2016-peripheral artery disease

8172019 2016-Peripheral Artery Disease

httpslidepdfcomreaderfull2016-peripheral-artery-disease 120

THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Peripheral Artery Disease

Evolving Role of Exercise Medical Therapy and

Endovascular Options

Jeffrey W Olin DOa Christopher J White MD b Ehrin J Armstrong MD MSCc Daniella Kadian-Dodov MDa

William R Hiatt MDd

JACC JOURNAL CME

This article has been selected as the monthrsquos JACC Journal CME activityavailable online at httpwwwaccorgjacc-journals-cme by selecting the

CME tab on the top navigation bar

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

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

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

commensurate with the extent of their participation in the activity

Method of Participation and Receipt of CME Certi1047297cate

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

provided must be answered correctly to obtain CME credit

4 Complete a brief evaluation

5 Claim your CME credit and receive your certi1047297cate electronically by

following the instructions given at the conclusion of the activity

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

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

peripheral artery disease so as to decrease the likelihood of experiencinga myocardial infarction stroke and cardiovascular death 2) for your

patients with claudication counsel on lifestyle modi1047297cations to improve

their qualityof life and3) diagnose patients with critical limb ischemiaso

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

Author Disclosures Dr Olin serves on the steering committee and

scienti1047297c advisory board for Merck for the TRAP2 trial serves on the

international steering committee for the EUCLID Trial and is a site

investigator for AstraZeneca Dr White serves on the research advi-

sory board for Lutonix and Surmodics Dr Armstrong is a consultant

advisory board member for Abbott Vascular Medtronic Merck P1047297zer

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

Medium of Participation Print (article only) online (article and quiz)

CME Term of Approval

Issue Date March 22 2016

Expiration Date March 21 2017

From the aZena and Michael A Wiener Cardiovascular Institute amp Marie-Joseeacute 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 Colo-

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

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

steering committee and scienti1047297c advisory board for Merck for the TRAP2 trial serves on the international steering committee for

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 consultantadvisory board member for Abbott Vascular Medtronic Merck P 1047297zer and Spec-

tranetics 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

Listen to this manuscriptrsquos

audio summary by

JACC Editor-in-Chief

Dr Valentin Fuster

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P U B L I S H E D B Y E L S E V I E R h t t p d x d o i o r g 1 0 1 0 1 6 j j a c c 2 0 1 5 1 2 0 4 9






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 ldquoendovascular 1047297rstrdquo 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 2016671338ndash57)

copy 2016 by the American College of Cardiology Foundation

Peripheral artery disease (PAD) refers to athero-

sclerosis involving the aorta iliac and lower-

extremity arteries and is associated with

signi1047297cant morbidity and mortality (12) Since the

last iteration of the guidelines focused on PAD ( 2ndash4)

published data have emerged that may alter the stan-

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

view will delve in great detail into the management

of PAD patients highlighting the roles of exercise

optimal medical management and endovascular

therapy Surgical revascularization will not be dis-

cussed because current expert consensus documents

recommend an ldquoendovascular 1047297rstrdquo approach for the

majority of PAD patients requiring revascularization

(23)

Despite initiatives to improve on the identi1047297cation

and management of PAD (25) the number of people

affected and disease morbidity continues to rise As

of 2010 more than 200 million people worldwide areliving with PAD which represents a 287 increased

prevalence in low- and middle-income countries and

a 131 increase in high-income countries over a

10-year period (67) Prevalence studies in the United

States estimate that 59 of Americans over 40 years

of age have PAD (8) When speci1047297c high-risk pop-

ulations are evaluated estimates of PAD prevalence

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

PAD is increased in African Americans and Hispanics

(10) A recent retrospective cohort study evaluating

nearly 12 million insured American adults reported

mean annual incidence rates of PAD and critical limbischemia (CLI) of 235 and 035 respectively (11)

The risk factors for PAD mirror those of cerebrovas-

cular and coronary atherosclerosis including a posi-

tive family history diabetes mellitus smoking

chronic kidney disease hypertension and hyperlip-

idemia (59101213) Smoking and diabetes are

particularly virulent and are associated with worse

outcomes independent of other risk factors (14)

Identi1047297cation of patients with PAD is important

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

diovascular events even in the setting of asymp-

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

patients with PAD will experience a nonfatal cardio-

vascular event and 15 to 20 will die (most of

cardiovascular causes) (816)

Most patients with PAD fall into 1 of 3 groups

classic claudication (10 to 30) atypical leg pain

(20 to 40) or asymptomatic (nearly 50) Formal

testing to assess functional capacity and endurance

shows signi1047297cant impairment in patients with PADeven if asymptomatic Although the majority of pa-

tients report leg symptoms other than classic claudi-

cation greater functional decline is associated with

greater severity of disease lower baseline ankle-

brachial index (ABI) and increased numbers of

cardiovascular events (17ndash20) In patients with CLI

outcomes are dire at 1 year 10 will experience a

fatal cardiovascular event and 25 will undergo limb

amputation (2)

