-antiplatelet therapy (DAPT) with low-dose
aspirin (75 to 162 mg daily) and clopidogrel 75 mg
daily was studied in the CHARISMA (Clopidogrel for

ASPIRIN. Aspirin has been a mainstay of drug ther-

High Atherothrombotic Risk and Ischemic Stabiliza-

apy among patients with PAD; however, the data

tion, Management, and Avoidance) trial, which

supporting aspirin use in patients with PAD have not

included patients at high risk for atherothrombotic

been well substantiated (76,77).

events. The overall results of this trial were not sig-

Recent studies investigating the benet of aspirin

nicant, although in subgroup analyses, there was a

among patients with asymptomatic PAD have yielded

benet of DAPT among patients with symptomatic

negative results. Both the POPADAD (Prevention of

atherothrombosis (81). In an analysis of the 3,096 pa-

Progression of Arterial Disease and Diabetes) trial and

tients in the trial with PAD, DAPT was associated with

the AAA (Aspirin for Asymptomatic Atherosclerosis)

a lower rate of myocardial infarction (2.3% vs. 3.7%;

1345

1346

Olin et al.

JACC VOL. 67, NO. 11, 2016

MARCH 22, 2016:133857

Management of Patients With Peripheral Artery Disease

HR: 0.63; 95% CI: 0.42 to 0.96; p 0.02) and hospital-

monophosphate (cAMP) levels subsequently decrease,

ization for ischemic events (16.5% vs. 20.1%; HR: 0.81;

which leads to increased platelet aggregation and

95% CI: 0.68 to 0.95; p 0.011) but not the overall

release of further activating factors. Vorapaxar inhibits

composite primary endpoint (82). There was no dif-

PAR-1,

ference between the groups in moderate, severe, or

mediated platelet activation.

fatal bleeding, but there was an increase in minor

bleeding in the DAPT group.
among

patients

signicantly

reducing

thrombin-

The TRA 2  P-TIMI 50 trial (Thrombin Receptor

Antagonist for Secondary PreventionThrombolysis

In a recent propensity-matched observational

study

thereby

undergoing

in Myocardial Infarction Study Group) studied vor-

endovascular

apaxar sulfate 2.5 mg daily versus placebo (ASA and/

intervention, there was a signicant reduction in

or clopidogrel therapy, at the investigators discre-

MACE among patients taking DAPT (adjusted HR:

tion) among 26,449 patients with a recent myocardial

0.65; 95% CI: 0.44 to 0.96; p 0.03) compared with

infarction, recent ischemic stroke, or symptomatic

those taking aspirin monotherapy (83). The discor-

PAD. At 3 years, there was a signicant reduction in

dant ndings between this study and the CHARISMA

the primary endpoint of MACE (absolute event rates:

trial may be explained by inclusion of a cohort

9.3% vs. 10.5%; HR: 0.87; 95% CI: 0.80 to 0.94;

with more advanced atherosclerotic disease under-

p < 0.001) (79). After 2 years, the data and safety

going endovascular intervention, including >50% of

monitoring board recommended stopping the study

patients with CLI.

drug in the patient subgroup entered with prior

The CASPAR (Clopidogrel and Acetylsalicylic Acid

ischemic stroke because of an increased risk of

in Bypass Surgery for Peripheral Arterial Disease) trial

intracranial hemorrhage. Among the 3,787 patients

studied DAPT versus aspirin 75 to 100 mg daily among

with PAD, the majority were treated with aspirin

patients undergoing below-knee surgical bypass for

monotherapy plus vorapaxar or placebo. The reduc-

treatment of CLI (84). The primary endpoint of death,

tion in MACE was not statistically signicant in those

major amputation, index-graft occlusion, or revascu-

assigned to vorapaxar (absolute event rates: 11.3% vs.

larization

versus

11.9%; HR: 0.94; 95% CI: 0.78 to 1.14). Similarly

acetylsalicylic acid (ASA) monotherapy. In a pre-

negative results were observed among patients with

specied subgroup analysis, there was a signicant

PAD who were enrolled in the TRACER (Thrombin

benet of DAPT in patients treated with prosthetic

Receptor Antagonist for Clinical Event Reduction in

grafts (HR: 0.65; 95% CI: 0.45 to 0.95; p 0.025) but

Acute Coronary Syndrome) trial (86). Additionally,

not in those treated with vein grafts. A similar trial,

vorapaxar is associated with a signicantly increased

the CAMPER study (Clopidogrel and Aspirin in the

risk of major bleeding. However, in both of these

Management of peripheral Endovascular Revascular-

trials, there were relatively few MACE in the PAD

ization), tested DAPT versus aspirin in patients un-

subgroup. The PAD group was underpowered to draw

dergoing infrainguinal endovascular therapy. The

any conclusions on efcacy.

was

not

different

for

DAPT

study was never completed because of poor enroll-

Pre-specied analysis of limb-related outcomes in

ment (doctors would not randomize patients to ASA

the TRA 2  P-TIMI 50 trial demonstrated that patients

alone); continued funding could not be justied.

assigned to vorapaxar had signicantly reduced rates

DAPT is often prescribed after endovascular inter-

of acute limb ischemia (2.3% vs. 3.9%; HR: 0.58; 95%

vention, although the data supporting duration of

CI: 0.39 to 0.86; p 0.006), as well as peripheral

DAPT are sparse. In practice, most physicians prescribe

artery revascularization (18.4% vs. 22.2%; HR: 0.84;

DAPT for a time period ranging from 1 to 3 months post-

95% CI: 0.73 to 0.97; p 0.017) during the 3-year

intervention. The ASPIRE-PAD study (Antiplatelet

follow-up (Figure 2) (87). These efcacy endpoints

Strategy for Peripheral Arterial Interventions for

must be balanced by a signicantly increased rate of

Revascularization of Lower Extremities) is currently

major bleeding among patients prescribed vorapaxar.

evaluating comparative outcomes of 1 versus 12

Further research into the mechanism by which

months of DAPT after endovascular intervention (85).

vorapaxar led to improved limb outcomes is required

VORAPAXAR

to fully understand these effects.

CELL-BASED AND ANGIOGENIC THERAPIES

Thrombin acts through platelets via a unique mechanism: binding of the protease activating receptor-1

Modulation and enhancement of lower-extremity

(PAR-1), a G protein-coupled receptor expressed on

blood ow via angiogenesis, arteriogenesis, or vas-

the platelet surface, leads to receptor activation

culogenesis could provide a promising breakthrough

and increased intracellular Ca 2; cyclic adenosine

therapy for patients with PAD (88). Additionally,

MARCH 22, 2016:133857

Management of Patients With Peripheral Artery Disease

there has been much interest in the use of stem cell

derived endothelial cells or modication of resident
stem cells (89). Potential benets of these therapies
include improved wound healing and limb salvage

F I G U R E 2 Limb-Related Events in Patients Treated With Vorapaxar

among patients with CLI, as well as improved clau-

3.5%

promising results in early clinical trials, none of these

3.0%

ONGOING CLINICAL TRIALS

There are currently 2 clinical trials studying novel

Event Rate (%)

angiogenic therapies have been tested, and despite

agents have shown benet in larger trials.

antiplatelet and anticoagulant agents to reduce MACE

potentially

modify

limb-related

Hospitalization for Acute Limb Ischemia

4.5%

Placebo

2.5%
2.0%
1.5%
1.0%

2.3% vs. 3.9%

HR 0.58 (0.39 0.86)
P=0.006

outcomes.

EUCLID (Study Comparing Cardiovascular Effects of

0.5%

Ticagrelor and Clopidogrel in Patients With Periph-

0.0%

eral Artery Disease) is a randomized, blinded, double-

180

dummy trial comparing ticagrelor 90 mg twice daily

to clopidogrel monotherapy among 13,500 patients

with PAD (90). All patients are tested for clopidogrel

resistance

before

randomization.

The

Vorapaxar

4.0%

dication distance. To date, numerous cell-based and

and

1347

Olin et al.

JACC VOL. 67, NO. 11, 2016

540
720
360
Days Since Randomization

900

1080

Peripheral Revascularization

25.0%

Placebo

Vorapaxar

primary

endpoint is a composite of MACE, and results are

20.0%

the Prevention of Major Cardiovascular Events in

Coronary or Peripheral Artery Disease) trial is evaluating low-dose rivaroxaban alone versus placebo,
aspirin alone, or rivaroxaban and aspirin among
21,400 patients with a history of myocardial infarc-

Event Rate (%)

expected in late 2016. The COMPASS (Rivaroxaban for

15.0%

10.0%
18.4% vs. 22.2%
HR 0.84 (0.73 0.97)
P=0.017

tion or PAD; the primary endpoint of this trial is a

5.0%

composite of MACE (91).

ENDOVASCULAR THERAPY

0.0%
0

Endovascular revascularization plays a key role in the

180

720
360
540
Days Since Randomization

900

1080

management of patients with PAD. Patients with stable claudication have a low risk of limb loss but may be

In the TRA 2 P-TIMI 50 trial, patients randomized to vorapaxar had signicantly lower

severely limited by their symptoms. In most circum-

rates of (A) acute limb ischemia and (B) peripheral revascularization. Reproduced with

stances, patients with claudication should be offered a

permission from Bonaca et al. (87). HR hazard ratio.

trial of cilostazol and an exercise program as initial

therapy. If the patient is not satised after a trial of
medical therapy, endovascular revascularization can
be considered. Patients with CLI require more urgent

anatomic unit of tissue (consisting of skin, subcu-

revascularization because of an increased risk of tissue

taneous tissue, fascia, muscle, and bone) that is fed

loss and amputation, as well as an extremely high risk

by a source artery and drained by specic veins.

If the patient is a candidate for either endovascular

of cardiovascular events (92).

There are 2 well-established classication schemes

or open surgery, the less invasive option (i.e., an

to describe the severity of PAD. The rst is a func-

endovascular-rst strategy) is the current standard of

tional assessment (Fontaine or Rutherford classica-

care. The selection of a complex lesion (TASC D), for

tion [RC]) (Table 2), and the second is an anatomic

endovascular therapy will vary with the skill and

lesion

Inter-Society

experience of the interventionalist. The goal in

Consensus [TASC]) (Table 3) (4,5). In addition, there

treating a patient who has functional impairment

has been recent interest in the angiosome concept, in

because of claudication is durable relief of symptoms.

helping to inuence optimal revascularization stra-

In patients with CLI and a threatened limb or tissue

tegies for limb salvage (93). An angiosome is an

loss, the goal is rapid reperfusion of the ischemic

classication

(Trans-Atlantic

1348

Olin et al.

JACC VOL. 67, NO. 11, 2016

MARCH 22, 2016:133857

Management of Patients With Peripheral Artery Disease

diffuse disease (TASC D). This preference for less

T A B L E 2 Classications of Severity of PAD

Fontaine
Stage

invasive therapy is evidence based and driven by

Rutherford

Clinical

Grade

Category

shorter length of stay (or treatment as an outpatient

Clinical

entirely) and lower periprocedural morbidity and

Asymptomatic

Asymptomatic

mortality rates, while achieving comparable patency

IIa

Mild claudication

Mild claudication

rates (4- to 5-year primary patency of 60% to 86%,

IIb

Moderate-severe
claudication

Moderate claudication

Severe claudication

with secondary patency rates of 80% to 98%) (94).

CURRENT BEST PRACTICES (EVIDENCE-BASED AND

III

Ischemic rest pain

II

Ischemic rest pain

GUIDELINES). In 2011, the European Society of Car-

IV

Ulceration or
gangrene

III

Minor tissue loss

diology (ESC) (3) and ACC/AHA PAD guidelines (2)

IV

Ulceration or gangrene

recommended an endovascular-rst approach for

aortoiliac lesions, recommended that borderline

PAD peripheral artery disease.

lesions be assessed with hemodynamic gradients, and

supported primary stent placement in the aortoiliac
arteries (Table 4). The current expert consensus

tissue to relieve the ischemia, prevent amputation,

document from the Society for Cardiac Angiography

and restore ambulation.

and Interventions (SCAI) on appropriate use criteria

AORTOILIAC OCCLUSIVE DISEASE

(AUC) for aortoiliac intervention are similar to the

current guidelines (95).

There has been a practice shift over the past 25 years

CLINICAL TRIAL UPDATE. The results of the CLEVER

as the treatment of aortoiliac disease transitioned

trial were discussed previously in the section on

from open surgery with aortobiiliac or aortobifemoral

exercise. BRAVISSIMO (Belgian-Italian-Dutch Trial

bypass to endovascular treatments for complex and

Investigating Abbott Vascular Iliac Stents in the

T A B L E 3 TASC Classication

TASC A

Aortoiliac

Unilateral or bilateral
stenoses of CIA
Unilateral or bilateral single
short (#3 cm) stenosis
of EIA

Femoral-popliteal Single stenosis #10 cm in

length
Single occlusion #5 cm in
length

Infrapopliteal

TASC B

TASC C

TASC D

Short (#3 cm) stenosis of

infrarenal aorta
Unilateral CIA occlusion
Single or multiple stenoses
totaling 310 cm involving
the EIA, not extending into
the CFA
Unilateral EIA occlusion not
involving the origins of
internal iliac or CFA

Bilateral CIA occlusions

Bilateral EIA stenoses 310 cm
long, not extending into
the CFA
Unilateral EIA stenosis
extending into the CFA
Unilateral EIA occlusion that
involves the origins of
internal iliac and/or CFA
Heavily calcied unilateral EIA
occlusion with or without
involvement of origins of
internal iliac and/or CFA

Infrarenal aortoiliac occlusion

Diffuse disease involving the
aorta and both iliac arteries
Diffuse multiple stenoses
involving the unilateral CIA,
EIA, and CFA
Unilateral occlusions of both CIA
and EIA
Bilateral occlusions of EIA
Iliac stenoses in patients with
AAA not amenable to
endograft placement

Multiple lesions (stenoses or

occlusions), each #5 cm
Single stenosis or
occlusion #15 cm, not
involving the
infrageniculate popliteal
artery
Heavily calcied occlusion
#5 cm in length
Single popliteal stenosis

Multiple stenoses or
occlusions totaling
>15 cm, with or without
heavy calcication
Recurrent stenoses or
occlusions after failing
treatment

Chronic total occlusions of CFA

or SFA (>20 cm, involving
the popliteal artery)
Chronic total occlusion of
popliteal artery and
proximal trifurcation vessels

Multiple stenoses in the

Multiple occlusions involving
Single focal stenosis, #5 cm in Multiple stenoses, each #5
target tibial artery and/or
the target tibial artery with
length, in the target tibial
cm in length, or total
single occlusion with total
total lesion length >10 cm,
artery, with occlusion or
length #10 cm, or single
occlusion #3 cm in length,
lesion length >10 cm with
or dense lesion calcication
stenosis of similar or
in the target tibial artery
occlusion or stenosis of
or nonvisualization of
worse severity in the other
with occlusion or stenosis
similar or worse severity in
collaterals; the other tibial
tibial arteries
the other tibial arteries
arteries occluded or with
of similar or worse severity
in the other tibial arteries
dense calcication

Reprinted with permission from Norgren et al. (4) and Jaff et al. (5).
AAA abdominal aortic aneurysm; CFA common femoral artery; CIA common iliac artery; EIA external iliac artery; SFA supercial femoral artery;
TASC Trans-Atlantic Inter-Society Consensus.

Olin et al.

JACC VOL. 67, NO. 11, 2016

MARCH 22, 2016:133857

1349

Management of Patients With Peripheral Artery Disease

Treatment of TASC A, B, C, and D Iliac Lesions) reported 100% technical success in 325 patients with

T A B L E 4 Aortoiliac Guideline-Based Recommendations for

Stable Limb Ischemia (Claudication)

aortoiliac lesions with a 24-month primary patency

rate of 87.9% (96). Neither TASC category nor lesion
length was predictive of restenosis. These data
further

support

the

endovascular-rst

strategy,

regardless of TASC classication, and take into

consideration the evolution of devices (i.e., re-entry
catheters,

crossing

devices,

and

stents),

which

improve success rates for the most complex lesions.

COMMON FEMORAL DISEASE

Patients with common femoral artery (CFA) disease
are particularly symptomatic because the obstruction
not only occurs proximal to the supercial femoral
artery (SFA) but also proximal to the deep femoral
artery (profunda femoris), which is the major collateral artery supplying blood to the lower limb when

ACC/AHA PAD Guidelines (2006, 2011)

ESC PAD Guidelines (2011)

Endovascular procedures are indicated for

patients with a vocational or lifestylelimiting disability due to intermittent
claudication when clinical features suggest
a reasonable likelihood of symptomatic
improvement with endovascular
intervention and: 1) there has been an
inadequate response to exercise or
pharmacological therapy; and/or 2) there is
a very favorable risk-benet ratio (e.g.,
focal aortoiliac occlusive disease) (Class I,
Level of Evidence: A)

When revascularization is indicated, an

endovascular-rst strategy is
recommended in all aortoiliac TASC AC
lesions (Class I, Level of Evidence: C)

Translesional pressure gradients (with and

without vasodilation) should be obtained to
evaluate the signicance of angiographic
iliac arterial stenoses of 50% to 75%
diameter before intervention (Class I, Level
of Evidence: C)

A primary endovascular approach may be

considered in aortoiliac TASC D lesions in
patients with severe comorbidities, if
done by an experienced team (Class IIb,
Level of Evidence: C)

Stenting is effective as primary therapy for

common iliac artery stenosis and occlusions
(Class I, Level of Evidence: B)

Primary stent implantation, rather than

provisional stenting, may be considered
for aortoiliac lesions (Class IIb, Level of
Evidence: C)

there is SFA obstruction. Traditionally, common

femoral endarterectomy has been the CFA revascularization

procedure

of

choice

(2,3),

although

ACC American College of Cardiology; AHA American Heart Association; ESC European Society of
Cardiology; PAD peripheral artery disease; TASC Trans-Atlantic Inter-Society Consensus.

advances in endovascular therapy have shown some

promising results (97). A review of the National Sur-

femoral-popliteal lesions for patients with CLI or for

gical Quality Improvement Program database for 2005

patients with claudication who have had a suboptimal

to 2010 found a combined mortality and morbidity

response

rate of 15% for common femoral endarterectomy,

endovascular-rst approach is recommended for

which was higher than expected (98). Patients

TASC A through C lesions and is a reasonable option

requiring CFA revascularization who are at increased

for TASC D lesions, depending on the experience of

surgical risk may be considered for less invasive

the operator, the patients comorbidities, and proce-

endovascular options.

dure safety (Table 5) (2,3,95).

FEMORAL-POPLITEAL DISEASE

primary stent placement in the femoral-popliteal ar-

to

trial

of

exercise

(Table

5).