Patient-reported symptoms underestimate PAD

prevalence and the physical examination is not a

reliable tool for the identi1047297cation of disease Diag-nosis and prevention of adverse outcomes may

J A C C V O L 6 7 N O 1 1 2 0 1 6 Olin et al

M A R C H 2 2 2 0 1 6 1 3 3 8 ndash 5 7 Management of Patients With Peripheral Artery Disease

1339



therefore be elusive unless patients are

identi1047297ed with targeted diagnostic testing

(ie ankle-brachial index [ABI]) (21) T he

treatment of underlying cardiovascular risk

factors results in reduced morbidity and

mortality for patients with PAD although this

population continues to be under-recognized

and undertreated for their cardiovascular risk

(28) Among 7458 participants with PAD in

the 1999 to 2004 NHANES (National Health

and Nutrition Examination Survey) data only

305 of subjects were taking statins 249

were taking angiotensin-converting enzyme

inhibitors (ACEI) or angiotensin receptor

blockers and 358 were admini stered

aspirin Among patients with PAD (and no

other clinical cardiovascular disease) use of

multiple preventive therapies was associated

with a 65 lower all-cause mortality (hazard ratio

[HR] 035 p frac14 002) (8)

The diagnosis of PAD can be made using the ABI

Using a handheld continuous-wave Doppler device

the ABI can be measured by taking the higher of the

2 systolic pressures in the dorsalis pedis and posterior

tibial artery in each leg and dividing by the higher of

the brachial artery systolic blood pressures in each

arm An abnormal ABI is diagnostic for PAD (21)

A normal ABI is between 100 and 140 An ABI 090

demonstrates 90 sensitivity and 95 speci1047297city for

PAD and is the accepted threshold for diagnosis (221)

Values between 091 and 100 are considered border-

line however the cardiovascular event rate for an ABI

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

gt140 the identi1047297cation of PAD is not accurate

because of the presence of arterial calci1047297cation and

noncompressibility of the blood vessels a 1047297nding

frequently encountered in the very elderly and in

those with diabetes and chronic kidney diseaseIn this

setting the toe-brachial index is used and considered

abnormal when lt070 (421) There is a strong and

consistent relationship between an abnormal ABI andthe presence of coronary or cerebrovascular disease

(51622) In addition the ABI is a predictor of cardio-

vascular morbidity and mortality independent of

clinical risk prediction scores such as the Framingham

Risk Score and other surrogate markers of systemic

atherosclerosis suchas the coronary calciumscore and

carotid artery intimal-medial thickness (23) There is

alsoa higher cardiovascular event ratein patientswith

PAD (even in asymptomatic patients) with known

coronary artery disease (CAD) (24)

Several consensus documents and practice guide-

lines recommend screening for the presence of PADusing the ABI in patients $65 years old or those who

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

smoking (2ndash4925) The goal is to identify and treat

patients with increased cardiovascular risk Despite

these recommendations and the fact that nearly one-

half of all PAD patients are asymptomatic there is no

reimbursement for the performance of an ABI in the

absence of clinical symptoms of PAD Alternative

diagnostic methods for PAD are beyond the scope of

this review

Serum biomarkers have been used for risk predic-

tion and the detection of PAD (26) A combined

biomarker pro1047297le that includes fasting glucose high-

sensitivity C-reactive protein b2-microglobulin and

cystatin C demonstrated ef 1047297cacy in the identi1047297cation

of PAD and reclassi1047297cation of cardiovascular risk

assessment by Framingham Risk Score in patients who

would have otherwise been misidenti1047297ed (27) The

BRAVO (Biomarker Risk Assessment in Vulnerable

Outcomes) study evaluated 595 patients with PAD and

followed them for 3 years The primary outcome was

ischemic heart disease events (myocardial infarction

unstable angina or ischemic heart disease death) Of

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

higher 2 months before the event than the values 10

months 12 months 16 months 20 months 26 months

and 32 months before the event There was no change

in the serum amyloid A or CRP 2 months before an

event (28) Although there is a clear association

betwe en various biomar kers and PAD the overall

clinical value related to patient outcomes remains

unclear and thus there is no clinical bene1047297t in

measuring biomarkers at this time

THE ROLE OF EXERCISE

Patients with PAD have a profound limitation in

exercise performance that is related to a complex

pathophysiology (29) Although reduced exercise

performance is a hallmark of PAD the symptomatic

manifestations are quite varied as described previ-

ously (30) Not surprisingly patients with claudica-tion slow their walking pace and often avoid walking

altogether Thus patients with PAD present with a

complex array of symptoms health beliefs and

exercise limitations in their daily lives (3132) These

perceptions and attitudes must be addressed if a

treatment plan is to be successful

The overall goal in treating the exercise limitation

from PAD is to improve exercise performance with a

corollary improvement in quality of life (QOL) and

functional status In this regard treatments that

improve treadmill exercise performance 6-min

walking distance and patient-related QOL can serveas a basis for obtaining regulatory approval of a