An

The 2 guidelines are in conict over the use of

teries, with the ACC/AHA guideline giving it a Class III

This segment begins at the bifurcation of the CFA into

recommendation (do not do) and the ESC guideline

the SFA and the deep femoral (profunda femoris)

making primary femoral stenting reasonable rst-line

artery. The SFA is subject to exion, elongation,

therapy (Class IIa) for intermediate-length lesions

compression, and torsion unlike any other lower-

(108,109). The current evidence from several ran-

extremity artery. This complexity leads to many

domized controlled trials supports primary stenting

challenges for endovascular technology, but despite

in intermediate-length femoral stenoses and occlu-

this, an endovascular-rst approach is currently the

sions (108110). The soon-to-be-published updated

standard of therapy for the majority of lesions

ACC/AHA guidelines will readdress this issue. In

because of the very high procedural success rate and

current practice, the standard is to primarily stent

low risk (3). Some of the most lengthy and complex

intermediate to long SFA lesions.

lesions (TASC D) are more approachable because of

The ACC/AHA guideline broadly lump stents

the re-entry and crossing devices, more experienced

together with atherectomy devices, cryotherapy, laser,

operators, drug-eluting stents (DES) (99,100), and

and cutting balloons, stating they may be useful as

drug-coated balloons (DCBs) (101107) that promise

salvage therapy (Class IIa), but also stating that their

improved long-term patency for patients with clau-

effectiveness remains to proven (Class IIb). Stents

dication (99,100,103,105).

should be removed from this group, because their

CURRENT BEST PRACTICES (EVIDENCE-BASED AND

effectiveness has been established in intermediate-

GUIDELINES). The ACC/AHA (2006, 2011) and ESC

length femoral lesions. Other than the use of the cut-

(2011)

AUC document

ting balloon and rotational atherectomy in lesions that

from the SCAI recommend revascularization in

are resistant to dilation, there is no comparative

PAD

guidelines

and the

1350

Olin et al.

JACC VOL. 67, NO. 11, 2016

MARCH 22, 2016:133857

Management of Patients With Peripheral Artery Disease

intermediate-length (128 mm) femoral lesions treated

T A B L E 5 Femoral-Popliteal Guideline Based Recommendations for

with self-expanding BMS (114). These results need to

Stable Limb Ischemia (Claudication)

be conrmed before this can be recommended as

ACC/AHA PAD Guidelines (2006, 2011)

ESC PAD Guidelines (2011)

Endovascular procedures are indicated for patients

with a vocational or lifestyle-limiting disability
due to intermittent claudication when clinical
features suggest a reasonable likelihood of
symptomatic improvement with endovascular
intervention and: 1) there has been an
inadequate response to exercise or
pharmacological therapy, and/or 2) there is a
very favorable risk-benet ratio (e.g., focal
stenosis) (Class I, Level of Evidence: A)

When revascularization is indicated, an

endovascular-rst strategy is
recommended in all femoropopliteal
TASC AC lesions (Class I, Level of
Evidence: C)

Stents (and other adjunctive techniques such as

lasers, cutting balloons, atherectomy devices,
and thermal devices) can be useful in the
femoral, popliteal, and tibial arteries as salvage
therapy for a suboptimal or failed result from
balloon dilation (e.g., persistent translesional
gradient, residual diameter stenosis >50%, or
ow-limiting dissection) (Class IIa, Level of
Evidence: C)

Primary stent implantation should be

considered in femoropopliteal TASC
B lesions (Class IIa, Level of
Evidence: A)

The effectiveness of stents, atherectomy, cutting

balloons, thermal devices, and lasers for the
treatment of femoral-popliteal arterial lesions is
not well established (except to salvage a
suboptimal result from balloon dilation) (Class
IIb, Level of Evidence: A)

A primary endovascular approach may

also be considered in TASC D lesions
in patients with severe comorbidities
if an experienced interventionist is
available (Class IIb, Level of
Evidence: C)

standard therapy.
Recent randomized controlled trials demonstrating
benet for DES (99,100), DCB (103,105,106), and
covered stents (115117) in femoral-popliteal arteries
will likely result in a change in the guidelines and
indications (Table 6, Figure 3).
There has been some enthusiasm for self-expanding
covered (expanded polytetrauoroethylene) stent
grafts in complex or lengthy femoral-popliteal segments. Two randomized trials comparing covered
stents to BMS had divergent results. One showed a
benet for 2-year primary patency but no difference in
target-lesion revascularization (TLR) or clinical outcomes (116), whereas the other, in longer (>8 cm) lesions, found no difference for primary patency (115
117). When covered stents were compared with
above-the-knee femoral bypass with synthetic graft
material in a broad range of SFA lesion types (TASC A
thru D), no difference was found in the 4-year primary

Primary stent placement is not recommended in the

femoral, popliteal, or tibial arteries (Class III,
Level of Evidence: C)

patency between the 2 options (118).

The Zilver paclitaxel-eluting self-expanding DES

Endovascular intervention is not indicated as

prophylactic therapy in an asymptomatic patient
with lower-extremity PAD (Class III, Level of
Evidence: C)

was superior to PTA in a randomized femoralpopliteal trial, with 1-year patency rates of 83.1% for
primary DES and 32.8% for PTA (p < 0.001) (Figure 3,

Abbreviations as in Table 4.

Table 6) (99). There was also a 1-year patency

advantage for provisional DES after failed PTA
(89.9%) compared with provisional BMS (73.0%,

evidence suggesting that the more expensive atherectomy devices, cryoplasty, or laser angioplasty

p 0.01). The benet was sustained at 2 years, with

primary patency for the DES (74.8%) signicantly

should be preferred over conventional therapy

better than PTA (26.5%, p < 0.01) (100). To date, there

(percutaneous transluminal angioplasty [PTA] and

has been no head-to-head comparison of primary DES

bare-metal stents [BMS]). The ESC guideline distin-

to either BMS or DCB in femoral-popliteal arteries,

guishes

from

but Zeller et al. (104) published a propensity score

adjunctive devices, such as atherectomy devices, cit-

based comparison of DES and DCB in consecutive

ing

patients with TASC C and D long (>10 cm) lesions and

the

bare-metal
proven

self-expanding

benet

of

BMS

stents
over

PTA

in

found no signicant differences in 1-year patency

intermediate-length femoral-popliteal lesions.

(Figure 3, Table 6).

CLINICAL TRIAL UPDATE. Three randomized controlled

DCBs offer the promise of improved patency with a

trials of self-expanding BMS compared with PTA have

reduced need for stents. This is particularly important

shown that the advantage for primary stenting is

in the dynamic environment of the supercial femoral

related to lesion length. For relatively discrete lesions

and popliteal arteries, where mechanical fatigue may

(mean 45 mm) (110), there was no advantage for pri-

lead to stent fracture and increased risk of in-stent

mary stent placement; however, 2 other trials

restenosis. Each DCB is unique with respect to the

(108,109) with longer lesions (>70 mm) showed a

paclitaxel dose (varying from 2 to 3.5 m g/mm2 ), the

signicant patency and functional benet for primary

carrier molecule (excipient), the balloon material, and

femoral-popliteal BMS (Figure 3, Table 6). The proce-

the coating technology used. Superiority for paclitaxel

dural

in

DCB over PTA was rst reported in 2008 (101,102)

femoral-popliteal lesions is very high, but in stable

(Figure 3, Table 6). Subsequently, new DCBs have

limb ischemia, durable patency remains a barrier.

emerged, including the IN.PACT (105,106,111,113) and

Cilostazol has been shown to reduce 1-year restenosis

the Lutonix (103,106) balloons, both of which showed

by more than one-half (20% vs. 49%, p 0.0001) in

clinical superiority to PTA in femoral-popliteal lesions

success

rate

of

endovascular

therapy

Olin et al.

JACC VOL. 67, NO. 11, 2016

MARCH 22, 2016:133857

Management of Patients With Peripheral Artery Disease

F I G U R E 3 Relationship Between Target-Lesion Length and Patency in Comparative Femoral Popliteal Trials

100%
90%
80%
ZILVER PTA
Lesion length: 63.1
Restenosis: 67.2%

Restenosis (%)

70%

ABSOLUTE PTA
Lesion length: 127
Restenosis: 63.5%

ASTRON PTA
Lesion length: 71
Restenosis: 61.1%

60%
THUNDER PTA
Lesion length: 74
Restenosis: 50%

50%

FEMPAC PTA
Lesion length: 47
Restenosis: 40%

IN.PACT SFA PTA

Lesion length: 88.1
Restenosis: 47.6%

FAST PTA
Lesion length: 44.5
Restenosis: 38.6%

40%

FAST BMS
Lesion length: 45.2
Restenosis: 31.7%

30%

ZELLER DES
Lesion length: 195
Restenosis: 30.4%

ASTRON BMS
Lesion length: 98
Restenosis: 34.4%

PACIFIER PTA
Lesion length: 66
Restenosis: 32.4%

VIASTAR BMS
Lesion length: 127
Restenosis: 63.0%
ABSOLUTE BMS
Lesion length: 132
Restenosis: 31.7%

20%

THUNDER DCB
Lesion length: 75
Restenosis: 24%
FEMPAC DCB
Lesion length: 40
Restenosis: 17%

10%

ZILVER DES
Lesion length: 66.4
Restenosis: 16.9%

ZELLER DCB
Lesion length: 194
Restenosis: 23.9%

IN.PACT SFA DCB

Lesion length: 89.4
Restenosis: 17.8%

VIASTAR CS
Lesion length: 132
Restenosis: 37.0%

PACIFIER DCB
Lesion length: 70
Restenosis: 8.6%

50

100

150

200

Lesion Length (in MM)

T A B L E 6 Comparative Femoral-Popliteal Trials

Clinical Trial Name (Ref. #)

FAST (110)
ABSOLUTE (108)
ASTRON (109)
ZILVER (100)
Zeller (104)
THUNDER (111)
FEMPAC (102)
IN.PACT SFA (112)
LEVANT-2 (106)
PACIFIER (113)

Device

Lesion length (mm)

Restenosis (%)

IC/CLI (%)

TLR (%)

De Novo (%)

Occlusions (%)

PTA

121

45  28

38.6

96.5/3.5

18.3

59.5

24.8

RVD (mm)

5.1

BMS

123

45  27

31.7

97.5/2.5

14.9

65.9

36.6

5.3

PTA

53

92  75

63.0

87/13

31

100

32

NR

BMS

51

101  75

37.0*

88/12

28

100

37

NR
NR

PTA

39

65  46*

61.1

97/3

NR

100

39

BMS

34

82  67

34.4*

91/9

NR

100

38

NR

PTA

238

63  41

67.2

90.7/8.5

17.5

24.7

NR

NR

DES

241

66  39

16.9*

90.2/8.9

DES

97

195  65

30.4

91.7/7.2

DCB

131

194  86

23.9

PTA

54

74  67

44.0

DCB

48

75  62

17.0*

PTA

42

47  42

47.0

DCB

45

40  44

19.0*

29.6

NR

NR

21.5

55.7

62.9

NR

19.3

48.1

52.7

NR

NR

48

30

26

4.7

NR

10

38

27

5.2

93/7

17

34

19

5.1

96/4

35

13

5.2

93.7/6.3

20.6

94.6

19.5

4.68

95

25.8

5.0

87.5

21.9

4.8

81/16.8

9.5*

PTA

111

88  51

47.6

DCB

220

89  48

17.8*

PTA

160

63  40

47.4

DCB

316

63  41

34.8*

92.1/7.9

38

83.9

20.6

4.8

PTA

47

66  55

32.4

95.7/4.3

21.4

82.9

38.3

4.9

DCB

41

70  53

95.5/4.5

7.1

68.2

22.7

4.96

8.6*

95/5.0
91.9/8.1

2.4*
37.5

*p < 0.05.
ABSOLUTE Balloon Angioplasty Versus Stenting With Nitinol Stents in the Supercial Femoral Artery; ASTRON Balloon angioplasty versus stenting with nitinol stents
in intermediate length supercial femoral artery lesions; BMS bare-metal stent; CLI critical limb ischemia; CS covered stent; DCB drug-coated balloon; DES drugeluting stent; FAST The Femoral Artery Stenting Trial; FEMPAC Femoral Paclitaxel Trial; IC intermittent claudication; IN.PACT SFA Randomized Trial of IN.PACT
(Paclitaxel) Admiral Drug-Coated Balloon (DCB) vs. Standard Percutaneous Transluminal Angioplasty (PTA) for the Treatment of Atherosclerotic Lesions in the Supercial
Femoral Artery (SFA) and/or Proximal Popliteal Artery (PPA); LEVANT-2 The Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis; NR not
reported; PACIFIER Paclitaxel-coated Balloons in Femoral Indication to Defeat Restenosis; PTA percutaneous transluminal (balloon) angioplasty; RVD reference vessel
diameter; THUNDER Local Taxan With Short Time Contact for Reduction of Restenosis in Distal Arteries; TLR target-lesion revascularization; ZELLER Drug-coated
balloons vs. drug-eluting stents for treatment of long femoropopliteal lesions; ZILVER PTX Randomized Trial.

1351

1352

Olin et al.

JACC VOL. 67, NO. 11, 2016

MARCH 22, 2016:133857

Management of Patients With Peripheral Artery Disease

T A B L E 7 Tibial-Peroneal (Below-Knee) Guideline-Based Recommendations

for CLI

In general, nonambulatory patients with a shortened life expectancy and extensive lower-extremity
tissue necrosis should undergo amputation. Patients

ACC/AHA PAD Guidelines (2006, 2011)

ESC PAD Guidelines (2011)

For individuals with combined inow and

outow disease with CLI, inow lesions
should be addressed rst (Class I, Level
of Evidence: C)

who have the opportunity to regain ambulatory

function should undergo magnetic resonance angiography, computed tomography angiography, or

For patients with limb-threatening lowerextremity ischemia and an estimated life

expectancy #2 years in whom an
autogenous vein conduit is not available,
balloon angioplasty is reasonable to
perform when possible as the initial
procedure to improve distal blood ow
(Class IIa, Level of Evidence: B)

For infrapopliteal lesions,

angioplasty is the preferred
technique, and stent
implantation should be
considered only in the case
of insufcient PTA (Class IIa,
Level of Evidence: C)

The effectiveness of uncoated/uncovered

stents, atherectomy, cutting balloons,
thermal devices, and lasers for the
treatment of infrapopliteal lesions
(except to salvage a suboptimal result
from balloon dilation) is not well
established. (Class IIb, Level of
Evidence: C)

When revascularization in the

infrapopliteal segment is
indicated, the endovascularrst strategy should be
considered (Class IIa, Level
of Evidence: C)

catheter-based angiography to visualize the extent of

lower-extremity

vascular

disease.

The

goal

for

revascularization in patients with CLI is to establish

straight-line ow from the hip to the foot.
CURRENT BEST PRACTICES (EVIDENCE-BASED AND
GUIDELINES). The ACC/AHA (2006, 2011) and ESC

(2011) PAD guidelines agree that an endovascular-rst

approach is reasonable in patients with CLI and
infrapopliteal arterial disease (Table 7) (2,3). In candidates for endovascular treatment, both guidelines
support PTA as the initial approach, with the use of

Primary stent placement is not recommended

in the femoral, popliteal, or tibial arteries
(Class III, Level of Evidence: C)

BMS as needed for bailout lesions (Table 7) (2,3). The

Surgical and endovascular intervention is not

indicated in patients with severe
decrements in limb perfusion (e.g.,
ABI <0.4) in the absence of clinical
symptoms of CLI (Class III, Level of
Evidence: C)

recent evidence demonstrating that DES and DCBs are

guidelines, however, have lagged behind the most

superior to angioplasty alone and BMS for infrapopliteal disease (Table 8).
The expert consensus infrapopliteal AUC document
from the SCAI supports endovascular intervention
for patients with severe claudication and focal target

ABI ankle-brachial index; other abbreviations as in Table 6.

lesions, as well as for anatomically suitable lesions

in patients with CLI (RC 4 to 6) (126). Endovascular
and excellent safety proles (Figure 3, Table 6). The

therapy may be appropriate in patients with moderate

durability of a paclitaxel-eluting DCB in the SFA has

to severe claudication with occlusions or diffuse dis-

been demonstrated at 2 and 5 years (107,111). At 2 years,

ease of 2 or 3 infrapopliteal vessels and for ischemic

patients treated with DCB showed signicantly higher

rest pain or minor tissue loss with 1- or 2-vessel

primary patency than those treated with PTA (78.9%

infrapopliteal disease. It would rarely be appropriate

vs. 50.1%; p < 0.001), including lower clinically driven

to perform infrapopliteal intervention for mild clau-

TLR and similar functional status improvement, with

dication (RC 1) or for moderate to severe claudication

fewer

with major tissue loss for single-vessel infrapopliteal

repeat

interventions.

Five-year

follow-up

demonstrated that TLR remained signicantly lower in

the DCB group (21%) than for PTA (56%, p 0.0005)
(117). The TLR benet in femoral-popliteal arteries was
independent of lesion length. There have been no
safety concerns raised for DCB regarding aneurysm
formation or brotic constriction.

TIBIAL-PERONEAL DISEASE

obstruction (i.e., 2 vessels are patent to the foot).

CLINICAL TRIAL UPDATES. There have been 4 ran-

domized trials (Table 8) (120122,125,127) demonstrating superiority for infrapopliteal DES versus
either PTA, BMS, or DCB. These data provide
convincing evidence favoring infrapopliteal DES over
PTA, BMS, or DCB for: 1) patency; 2) reduced reinterventions; 3) reduced amputation; and 4) improved

Infrapopliteal or below-the-knee disease begins with

event-free survival. These results are not limited to

the popliteal artery at the knee joint and continues

patients with CLI, because most trials have included

to the tibial and peroneal arteries to the ankle.

patients with severe claudication. It would be

Revascularization is indicated in patients with CLI

appropriate to revise the guideline statements in

and, rarely, for those with claudication. The BASIL

favor of DES for infrapopliteal lesions at this time.

(Bypass Versus Angioplasty in Severe Ischaemia

The evidence supporting the use of DCB for infra-

of the Leg) trial compared PTA (balloon alone) to

popliteal lesions is less certain. The DEBATE-BTK

surgery in 452 CLI patients and found no difference

(Drug-Eluting Balloon in Peripheral Intervention for

for amputation-free survival but a lower cost with

Below the Knee Angioplasty Evaluation) trial ran-

PTA (119).

domized

158

infrapopliteal

lesions

in

diabetic

Olin et al.