A B B R E V I A T I O N S

A N D A C R O N Y M S

BMS = bare-metal stent

CLI = critical limb ischemia

DAPT = dual-antiplatelet

therapy

DCB = drug-coated balloon

DES = drug-eluting stent

MACE = major adverse

cardiovascular event

PAD = peripheral artery

disease

QOL = quality of life

SFA = super1047297cial femoral

artery

TASC = Trans-Atlantic Inter-

Society Consensus

Olin et al J A C C V O L 6 7 N O 1 1 2 0 1 6

Management of Patients With Peripheral Artery Disease M A R C H 2 2 2 0 1 6 1 3 3 8 ndash 5 7

1340



claudication therapy In contrast changes in limb

hemodynamics such as an improvement in the ABI or

imaging after a successful revascularization serve

only as surrogate measures of clinical bene1047297t

Exercise training has been a mainstay of treatment

for symptomatic PAD with a well-established bene1047297t

after a typical 12-week exercise training program

(3334) Exercise training directly modi1047297es several

pathophysiological mechanisms in PAD including

improved skeletal muscle metabolism endothelial

function and gait biomechanics (35)

SUPERVISED EXERCISE TRAINING I MPROVES 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

(3738) 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 bene1047297t SE programs

have not been accepted by payers providers or

patients for a variety of reasons including questionsof long-term adherence and the bene1047297t of exercise as a

lifestyle intervention coupled with the desire by most

patients and vascular physicians for a more immedi-

ate approach to relieving claudication with endovas-

cular therapy (40) Therefore SE training programs

for claudication are very limited and not reimbursed

HOME-BASED EXERCISE DATA AND GENERALIZABILITY

OF THE FINDINGS The methodology to provide a

community (home)-based exercise intervention has

improved considerably over the past decade and

these exercise training methods have provided

encouraging resultsThe least resource-intensive home-based program

can employ education and behavioral interventions

that prepare patients for exercise training (41)

Notably adherence to a community program may be

poor without proper motivation and engagement

There are a number of new devices that monitor

the intensity and duration of an exercise session

performed in the home environment A pilot study

that used a program of training monitoring and

coaching had encouraging results in a subgroup of

subjects but was too small to de1047297nitively establish the

bene1047297ts of the interventions (42) Two larger trialsused a step activity monitor to record the duration

and intensity of the walking exercise to inform the

research staff and patient as to the patientrsquos exercise

prescription One randomized trial combined the

activity monitor with a home-based program that

used the principles of a hospital-based supervised

program (43) Adherence to the home program was

gt80 and the results on improvements in treadmill

exercise performance were comparable between

home and supervised programs A follow-up study

demonstrated similar results (44)

McDermott et al (45) have developed a coordinated

exercise program (group-mediated cognitive behav-

ioral therapy) that includes weekly group sessions run

by a trained facil itato r In a rando mized controlled

trial of 194 patients subjects in the intervention group

improved their 6-min walkingdistance 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-ef 1047297cacy satisfaction with functioning

pain acceptance and social functioning and these

bene1047297ts weresustained at the 12-monthendpoint (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 recommen-

dation between the physician and the patient to exer-

cise is usually ineffective the physician can provide

a comprehensive exercise prescription (Table 1) on

how to structure a home exercise program (5051)

This is not a 1-time recommendation but an ongoing

discussion between the physician and the patient

in an attempt to change patient behavior Patients

who are compliant with such a program often experi-

ence considerable improvement in walking distance

and QOLS TU D I E S O N E X E RC I SE V E RS U S E N D O V A S C U LA R

THERAPY ARE WE ASKING THE RIGHT QUESTIONS

Several studies have compared an SE program to

revascula ri za ti on i n p atients wi th PAD a nd

exercise-limiting claudication (5253) G iven t he

tremendous expansion and effectiveness of endovas-

cular treatments for symptomatic PAD as well as

patient reluctance to enter an exercise-lifestyle treat-

ment program (as discussed previously) the most

prudent approach would be to include both modalities

in the treatment plan exercise and revascularization

In fact both exercise training and revascularizationcan greatly improve patient exercise performance



1341



and QOL but by very different mechanisms Revascu-

larization primarily improves exercise blood 1047298ow

whereas exercise training does not (29) In contrast

exercise training induces a variety of adaptive re-

sponses including improved skeletal muscle mito-

chondrial oxidative metabolismimproved endothelialfunction and more ef 1047297cient biomechanics of walking

Thus the obvious ldquo bestrdquo treatment strategy would

appear to be the combined program utilizing endo-

vascular revascularization and an optimal home-based

and long-term exercise program This hypothesis

was initially tested more than 25 years ago and the

combination of bypass surgery and exercise training

was superior to either treatment alone (54)

The CLEVER (Claudication Exercise Versus Endo-

luminal Revascularization) study was an important

and well-designed comparative effectiveness trial

that compared the outcomes for stenting of aortoiliacdisease with SE on a background of optimal medical

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 signi1047297cantly

improved in both the exercise and stent groups

compared with optimal medical management but the

peak walking time was signi1047297cantly higher in the

exercise group than in the stent group (52) The sec-

ondary endpoints were changes in responses to QOL

questionnaires Both of these patient-reported out-

comes were improved with exercise or stenting over

optimal medical management however improve-

ments 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

time remained for both the exercise and stenting

groups over optimal medical therapy but the differ-

ences in peak walking time between the exercise and

stenting groups were no longer statistically signi1047297-

cant Improved patient-reported outcomes remained

for both the exercise and stent groups

CLEVER clearly established the independent long-

term and broad-based bene1047297ts of both exercise

training and stent revascularization in symptomatic

PAD Similar to many such trials of the nearly 1000

patients evaluated only 11 were randomized and

fewer were available for 18-month follow-up Unfor-

tunately the arm of CLEVER that would have tested

the combination of exercise plus stenting was drop-

ped 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-

ment in maximum walking distance (MWD) and

health-related QOL scores than the group randomized

to SE alone however both groups demonstrated

dramatic improvement in MWD pain-free walking

distance and QOL The supervised exercise group

increased MWD from 285 m to 1240 m for animprovement of 955 m The combination group

increased MWD from 264 m to 1501 m for an

improvement of 1237 m This study illustrates

2 important points 1) the combinationof endovascular

therapy and SE is the most effective therapy for many

patients with claudication and 2) even the group

randomized to SE alone showed marked improvement

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

The cost of therapy must also be considered when

planning a particular strategy to treat symptomatic

PAD In a single-center Dutch randomized trial

endovascular revascularization had similar bene1047297t but highe r total mean cumula tive costs per patie nt

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

1 Begin at 2 mph and a grade of 0 (1047298at)

2 Try not to hold onto the treadmill Use the side panels for balanceonly

3 Stop the treadmill completely when pain is 3ndash4 on claudicationdiscomfort scale

4 When the discomfort has ceased resume exercise at the sameintensity

5 Repeat restexercise cycles

6 Progress to a higher workload when you can walk for 8 minwithout having to stop for leg symptoms

a) Increase speed by 02 mph each time you can walk for 8 min

b) Once you are able to walk at 34 mph or reach a speed at whichyou can no longer keep up begin increasing the grade by 1

Duration

The total exercise period including rest periods should equal45 min per day

Tips for success

1 Do not continue walking past 3ndash4 on claudication paindiscomfortscale This way the paindiscomfort should go away in 2ndash5 min If you walk until you are in severe pain you will build up lactic acidin your muscles and it will take much longer for the pain to goaway

2 When at 3ndash4 on paindiscomfort scale stop walking completelyDo not slow down but stop and stand on the treadmill until thediscomfort is gone

This works if you do it Not only will this improve your walkingperformance decrease your discomfort and improve your

quality of life this type of program is also bene1047297cial for yourheart blood pressure and lipid (cholesterol and triglyceride)levels

Claudication pain scale 1 frac14 no pain or discomfort 2 frac14 onset of claudication

3 frac14 mild pain or discomfort 4 frac14 moderate pain or discomfort 5 frac14 severe pain or

discomfort Adapted from Weinberg et al (49)

PAD frac14 peripheral artery disease



1342



compared with a hospital-based exercise program

(57) Another study from a Dutch health-care databaseof 4954 patients demonstrated that a stepped

approach of exercise therapy followed by endovas-

cular revascularization was more cost-effective than

revascularization only (58)

Thus future studies should address not only the

clinical bene1047297ts but also the effectiveness of the

combination of an exercise program and limb revas-

cularization 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 out-comes are obtained

OPTIMAL MEDICAL THERAPY FOR

PATIENTS WITH PAD

Medical therapy for PAD should address treatment for

limb-related outcomes (improve claudication symp-

toms and prevent CLI and amputation) and treatment

to prevent major adverse cardiovascular events

(MACE myocardial infarction stroke and cardio-

vascular death) (Central Illustration)

Despite the recommendations from societal

guidelines on the management of patients with PAD(2) these patients continue to be undertreated

compared with patients with CAD (859) Adherence

to these guidelines in real-world practice is associatedwith improved outcomes (Figure 1) which empha-

sizes the bene1047297t of multifactorial risk reduction in

this high-risk population (12) Performance measures

for PAD will help improve quality of care and may be

incorporated into future quality metrics (60)

SMOKING CESSATION

Smoking is a major risk factor for the developmentand

progression of PAD A multidisciplinary approach to

smoking cessation should be used including group-

based programs and cognit ive beha viora l therapy

A recent study evaluated the association betweensuccessful quitting after endovascular intervention

and long-term outcomes (61) Among 739 patients

undergoing lower-extremity angiography 28 were

active smokers at the time of endovascular interven-

tion In the subsequent year 30 of active smokers

successfully quit Those who remained off tobacco

had signi1047297cantly lower 5-year mortality (14 vs 31)

and improved amputation-free survival (81 vs

60) Discontinuation of smoking is the most

important lifestyle modi1047297cation in preventing CLI

amputation and MACE in patients with PAD This

needs to be conveyed to the patient in an empatheticand nonjudgmental way during every of 1047297ce visit The