JACC VOL. 67, NO. 11, 2016

MARCH 22, 2016:133857

Management of Patients With Peripheral Artery Disease

T A B L E 8 Comparative Tibial-Peroneal Trials

Clinical Trial Name (Ref. #)

ACHILLES (120)
DESTINY (121)
YUKON-BTX (122)
DEBATE-BTK (123)
IN.PACT DEEP CLI (124)
IDEAS (125)

Device

Lesion length (mm)

Restenosis (%)

IC/CLI (%)

TLR (%)

De Novo (%)

Occlusions (%)

RVD (mm)

PTA

101

27  21

42.9

NR

16.5

98.2

75.4

2.6

DES

99

27  21

22.4*

NR

10.0

94.7

81.3

2.6

BMS

66

19  10

36.0

0/100

35.0

100

17.0

2.9

DES

74

16  10

17.0

0/100

100

15.0

3.0

BMS

79

31  9

44.4

58.2/41.8

17.5

100

21.5

3.0

DES

82

30  8

19.4*

48.8/51.2

9.7

100

23.2

3.0
2.9

8.0*

PTA

67

131  79

74.0

0/100

43.0

NR

82.1

DCB

65

129  83

27.0*

0/100

18.0

NR

77.5

2.9

PTA

119

129  95

35.5

0.8/99.2

13.1

88.2

45.9

12.9

DCB

239

102  91

41.0

0/100

77.2

38.6

10.2

DCB

25

148  57

57.9

NR

13.6

NR

12.0

NR

DES

27

127  47

28.0*

NR

7.7

NR

23.0

NR

9.2

*p < 0.05.
ACHILLES Comparing Angioplasty and DES in the Treatment of Subjects With Ischemic Infrapopliteal Arterial Disease; DEBATE-BTK Drug-Eluting Balloon in Peripheral
Intervention for Below the Knee Angioplasty Evaluation trial; DESTINY Drug Eluting Stents in the Critically Ischemic Lower Leg; IDEAS Infrapopliteal Drug Eluting Angioplasty Versus Stenting for the Treatment of Long-segment Arterial Disease: The IDEAS-I Randomized Controlled Trial; IN.PACT DEEP CLI Randomized Study of IN.PACT
Amphirion Drug Eluting Balloon vs. Standard PTA (Percutaneous Transluminal Angioplasty) for the Treatment of Below the Knee Critical Limb Ischemia; YUKON-BTX
YUKON-drug-eluting Stent Below The Knee - Prospective Randomized Double-blind Multicenter Study; other abbreviations as in Table 6.

patients with CLI to either DCB (In.Pact Amphirion,

BEST-CLI (Best Endovascular Versus Best Surgical

Medtronic, Minneapolis, Minnesota) or PTA (123). The

Therapy in Patients With CLI) trial has just been

mean lesion length was 129  83 mm, signicantly

launched and will answer the question of whether

(w100 mm) longer than those in the infrapopliteal

surgery in selected patients with CLI and with

DES randomized trials. The primary endpoint, reste-

good-quality saphenous veins is a better choice than

nosis at 1 year, occurred in 27% of patients in the DCB

endovascular therapy (128).

group and 74.3% of those in the PTA group

(p < 0.001). Twelve-month major adverse events

THE FUTURE OF ENDOVASCULAR THERAPY

occurred less frequently in the DEB (31%) than in the

PTA (51%) group (p 0.02), driven mainly by a

The emphasis on value-based care that offers the

reduction in TLR and better ulcer healing. However,

right procedure for the right patient at the right time

there was no difference in the rate of amputation,

requires justication of expensive devices in the

limb salvage, or mortality between the groups.

context of cost-conscious medical care. Unfortu-

In contrast, the results of the In.Pact Deep CLI trial

nately, we often lack head-to-head comparative data

resulted in the DCB (In.Pact Amphirion) being with-

to determine which device or strategy is preferred for

drawn from the market worldwide by the sponsor

specic clinical situations. It is reasonable to choose

(124). The trial enrolled 358 CLI patients with infra-

lower-cost strategies, unless there is evidence justi-

popliteal lesions and randomized them 2:1 to DCB and

fying a more expensive choice.

PTA, respectively. The restenosis rate and TLR were

AUC have been introduced in a variety of cardio-

not different between the 2 groups. There was a

vascular subspecialties. AUC are intended to aid

nonsignicant trend toward higher amputation rates

clinicians in improving patient quality and safety by

in the DEB (8.8%) compared with the PTA group

reducing (but not eliminating) variation in clinical

(3.6%, p 0.08). It seems clear that more data and

practice. Essentially, AUC offer care pathways that

more experience are needed to understand the rela-

are meant to offer guidance. It is recognized that

tive benets of DEB for infrapopliteal lesions (124).

deviation from the care pathway will be the right

In practical terms, an endovascular-rst approach

thing to do in specic cases. Responsible clinicians

is the current standard of care for symptomatic

should be able to articulate their reasons for deviating

infrainguinal atherosclerotic disease. Adverse peri-

from the appropriate care pathway, thereby navi-

procedural events with endovascular therapy for

gating the Scylla and Charybdis of cost-effectiveness

the treatment of infrapopliteal disease appear to be

and clinical necessity.

low, with mortality rates in observational series <1%.

Independent accreditation of hospital facilities,

The recent technological advances of DES and DEBs

such as noninvasive and invasive laboratories, is a

will strengthen this consensus recommendation. The

valuable tool for benchmarking quality of care and

1353

1354

Olin et al.

JACC VOL. 67, NO. 11, 2016

MARCH 22, 2016:133857

Management of Patients With Peripheral Artery Disease

reducing variation. Accreditation for Cardiovascular

yet they are still not offered to a large percentage of

Excellence (ACE) offers on-site reviews for cardiac,

patients with PAD. Additionally, there have been

peripheral, carotid, electrophysiology, and congenital

many advances in minimally invasive techniques to

heart disease. Importantly, accreditation must be

improve the circulation to the lower extremities, and

independent of professional societies, regulators,

in the past decade, more physicians have become

and payers to avoid bias. The value of accreditation

competent to provide high-level care to patients with

is in establishing ongoing procedures to ensure

claudication and CLI. The endovascular arena has

quality and safety. When done properly, independent

changed so dramatically over the past 5 years that it is

accreditation functions more like a coach than a

difcult for the guidelines to keep up with these

policeman to promote a culture of continuous

changes. The goal for the future should be early

improvement. Payers and regulators should require

identication of the PAD patient so that progression to

or reward independent accreditation to support

CLI and amputation can be prevented and appropriate

value-based health care.

therapy to prevent MACE can be implemented. The

optimal treatment of an individual patient involves a

CONCLUSIONS

combination of exercise, pharmacological therapy,

and revascularization (endovascular or open surgery).

Despite the increased prevalence over the past 20

years, PAD continues to be underdiagnosed and

REPRINT REQUESTS AND CORRESPONDENCE: Dr. Jeffrey

undertreated compared with CAD. Because most

W. Olin, Vascular Medicine and Vascular Diagnostic

deaths in patients with PAD are attributable to car-

Laboratory, Zena and Michael A. Wiener Cardiovascular

diovascular disease, patients with PAD (even those

Institute and Marie-Jose and Henry R. Kravis Center for

who are asymptomatic) who are not diagnosed or

Cardiovascular Health, Icahn School of Medicine at

treated will needlessly experience MACE. There are

Mount Sinai, One Gustave L. Levy Place, New York, New

effective therapies to prevent cardiovascular events,

York 10029. E-mail: jeffrey.olin@mountsinai.org.

REFERENCES
1. Patel MR, Conte MS, Cutlip DE, et al. Evaluation
and treatment of patients with lower extremity
peripheral artery disease: consensus denitions
from Peripheral Academic Research Consortium
(PARC) [published correction appears in J Am Coll
Cardiol 2015;65:25782579]. J Am Coll Cardiol
2015;65:93141.
2. Rooke TW, Hirsch AT, Misra S, 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.
J Am Coll Cardiol 2013;61:155570.
3. Tendera M, Aboyans V, Bartelink M, et al. ESC
guidelines on the diagnosis and treatment of peripheral artery disease. Eur Heart J 2011;32:
2851906.
4. Norgren L, Hiatt WR, Dormandy JA, et al., TASC II,
Working Group. Inter-society Consensus for the
Management of Peripheral Arterial Disease (TASC II).
Eur J Vasc Endovasc Surg 2007;33 Suppl 1:S175.
5. TASC Steering Committee, Jaff MR, White CJ,
et al. An update on methods for revascularization
and expansion of the TASC lesion classication to
include below-the-knee arteries: a supplement to
the Inter-Society Consensus for the Management
of Peripheral Arterial Disease (TASC II). Vasc Med
2015;20:46578.
6. Fowkes FG, Rudan D, Rudan I, et al. Comparison of
global estimates of prevalence and risk factors for
peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013;382:132940.

7. Sampson U, Fowkes F, McDermott M, et al.

Global and regional burden of death and disability
from peripheral artery disease: 21 world regions,
1990-2010. Glob Heart 2014;9:14558.e21.

15. Leng GC, Fowkes FG, Lee AJ, Dunbar J,

Housley E, Ruckley CV. Use of ankle brachial
pressure index to predict cardiovascular events
and death: a cohort study. BMJ 1996;313:14404.

8. Pande RL, Perlstein TS, Beckman JA, et al. Secondary prevention and mortality in peripheral artery
disease: National Health and Nutrition Examination
Study, 1999 to 2004. Circulation 2011;124:1723.

16. 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;

9. Hirsch AT, Criqui MH, Treat-Jacobson D, et al.

Peripheral arterial disease detection, awareness, and
treatment in primary care. JAMA 2001;286:131724.

17. McDermott MM, Greenland P, Liu K, et al. Leg

symptoms in peripheral arterial disease: associated
clinical characteristics and functional impairment.
JAMA 2001;286:1599606.

326:3816.