C E N T R A L I L L U S T R A T I O N The Peripheral Artery Disease Prescription

bull Control Blood Pressure to Goal -ACE Inhibitor

bull High-Dose Statin Therapy bull Good Foot Care

bull Antiplatelet Therapy bull Revascularization

-Moisturizing cream nail care treat and prevent tinea orthotics to

prevent abnormal pressure points

bull Discontinue Tobacco Use

bull Cilostazol


bull Walking Program bull Walking Program

Decrease the Risk of MI Strokeand CV Death

Improve Symptoms Quality of Life

and Prevent Amputation

Olin JW et al J Am Coll Cardiol 2016 67(11)1338ndash57

Management of patients with peripheral artery disease recommendations for improving outcomes and quality of life ACE frac14 angiotensin-converting

enzyme CV frac14 cardiovascular MI frac14 myocardial infarction



1343



VAPOR (Vascular Physician Offer and Report) trial is

currently evaluating methods to improve physician-

patient interactions to encourage patients with PAD

to abstain from smoking (62)

PHARMACOTHERAPY TO IMPROVE

CLAUDICATION SYMPTOMS

Cilostazol is a type III phosphodiesterase inhibitorwith a number of properties but the mechanism by

which cilostazol improves claudication is not known

(63) A pooled analysis of all of the randomized

trials shows an improvement in absolute claudica-

tion distance of approximately 50 compared with

placebo (64) Although cilostazol appears to be safe

for long-term administration adherence is low (gt60

discontinuation at 3 years) because of adverse effects

including headache palpitations and diarrhea (65)

Because of its mechanistic similarity to other type III

phosphodiesterase inhibitors such as milrinone cil-

ostazol is contraindicated in patients with a history of

heart failure The optimal dose of cilostazol is 100 mg

twice daily and it may take up to 4 months to derive

maximum bene1047297t from this drug (63)

Pentoxifylline is rarely used today to treat claudi-

cation because of a lack of ef 1047297cacy 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

States

ACEIs

ACEIs are associated with a signi1047297cant reduction in

MACE among patients with PAD These data are

derived primarily from the HOPE (Heart Outcomes

Prevention Evaluation) trial which randomized 9297

high-risk patients with vascular disease or diabetes

plus 1 other risk factor to ramipril 10 mg daily

or placebo Among these 1966 patients with PAD

(423) were randomized to ramipril and 2085

(448) to placebo The primary outcome (myocardial

infarction stroke cardiovascular death) occurred in

143 of those without PAD versus 220 of those

with PAD (67) In the 5231 patients without PAD the

primary outcome was observed in 126 in the ram-

ipril group and 149 in the placebo arm In those with

an ABI lt06the primary outcome occurred in 164 in

the ramipril arm versus 22 in the placebo arm Thecardiovascular bene1047297t of ramipril applies to patients

with both asymptomatic and symptomatic PAD across

a broad range of ABI values (68) Similar results have

also been observed with telmisartan which suggests a

possible class effect of ACEIangiotensin receptor

blockade among patients with PAD (6970)

STATINS

High-intensity statin medications are recommended

for a ll pa ti ents with PAD on the basis of the

most recent American College of Cardiology (ACC)American Heart Association (AHA) guidelines which

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

Outcomes in PAD

0 6 12 18 24 30 36Follow-Up (Months)

0 6 12 18 24 30 36

Follow-Up (Months)

0

1 0

2 0

3 0

4 0

M a j o r A d v e r s e C a r d i o v a s c u l a r E v e n t s

0

1 0

2 0

3 0

4 0

M a j o r A

d v e r s e L i m b E v e n t s

Hazard ratio 064 95 CI 045-089 P=0009

Hazard ratio 055 95 CI 037-083 P=0005

Number at risklt4 Guideline

4 Guideline502237

450222

391207

355180

322156

288143

256123


4 Guideline502237

306155

240133

201102

17594

14276

12564

lt4 Guideline Therapies 4 Guideline Therapies


A

B

Among patients with symptomatic peripheral artery disease (PAD) undergoing

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

antiplatelet agent statin angiotensin-converting enzyme inhibitor and abstention from

smoking is associated with a signi1047297cant reduction in (A) major adverse cardiovascularevents and (B) major adverse limb events Reproduced with permission from Armstrong

et al (12) CI frac14 con1047297dence interval PAD frac14 peripheral artery disease



1344



emphasize cardiovascular risk over low-density lipo-

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

port of statin use in patients with PAD are derived

from subset analysis of larger clinical trials The

Medical Research CouncilBritish Heart Foundationrsquos

Heart Protection Study randomized 20536 high-risk

patients to simvastatin 40 mg daily or placebo (72)

All-cause mortality occurred in 129 of patients

randomized to simvastatin and 147 randomized to

placebo (22 relative risk reduction p frac14 00003)

Observational studies have also con1047297rmed the car-

diovascular and overall mortality bene1047297t of statins

among patients with more advanced PAD including

CLI (73)

Recent data suggest that statin use is also associ-

ated with a reduction in adverse limb outcomes

including amputation In the REACH (Reduction of

Atherothrombosis for Continued Health) registry

statin therapy was associated with a signi1047297cant

reduction in the combined endpoint of worsening

claudication new CLI new revascularization or

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

220 versus 262 which emphasizes the highrate of

adverse limb events among patients with symptom-

atic PAD Importantly statin therapy was also associ-

ated with a signi1047297cant reduction in 4-year rates of

ischemic amputation (38 vs 56) In an analysis of

Medicare claims data of patients undergoing lower-

extremity revascularization statin use was associ-

ated 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 high-

intensity statin to reduce the risk of cardiovascular

events In most studies the rates of statin prescrip-

tion were lt75 which emphasizes the importance of

maximizing medical therapy among this high-risk

group of patients with advanced atheroscleroticdisease (59)

ANTIPLATELET THERAPY

ASPIRIN Aspirin has been a mainstay of drug ther-

apy among patients with PAD however the data

supporting aspirin use in patients with PAD have not

been well subst antia ted (7677)

Recent studies investigating the bene1047297t of aspirin

among patients with asymptomatic PAD have yielded

negative results Both the POPADAD (Prevention of

Progression of Arterial Disease and Diabetes) trial and

the AAA (Aspirin for Asymptomatic Atherosclerosis)

trial compared low-dose aspirin with placebo in

patients with a low ABI Neither study demonstrated

a reduction in fatal and nonfatal cardiovascular

events or revascularization with aspirin mono-

therapy although both notably included low-risk

patients with borderline ABI (099 in POPADAD

and 095 in AAA) (7778)

Consistent with these results a meta-analysis

speci1047297cally examined aspirin for PAD in 18 trials

involving 5269 patients In patients taking aspirin

monotherapy there was a nonsigni1047297cant reduction

in cardiovascular events (absolute event rate 82

vs 96 relative risk 075 95 con1047297dence inter-

val [CI] 048 to 118) however there was a sig-

ni1047297cant reduction in nonfatal stroke (HR 064 95

CI 042 to 099 p frac14 004) (76) In the last iteration

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

Level of Evidence A recommendation among pa-

tients with symptomatic PAD a Class IIa recom-

mendation among patients with asymptomatic PAD

and an ABI lt090 and a Class IIb indication among

asymptomatic patients with an ABI of 090 to 099

(2) Some of these recommendations may change in

the upcoming revision of the ACCAHA PAD prac-

tice guidelines

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 lt20 of

patients with PAD are prescribed clopidogrel in clin-

ical 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 bene1047297t compared with aspirin

325 mg daily in the overall population but there was a

238 relative risk reduction among the subgroup of

patients with symptomatic PAD (n frac14 6452 absolute

event rate 37 vs 49 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

High Atherothrombotic Risk and Ischemic Stabiliza-

tion Management and Avoidance) trial which

included patients at high risk for atherothrombotic

events The overall results of this trial were not sig-

ni1047297cant although in subgroup analyses there was a

bene1047297t of DAPT among patients with symptomatic

atherothrombosis (81) In an analysis of the 3096 pa-

tients in the trial with PAD DAPT was associated with

a lower rate of myocardial infarction (23 vs 37



1345



HR 063 95 CI 042 to 096 p frac14 002) and hospital-

ization for ischemic events (165 vs 201 HR 081

95 CI 068 to 095 p frac14 0011) but not the overall

composite primary endpoint (82) There was no dif-

ference between the groups in moderate severe or

fatal bleeding but there was an increase in minor

bleed ing i n th e DAPT group

In a recent propensity-matched observational

study among patients undergoing endovascular

intervention there was a signi1047297cant reduction in

MACE among patients taking DAPT (adjusted HR

065 95 CI 044 to 096 p frac14 003) compared with

those taking aspirin monotherapy (83) The discor-

dant 1047297ndings between this study and the CHARISMA

trial may be explained by inclusion of a cohort

with more advanced atherosclerotic disease under-

going endovascular intervention including gt50 of

patients with CLI

The CASPAR (Clopidogrel and Acetylsalicylic Acid

in Bypass Surgery for Peripheral Arterial Disease) trial

studied DAPT versus aspirin 75 to 100 mg daily among

patients undergoing below-knee surgical bypass for

treatment of CLI (84) The primary endpoint of death

major amputation index-graft occlusion or revascu-

larization was not different for DAPT versus

acetylsalicylic acid (ASA) monotherapy In a pre-

speci1047297ed subgroup analysis there was a signi1047297cant

bene1047297t of DAPT in patients treated with prosthetic

grafts (HR 065 95 CI 045 to 095 p frac14 0025) but

not in those treated with vein grafts A similar trial

the CAMPER study (Clopidogrel and Aspirin in the

Management of peripheral Endovascular Revascular-

ization) tested DAPT versus aspirin in patients un-

dergoing infrainguinal endovascular therapy The

study was never completed because of poor enroll-

ment (doctors would not randomize patients to ASA

alone) continued funding could not be justi1047297ed

DAPT is often prescribed after endovascular inter-

vention although the data supporting duration of

DAPTare sparseIn practice most physicians prescribe

DAPTfor a time periodrangingfrom1 to3 monthspost-intervention The ASPIRE-PAD study (Antiplatelet