10. Selvin E, Erlinger TP. Prevalence of and risk

factors for peripheral arterial disease in the United
States: results from the National Health and
Nutrition Examination Survey, 19992000. Circulation 2004;110:73843.
11. Nehler MR, Duval S, Diao L, et al. Epidemiology
of peripheral arterial disease and critical limb
ischemia in an insured national population. J Vasc
Surg 2014;60:68695.e2.
12. Armstrong EJ, Chen DC, Westin GG, et al.
Adherence to guideline-recommended therapy is
associated with decreased major adverse cardiovascular events and major adverse limb events
among patients with peripheral artery disease.
J Am Heart Assoc 2014;3:e000697.
13. Criqui MH, Aboyans V. Epidemiology of peripheral artery disease. Circ Res 2015;116:150926.
14. Joosten MM, Pai JK, Bertoia ML, et al. Associations between conventional cardiovascular risk
factors and risk of peripheral artery disease in
men. JAMA 2012;308:16607.

18. McDermott MM, Liu K, Greenland P, et al.

Functional decline in peripheral artery disease:
associations with the ankle brachial index and leg
symptoms. JAMA 2004;292:45361.
19. McDermott MM, Guralnik JM, Tian L, et al.
Associations of borderline and low normal anklebrachial index values with functional decline at
5-year follow-up: the WALCS (Walking and Leg Circulation Study). J Am Coll Cardiol 2009;53:105662.
20. McDermott MM, Greenland P, Tian L, et al.
Association of 6-minute walk performance and
physical activity with incident ischemic heart
disease events and stroke in peripheral artery
disease. J Am Heart Assoc 2015;4:e001846.
21. Aboyans V, Criqui MH, Abraham P, et al., for
the American Heart Association Council on Peripheral Vascular Disease, Council on Epidemiology and Prevention, Council on Clinical
Cardiology, Council on Cardiovascular Nursing,
Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery

Olin et al.

JACC VOL. 67, NO. 11, 2016

MARCH 22, 2016:133857

and Anesthesia. Measurement and interpretation

of the ankle-brachial index: a scientic statement
from the American Heart Association [published
correction appears in Circulation 2013;127:e264].
Circulation 2012;126:2890909.
22. Resnick HE, Lindsay RS, McDermott MM, et al.
Relationship of high and low ankle brachial index to
all-cause and cardiovascular disease mortality: the
Strong Heart Study. Circulation 2004;109:7339.
23. Ankle Brachial Index Collaboration. Ankle
brachial index combined with Framingham risk
score to predict cardiovascular events and mortality: a meta-analysis. JAMA 2008;300:197208.
24. Lee JY, Lee SW, Lee WS, et al. Prevalence and
clinical implications of newly revealed, asymptomatic abnormal ankle-brachial index in patients
with signicant coronary artery disease. J Am Coll
Cardiol Intv 2013;6:130313.
25. Diehm C, Schuster A, Allenberg JR, et al. High
prevalence of peripheral arterial disease and comorbidity in 6880 primary care patients: crosssectional study. Atherosclerosis 2004;172:95105.
26. Cooke JP, Wilson AM. Biomarkers of peripheral
arterial disease. J Am Coll Cardiol 2010;55:201723.
27. Hiatt WR, Zakharyan A, Fung ET, et al.
A validated biomarker panel to identify peripheral
artery disease. Vasc Med 2012;17:38693.
28. McDermott MM, Liu K, Green D, et al. Changes in
D-dimer and inammatory biomarkers before
ischemic events in patients with peripheral artery
disease: The BRAVO Study. Vasc Med 2016;21:1220.
29. Hiatt WR, Armstrong EJ, Larson CJ, Brass EP.
Pathogenesis of the limb manifestations and exercise limitations in peripheral artery disease. Circ
Res 2015;116:152739.
30. McDermott MM, Mehta S, Greenland P. Exertional leg symptoms other than intermittent
claudication are common in peripheral artery disease. Arch Intern Med 1999;159:38792.
31. Gorely T, Crank H, Humphreys L, Nawaz S, Tew GA.
Standing still in the street: experiences, knowledge
and beliefs of patients with intermittent claudication: a
qualitative study. J Vasc Nurs 2015;33:49.
32. Cunningham MA, Swanson V, Pappas E,
OCarroll RE, Holdsworth RJ. Illness beliefs and
walking behavior after revascularization for intermittent claudication: a qualitative study.

Management of Patients With Peripheral Artery Disease

peripheral artery disease. J Vasc Surg 2013;58:

167887.
37. Chang P, Nead KT, Olin JW, Myers J, Cooke JP,
Leeper NJ. Effect of physical activity assessment
on prognostication for peripheral artery disease
and mortality. Mayo Clin Proc 2015;90:33945.
38. Sakamoto S, Yokoyama N, Tamori Y, Akutsu K,
Hashimoto H, Takeshita S. Patients with peripheral
artery disease who complete 12-week supervised
exercise training program show reduce cardiovascular mortality and morbidity. Circ J 2009;73:
16773.
39. Gardner AW, Montgomery PS, Parker DE.
Optimal exercise program length for patients with
claudication. J Vasc Surg 2012;55:134654.
40. Popplewell MA, Bradbury AW. Why do health
systems not fund supervised exercise programmes
for intermittent claudication? Eur J Vasc Endovasc
Surg 2014;48:60810.
41. Collins TC, Lunos S, Carlson T, et al. Effects of
a home-based walking intervention on mobility
and quality of life in people with diabetes and
peripheral arterial disease: a randomized control
trial. Diabetes Care 2011;34:21749.
42. Mays RJ, Hiatt WR, Casserly IP, et al.
Community-based walking exercise for peripheral
artery disease: an exploratory pilot study. Vasc
Med 2015;20:33947.
43. Gardner AW, Parker DE, Montgomery PS,
Scott KJ, Blevins SM. Efcacy of quantied homebased exercise and supervised exercise in patients
with intermittent claudication: a randomized
controlled trial. Circulation 2011;123:4918.
44. Gardner AW, Parker DE, Montgomery PS,
Blevins SM. Step-monitored home exercise
improves ambulation, vascular function, and
inammation in symptomatic patients with peripheral artery disease: a randomized controlled
trial. J Am Heart Assoc 2014;3:e001107.
45. McDermott MM, Domanchuk K, Liu K, et al.
The Group Oriented Arterial Leg Study (GOALS) to
improve walking performance in patients with
peripheral arterial disease. Contemp Clin Trials
2012;33:131120.
46. McDermott MM, Liu K, Guralnik JM, et al.
Home-based walking exercise intervention in
peripheral artery disease: a randomized control

J Cardiopulm Rehabil Prev 2014;34:195201.

trial. JAMA 2013;310:5765.

33. Hiatt WR, Regensteiner JG, Hargarten ME,

Wolfel EE, Brass EP. Benet of exercise conditioning for patients with peripheral arterial disease. Circulation 1990;81:6029.

47. McDermott MM, Guralnik JM, Criqui MH, et al.

Home-based exercise in peripheral artery disease:
12-month follow-up of the GOALS randomized
trial. J Am Heart Assoc 2014;3:e000711.

34. Hiatt
WR,
Wolfel
EE,
Meier
RH,
Regensteiner JG. Superiority of treadmill walking
exercise versus strength training for patients with
peripheral arterial disease: implications for the

48. McDermott MM, Guralnik JM, Criqui MH, et al.

Unsupervised exercise and mobility loss in

mechanism of the training response. Circulation

1994;90:186674.

49. Weinberg MD, Lau JF, Roseneld K, Olin JW.

Peripheral artery disease, part 2: medical and endovascular treatment. Nat Rev Cardiol 2011;8:42941.

35. Hiatt WR, Regensteiner JG, Wolfel EE,

Carry MR, Brass EP. Effect of exercise training on
skeletal muscle histology and metabolism in peripheral arterial disease. J Appl Physiol (1985)
1996;81:7808.
36. Mays R, Rogers R, Hiatt WR, Regensteiner JG.
Community walking programs for treatment of

peripheral artery disease: a randomized controlled

trial. J Am Heart Assoc 2015;4:e001659.

50. Bronas UG, Hirsch AT, Murphy T, et al., for the

CLEVER Research Group. Design of the multicenter standardized supervised exercise training
intervention for the CLaudication: Exercise Vs
Endoluminal Revascularization (CLEVER) study.
Vasc Med 2009;14:31321.

51. Hamburg NM, Balady GJ. Exercise rehabilitation

in peripheral artery disease: functional impact and
mechanisms of benets. Circulation 2011;123:8797.
52. Murphy TP, Cutlip DE, Regensteiner JG, et al.,
for the CLEVER Study Investigators. Supervised
exercise versus primary stenting for claudication
resulting from aortoiliac peripheral artery disease:
six-month outcomes from the Claudication: Exercise Versus Endoluminal Revascularization
(CLEVER) study. Circulation 2012;125:1309.
53. Nordanstig J, Taft C, Henster M, Perlander A,
Osterberg K, Jivegrd L. Improved quality of life
after 1 year with an invasive versus a noninvasive
treatment strategy in claudicants: one-year results
of the Invasive Revascularization or Not in Intermittent Claudication (IRONIC) Trial. Circulation
2014;130:93947.
54. Lundgren F, Dahllf A, Lundholm K,
Scherstn T, Volkmann R. Intermittent claudication: surgical reconstruction or physical training?
A prospective randomized trial of treatment efciency. Ann Surg 1989;209:34655.
55. 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 [published
correction appears in J Am Coll Cardiol 2015;65:
2055]. J Am Coll Cardiol 2015;65:9991009.
56. Fakhry F, Spronk S, van der Laan L, et al.
Endovascular revascularization and supervised
exercise for peripheral artery disease and intermittent claudication: a randomized clinical trial.
JAMA 2015;314:193644.
57. Spronk S, Bosch JL, den Hoed PT, Veen HF,
Pattynama PM, Hunink MG. Cost-effectiveness of
endovascular revascularization compared to supervised hospital-based exercise training in patients
with intermittent claudication: a randomized
controlled trial. J Vasc Surg 2008;48:147280.
58. Fokkenrood HJ, Scheltinga MR, Koelemay MJ,
et al. Signicant savings with a stepped care model
for treatment of patients with intermittent claudication. Eur J Vasc Endovasc Surg 2014;48:4239.
59. Subherwal S, Patel MR, Kober L, et al. Missed
opportunities: despite improvement in use of
cardioprotective medications among patients with
lower-extremity peripheral artery disease, underuse remains. Circulation 2012;126:134554.
60. Olin JW, Allie DE, Belkin M, et al. ACCF/AHA/
ACR/SCAI/SIR/SVM/SVN/SVS 2010 performance
measures for adults with peripheral artery disease:
a report of the American College of Cardiology
Foundation/American Heart Association Task Force
on Performance Measures, the American College of
Radiology, the Society for Cardiac Angiography and
Interventions, the Society for Interventional Radiology, the Society for Vascular Medicine, the Society for Vascular Nursing, and the Society for
Vascular Surgery (Writing Committee to Develop
Clinical Performance Measures for Peripheral Artery
Disease). J Am Coll Cardiol 2010;56:214781.
61. Armstrong EJ, Wu J, Singh GD, et al. Smoking
cessation is associated with decreased mortality
and improved amputation-free survival among
patients with symptomatic peripheral artery disease. J Vasc Surg 2014;60:156571.

1355

1356

Olin et al.

JACC VOL. 67, NO. 11, 2016

MARCH 22, 2016:133857

Management of Patients With Peripheral Artery Disease

62. Dartmouth-Hitchcock Medical Center. Vascular

Physician Offer and Report (VAPOR) Trial. 2015.
Available at: https://clinicaltrials.gov/ct2/show/
NCT02220686?termNCT02220686&rank1.
Accessed January 7, 2016.
63. Dawson

DL,

Cutler

BS,

Meissner

MH,

Strandness DE Jr. Cilostazol has benecial effects

in treatment of intermittent claudication: results
from a multicenter, randomized, prospective,
double-blind trial. Circulation 1998;98:67886.
64. Pande RL, Hiatt WR, Zhang P, Hittel N,
Creager MA. A pooled analysis of the durability
and predictors of treatment response of cilostazol
in patients with intermittent claudication. Vasc
Med 2010;15:1818.
65. Hiatt WR, Money SR, Brass EP. Long-term
safety of cilostazol in patients with peripheral artery disease: the CASTLE study (Cilostazol: A
Study in Long-Term Effects). J Vasc Surg 2008;
47:3306.
66. De Backer T, Vander Stichele R, Lehert P, Van
Bortel L. Naftidrofuryl for intermittent claudication: meta-analysis based on individual patient
data. BMJ 2009;338:b603.
67. Heart Outcomes Prevention Evaluation Study
Investigators. Effects of an angiotensinconverting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients [published
corrections appear in N Engl J Med 2000;342:
1376 and N Engl J Med 2000;342:748]. N Engl J
Med 2000;342:14553.
68. stergren 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;25:1724.
69. ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular
events. N Engl J Med 2008;358:154759.
70. Armstrong EJ, Chen DC, Singh GD,
Amsterdam EA, Laird JR. Angiotensin-converting
enzyme inhibitor or angiotensin receptor blocker
use in associated with reduced major adverse
cardiovascular events among patients with critical
limb ischemia. Vasc Med 2015;20:23744.

patients with peripheral artery disease: insights from

the REACH registry. Eur Heart J 2014;35:286472.
75. Vogel TR, Dombrovskiy VY, Galianes EL,
Kruse RL. Preoperative statins and limb salvage after
lower extremity revascularization in the Medicare
population. Circ Cardiovasc Interv 2013;6:694700.
76. Berger JS, Krantz MJ, Kittelson JM, Hiatt WR.
Aspirin for the prevention of cardiovascular events
in a general population screened for a low anklebrachial index: a randomized controlled trial.
JAMA 2009;301:190919.
77. Fowkes FG, Price JF, Stewart MC, et al., for the
Aspirin for Asymptomatic Atherosclerosis Trialists.
Aspirin for prevention of cardiovascular events in a
general population screened for a low ankle
brachial index: a randomized controlled trial.
JAMA 2010;303:8418.
78. Belch J, MacCuish A, Campbell I, et al., on behalf
of 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.
79. Morrow DA, Braunwald E, Bonaca MP, et al.,
for the TRA 2P-TIMI 50 Steering Committee and
Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med
2012;366:140413.
80. CAPRIE Steering Committee. A randomised,
blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet
1996;348:132939.
81. Bhatt DL, Fox KAA, Hacke W, et al., for the
CHARISMA Investigators. Clopidogrel and aspirin
versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:170617.
82. Cacoub PP, Bhatt DL, Steg PG, Topol EJ,
Creager MA, for the CHARISMA Investigators. Patients with peripheral arterial disease in the
CHARISMA Trial. Eur Heart J 2009;30:192201.
83. Armstrong EJ, Anderson DR, Yeo KK, et al.
Association of dual-antiplatelet therapy with
reduced major adverse cardiovascular events in

71. Stone NJ, Robinson JG, Lichtenstein AH, et al.

2013 ACC/AHA guideline on the treatment of blood

patients with symptomatic peripheral arterial disease. J Vasc Surg 2015;62:15765.e1.

cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of
Cardiology/American Heart Association Task Force
on Practice Guidelines [published correction appears in J Am Coll Cardiol 2014;63 25 pt B:30245].
J Am Coll Cardiol 2014;63:2889934.

84. Belch JJF, Dormandy J, for the CASPAR

Writing Committee. Results of the randomized,
placebo-controlled clopidogrel and acetylsalicylic

72. Heart Protection Study Collaborative Group.

Randomized trial of the effects of cholesterollowering 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;45:64554.
73. Westin GG, Armstrong EJ, Bang H, et al. Association between statin medications and mortality, major adverse cardiovascular event, and
amputation-free survival in patients with critical

acid in bypass surgery for peripheral arterial disease (CASPAR) Trial [published correction appears
in J Vasc Surg 2011;53:564]. J Vasc Surg 2010;52:
82533, 833.e12.
85. University of Texas Southwestern Medical
Center. Antiplatelet Strategy For Peripheral Arterial Interventions for Revascularization of Lower
Extremities (ASPIRE PAD). 2014. Available at:
https://clinicaltrials.gov/ct2/show/NCT02317822?
termNCT02317822&rank1. Accessed January
7, 2016.

87. Bonaca MP, Scirica BM, Creager MA, et al.

Vorapaxar in patients with peripheral artery disease: results from TRA2 P-TIMI 50. Circulation
2013;127:15229.
88. Cooke JP, Losordo DW. Modulating the
vascular response to limb ischemia: angiogenic
and cell therapies. Circ Res 2015;116:156178.
89. Gupta NK, Armstrong EJ, Parikh SA. The current state of stem cell therapy for peripheral
artery disease. Curr Cardiol Rep 2014;16:447.
90. AstraZeneca. A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients with Peripheral Artery Disease (EUCLID).
2015. Available at: https://clinicaltrials.gov/ct2/
show/NCT01732822?termNCT01732822&rank1
www.clinicaltrials.gov. Accessed January 7, 2016.
91. Bayer. Rivaroxaban for the Prevention of Major
Adverse Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS). 2016. Available
at: https://clinicaltrials.gov/ct2/show/NCT01776424?
termNCT01776424&rank1. Accessed January 7,
2016.
92. Beckman JA, Creager MA. Critical limb
ischemia and intermediate-term survival. J Am
Coll Cardiol Intv 2014;7:14502.
93. Iida O, Soga Y, Kawasaki D, et al. Long-term
results of direct and indirect endovascular revascularization based on the angiosome concept in
patients with critical limb ischemia presenting with
isolated below-the-knee lesions. J Vasc Surg 2012;
55:36370.e5.
94. Jongkind V, Akkersdijk GJ, Yeung KK,
Wisselink W. A systematic review of endovascular
treatment of extensive aortoiliac occlusive disease. J Vasc Surg 2010;52:137683.
95. Klein AJ, Feldman DN, Aronow HD, et al. SCAI
expert consensus statement for aorto-iliac arterial
intervention appropriate use. Catheter Cardiovasc
Interv 2014;84:5208.
96. de Donato G, Bosiers M, Setacci F, et al.
24-Month data from the BRAVISSIMO: a largescale prospective registry on iliac stenting for
TASC A & B and TASC C & D lesions. Ann Vasc Surg
2015;29:73850.
97. Bonvini RF, Rastan A, Sixt S, et al. Endovascular treatment of common femoral artery disease: medium-term outcomes of 360 consecutive
procedures. J Am Coll Cardiol 2011;58:7928.
98. Nguyen BN, Amdur RL, Abugideiri M,
Rahbar R, Neville RF, Sidawy AN. Postoperative
complications after common femoral endarterectomy. J Vasc Surg 2015;61:148994.e1.
99. Dake MD, Ansel GM, Jaff MR, et al., on behalf
of the Zilver PTX Investigators. Paclitaxel-eluting
stents show superiority to balloon angioplasty and
bare metal stents in femoropopliteal disease:
twelve-month Zilver PTX randomized study results. Circ Cardiovasc Interv 2011;4:495504.