Strategy for Peripheral Arterial Interventions for

Revascularization of Lower Extremities) is currently

evaluating comparative outcomes of 1 versus 12

months of DAPT after endovascular intervention (85)

VORAPAXAR

Thrombin acts through platelets via a unique mecha-

nism binding of the protease activating receptor-1

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

the platelet surface leads to receptor activation

and increased intracellular Ca2thorn cyclic adenosine

monophosphate (cAMP) levels subsequently decrease

which leads to increased platelet aggregation and

releaseof further activatingfactors Vorapaxar inhibits

PAR-1 thereby signi1047297cantly reducing thrombin-

mediated platelet activation

T he T RA 2P-TIMI 50 trial (Thrombin Receptor

Antagonist for Secondary PreventionndashThrombolysis

in Myocardial Infarction Study Group) studied vor-

apaxar sulfate 25 mg daily versus placebo (ASA and

or clopidogrel therapy at the investigatorsrsquo discre-

tion) among 26449 patients with a recent myocardial

infarction recent ischemic stroke or symptomatic

PAD At 3 years there was a signi1047297cant reduction in

the primary endpoint of MACE (absolute event rates

93 vs 105 HR 087 95 CI 080 to 094

p lt 0001) (79) After 2 years the data and safety

monitoring board recommended stopping the study

drug in the patient subgroup entered with prior

ischemic stroke because of an increased risk of

intracranial hemorrhage Among the 3787 patients

with PAD the majority were treated with aspirin

monotherapy plus vorapaxar or placebo The reduc-

tion in MACE was not statistically signi1047297cant in those

assigned to vorapaxar (absolute event rates 113 vs

119 HR 094 95 CI 078 to 114) Similarly

negative results were observed among patients with

PAD who were enrolled in the TRACER (Thrombin

Receptor Antagonist for Clinical Event Reduction in

Acute Coronary Syndrome) trial (86) Additionally

vorapaxar is associated with a signi1047297cantly increased

risk of major bleeding However in both of these

trials there were relatively few MACE in the PAD

subgroup The PAD group was underpowered to draw

any conclusions on ef 1047297cacy

Pre-speci1047297ed analysis of limb-related outcomes in

the TRA 2P-TIMI 50 trial demonstrated that patients

assigned to vorapaxar had signi1047297cantly reduced rates

of acute limb ischemia (23 vs 39 HR 058 95

CI 039 to 086 p frac14 0006) as well as peripheral

artery revascularization (184 vs 222 HR 084

95 CI 073 to 097 p frac14 0017) during the 3-yearfollow-up (Figure 2) (87) These ef 1047297cacy endpoints

must be balanced by a signi1047297cantly increased rate of

major bleeding among patients prescribed vorapaxar

Further research into the mechanism by which

vorapaxar led to improved limb outcomes is required

to fully understand these effects

CELL-BASED AND ANGIOGENIC THERAPIES

Modulation and enhancement of lower-extremity

blood 1047298ow via angiogenesis arteriogenesis or vas-

culogenesis could provide a promising breakthrough

therapy for patients with PAD (88) Additionally



1346



there has been much interest in the use of stem cellndash

derived endothelial cells or modi1047297cation of resident

stem cells (89) Potential bene1047297ts of these therapies

include improved wound healing and limb salvage

among patients with CLI as well as improved clau-

dication distance To date numerous cell-based and

angiogenic therapies have been tested and despite

promising results in early clinical trials none of these

agents have shown bene1047297t in larger trials

ONGOING CLINICAL TRIALS

There are currently 2 clinical trials studying novel

antiplatelet and anticoagulant agents to reduce MACE

and potentially modify limb-related outcomes

EUCLID (Study Comparing Cardiovascular Effects of

Ticagrelor and Clopidogrel in Patients With Periph-eral Artery Disease) is a randomized blinded double-

dummy trial comparing ticagrelor 90 mg twice daily

to clopidogrel monotherapy among 13500 patients

with PAD (90) All patients are tested for clopidogrel

resistance before randomization The primary

endpoint is a composite of MACE and results are

expected in late 2016 The COMPASS (Rivaroxaban for

the Prevention of Major Cardiovascular Events in

Coronary or Peripheral Artery Disease) trial is evalu-

ating low-dose rivaroxaban alone versus placebo

aspirin alone or rivaroxaban and aspirin among

21400 patients with a history of myocardial infarc-tion or PAD the primary endpoint of this trial is a

composite of MACE (91)

ENDOVASCULAR THERAPY

Endovascular revascularization plays a key role in the

management of patients with PAD Patients with sta-

ble cl audication have a low ris k of lim b loss but may be

severely limited by their symptoms In most circum-

stances patients with claudication should be offered a

trial of cilostazol and an exercise program as initial

therapy If the patient is not satis1047297ed after a trial of

medical therapy endovascular revascularization can be consi dere d Patie nts with CLI require more urgent

revascularization because of an increased riskof tissue

loss and amputation as well as an extremely high risk

of cardiovascular events (92)