74. Kumbhani DJ, Steg PG, Cannon CP, et al., on

86. Jones WS, Tricoci P, Huang Z, et al. Vorapaxar

in patients with peripheral artery disease and
acute coronary syndrome: insights from Thrombin
Receptor Antagonist for Clinical Event Reduction

100. Dake MD, Ansel GM, Jaff MR, et al., for the
Zilver PTX Investigators. Sustained safety and
effectiveness of paclitaxel-eluting stents for femoropopliteal lesions: 2-year follow-up from the
Zilver PTX randomized and single-arm clinical
studies [published correction appears in J Am Coll

behalf of the REACH Registry Investigators. Statin

therapy and long-term adverse limb outcomes in

in Acute Coronary Syndrome (TRACER). Am Heart

J 2014;168:58896.

Cardiol 2013;62:666]. J Am Coll Cardiol 2013;61:

241727.

limb ischemia. J Am Coll Cardiol 2014;63:68290.

Olin et al.

JACC VOL. 67, NO. 11, 2016

MARCH 22, 2016:133857

101. Tepe G, Zeller T, Albrecht T, et al. Local delivery

of paclitaxel to inhibit restenosis during angioplasty
of the leg. N Engl J Med 2008;358:68999.
102. Werk M, Langner S, Reikensmeier B, et al.
Inhibition of restenosis in femoropopliteal arteries:
paclitaxel-coated versus uncoated balloon:
femoral paclitaxel randomized pilot trial [published correction appears in Circulation 2008;118:
e670]. Circulation 2008;118:135865.
103. Scheinert D, Duda S, Zeller T, et al. The
LEVANT I (Lutonix Paclitaxel-Coated Balloon for
the Prevention of Femoropopliteal Restenosis)
trial for femoropopliteal revascularization: rst-inhuman randomized trial of low-dose drug-coated
balloon versus uncoated balloon angioplasty.
J Am Coll Cardiol Intv 2014;7:109.
104. Zeller T, Rastan A, Macharzina R, et al. Drugcoated balloons vs. drug-eluting stents for treatment of long femoropopliteal lesions. J Endovasc
Ther 2014;21:35968.
105. Scheinert D, Schulte KL, Zeller T, Lammer J,
Tepe G. Paclitaxel-releasing balloon in femoropopliteal lesions using a BTHC excipient:
twelve-month results from the BOLUX P-I randomized trial. J Endovasc Ther 2015;22:1421.
106. Roseneld K, Jaff MR, White CJ, et al., for the
LEVANT 2 Investigators. Trial of a paclitaxelcoated balloon for femoropopliteal artery dis-

Management of Patients With Peripheral Artery Disease

versus standard percutaneous transluminal angioplasty for the treatment of supercial femoral
and popliteal peripheral artery disease: 12-month
results from the IN.PACT SFA randomized trial.
Circulation 2015;131:495502.
113. Werk M, Albrecht T, Meyer DR, et al. Paclitaxelcoated balloons reduce restenosis after femoropopliteal angioplasty: evidence from the randomized
PACIFIER trial. Circ Cardiovasc Interv 2012;5:83140.
114. Iida O, Yokoi H, Soga Y, et al., for the STOP-IC
investigators. Cilostazol reduces angiographic
restenosis after endovascular therapy for femoropopliteal lesions in the Sufcient Treatment of
Peripheral Intervention by Cilostazol Study. Circulation 2013;127:230715.
115. Lammer J, Zeller T, Hausegger KA, et al.
Heparin-bonded covered stents versus bare-metal
stents for complex femoropopliteal artery lesions:
the randomized VIASTAR trial (Viabahn endoprosthesis with PROPATEN bioactive surface [VIA]
versus bare nitinol stent in the treatment of long
lesions in supercial femoral artery occlusive disease). J Am Coll Cardiol 2013;62:13207.
116. Lammer J, Zeller T, Hausegger KA, et al.
Sustained benet at 2 years for covered stents
versus bare-metal stents in long SFA lesions: the
VIASTAR trial [published correction appears in
Cardiovasc Intervent Radiol 2015;38:77980].

ease. N Engl J Med 2015;373:14553.

Cardiovasc Intervent Radiol 2015;38:2532.

107. Laird JR, Schneider PA, Tepe G, et al., for the

IN.PACT SFA Investigators. Durability of treatment
effect using a drug-coated balloon for femo-

117. Geraghty PJ, Mewissen MW, Jaff MR,

Ansel GM, for the VIBRANT Investigators. Three-

ropopliteal lesions: 24-month results of IN.PACT

SFA. J Am Coll Cardiol 2015;66:232938.
108. Schillinger M, Sabeti S, Loewe C, et al.
Balloon angioplasty versus implantation of nitinol
stents in the supercial femoral artery. N Engl J
Med 2006;354:187988.
109. Dick P, Wallner H, Sabeti S, et al. Balloon
angioplasty versus stenting with nitinol stents in
intermediate length supercial femoral artery lesions. Catheter Cardiovasc Interv 2009;74:10905.
110. Krakenberg H, Schlter M, Steinkamp HJ, et al.
Nitinol stent implantation versus percutaneous
transluminal angioplasty in supercial femoral artery lesions up to 10 cm in length: the Femoral Artery
Stenting Trial (FAST). Circulation 2007;116:28592.
111. Tepe G, Schnorr B, Albrecht T, et al. Angioplasty of femoral-popliteal arteries with drug
coated balloons: 5-year follow-up of the THUNDER trial. J Am Coll Cardiol Intv 2015;8:1028.
112. Tepe G, Laird J, Schneider P, et al., for the IN.
PACT SFA Trial Investigators. Drug-coated balloon

year results of the VIBRANT Trial of VIABAHN

endoprosthesis versus bare nitinol stent implantation for complex supercial femoral artery
occlusive disease. J Vasc Surg 2013;58:38695.e4.
118. McQuade K, Gable D, Pearl G, Theune B,
Black S. Four-year randomized prospective
comparison of percutaneous ePTFE/nitinol selfexpanding stent graft versus prosthetic femoralpopliteal bypass in the treatment of supercial
femoral artery occlusive disease. J Vasc Surg
2010;52:58490; discussion 5901, 591.e1e7.
119. Bradbury AW, Adam DJ, Bell J, et al., for the
BASIL Trial Participants. Bypass Versus Angioplasty
in Severe Ischaemia of the Leg (BASIL) trial: analysis
of amputation free and overall survival by treatment received [published correction appears in J
Vasc Surg 2010;52:1751]. J Vasc Surg 2010;51:
18S31S.
120. Scheinert D, Katsanos K, Zeller T, et al., for the
ACHILLES Investigators. A prospective randomized
multicenter comparison of balloon angioplasty and
infrapopliteal stenting with the sirolimus-eluting
stent in patients with ischemic peripheral arterial

disease: 1-year results from the ACHILLES trial.

J Am Coll Cardiol 2012;60:22905.
121. Bosiers M, Scheinert D, Peeters P, et al.
Randomized comparison of everolimus-eluting
versus bare-metal stents in patients with critical
limb ischemia and infrapopliteal arterial occlusive
disease. J Vasc Surg 2012;55:3908.
122. Rastan A, Tepe G, Krakenberg H, et al.
Sirolimus-eluting stents vs. bare-metal stents
for treatment of focal lesions in infrapopliteal
arteries: a double-blind, multi-centre, randomized
clinical trial. Eur Heart J 2011;32:227481.
123. Liistro F, Porto I, Angioli P, et al. Drug-eluting
balloon in peripheral intervention for below the
knee angioplasty evaluation (DEBATE-BTK): a
randomized trial in diabetic patients with critical
limb ischemia. Circulation 2013;128:61521.
124. Zeller T, Baumgartner I, Scheinert D, et al., for
the IN.PACT DEEP Trial Investigators. Drug-eluting
balloon versus standard balloon angioplasty for
infrapopliteal revascularization in critical limb
ischemia: 12-month results from the IN.PACT DEEP
randomized trial. J Am Coll Cardiol 2014;64:
156876.
125. Siablis D, Kitrou PM, Spiliopoulos S, Katsanos K,
Karnabatidis D. Paclitaxel-coated balloon angioplasty versus dug-eluting stenting for the treatment
of infrapopliteal long-segment arterial occlusive
disease: the IDEAS randomized controlled trial. J Am
Coll Cardiol Intv 2014;7:104856.
126. Gray BH, Diaz-Sandoval LJ, Dieter RS, Jaff MR,
White CJ. SCAI expert consensus statement for
infrapopliteal arterial intervention appropriate use.
Catheter Cardiovasc Interv 2014;84:53945.
127. Rastan A, Brechtel K, Krakenberg H, et al.
Sirolimus-eluting stents for treatment of infrapopliteal arteries reduce clinical event rate compared
to bare-metal stents: long-term results from a randomized trial. J Am Coll Cardiol 2012;60:58791.
128. Farber A, Roseneld K, Menard M. The BESTCLI Trial: a multidisciplinary effort to assess which
therapy is best for patients with critical limb
ischemia. Tech Vasc Interv Radiol 2014;17:2214.

KEY WORDS ankle-brachial index,

claudication, drug-eluting stents,
endovascular therapy, exercise therapy,
vascular diseases

Go to http://www.acc.org/jaccjournals-cme to take the CME

quiz for this article.

1357