There are 2 well-established classi1047297cation schemes

to describe the severity of PAD The 1047297rst is a func-

tional assessment (Fontaine or Rutherford classi1047297ca-

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

lesion classi1047297cation (Trans-Atlantic Inter-Society

Consensus [TASC]) (Table 3) (45) In addition there

has been recent interest in the angiosome concept in

helping to in1047298uence optimal revascularization stra-tegies for limb salvage (93) An angiosome is an

anatomic unit of tissue (consisting of skin subcu-

taneous tissue fascia muscle and bone) that is fed

by a source arte ry and drai ned by speci1047297c veins

If the patient is a candidate for either endovascular

or open surgery the less invasive option (ie an

endovascular-1047297rst strategy) is the current standard of

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

endovascular therapy will vary with the skill and

experience of the interventionalist The goal in

treating a patient who has functional impairment

because of claudi cation is dura ble relief of symptoms

In patients with CLI and a threatened limb or tissueloss the goal is rapid reperfusion of the ischemic

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

45

40

35

30

25

20

15

10

05

00

E v e n t R a t e ( )

0 180 360 540 720 900 1080

Days Since Randomization

0 180 360 540 720 900 1080


250

200

150

100

50

00


23 vs 39HR 058 (039 ndash 086)

P=0006

184 vs 222HR 084 (073 ndash 097)

P=0017

Hospitalization for Acute Limb Ischemia

Placebo Vorapaxar

Peripheral Revascularization

Placebo Vorapaxar

A

B

In the TRA 2P-TIMI 50 trial patients randomized to vorapaxar had signi1047297cantly lower

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

permission from Bonaca et al (87) HR frac14 hazard ratio



1347



tissue to relieve the ischemia prevent amputation

and restore ambulation

AORTOILIAC OCCLUSIVE DISEASE

There has been a practice shift over the past 25 years

as the treatment of aortoiliac disease transitioned

from open surgery with aortobiiliac or aortobifemoral

bypass to endovascular trea tment s for comple x and

diffuse disease (TASC D) This preference for less

invasive therapy is evidence based and driven by

shorter length of stay (or treatment as an outpatient

entirely) and lower periprocedural morbidity and

mortality rates while achieving comparable patency

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

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

CURRENT BEST PRACTICES (EVIDENCE-BASED AND

GUIDELINES) In 2011 the European Society of Car-

diology (ESC) (3) and ACCAHA PAD guidelines (2)

recommended an endovascular-1047297rst approach for

aortoiliac lesions recommended that borderline

lesions be assessed with hemodynamic gradients and

supported primary stent placement in the aortoiliac

arteries (Table 4) The current expert consensus

document from the Society for Cardiac Angiography

and Interventions (SCAI) on appropriate use criteria

(AUC) for aortoiliac intervention are similar to the

current guidelines (95)

CLINICAL TRIAL UPDATE The results of the CLEVER

trial were discussed previously in the section on

exercise BRAVISSIMO (Belgian-Italian-Dutch Trial

Investigating Abbott Vascular Iliac Stents in the

T A B L E 3 TASC Classi1047297cation

TASC A TASC B TASC C TASC D

Aortoiliac Unilateral or bilateralstenoses of CIA

Unilateral or bilateral singleshort (3 cm) stenosisof EIA

Short (3 cm) stenosis of infrarenal aorta

Unilateral CIA occlusionSingle or multiple stenoses

totaling 3ndash10 cm involvingthe EIA not extending intothe CFA

Unilateral EIA occlusion notinvolving the origins of internal iliac or CFA

Bilateral CIA occlusionsBilateral EIA stenoses 3ndash10 cm

long not extending intothe CFA

Unilateral EIA stenosisextending into the CFA

Unilateral EIA occlusion thatinvolves the origins of internal iliac andor CFA

Heavily calci1047297ed unilateral EIAocclusion with or without

involvement of origins of internal iliac andor CFA

Infrarenal aortoiliac occlusionDiffuse disease involving the

aorta and both iliac arteriesDiffuse multiple stenoses

involving the unilateral CIAEIA and CFA

Unilateral occlusions of both CIAand EIA

Bilateral occlusions of EIAIliac stenoses in patients with

AAA not amenable toendograft placement

Femoral-popliteal Single stenosis 10 cm inlength

Single occlusion 5 cm in

length

Multiple lesions (stenoses orocclusions) each 5 cm

Single stenosis or

occlusion 15 cm notinvolving theinfrageniculate poplitealartery

Heavily calci1047297ed occlusion5 cm in length

Single popliteal stenosis

Multiple stenoses orocclusions totalinggt15 cm with or without

heavy calci1047297cationRecurrent stenoses orocclusions after failingtreatment

Chronic total occlusions of CFAor SFA (gt20 cm involvingthe popliteal artery)

Chronic total occlusion of popliteal artery andproximal trifurcation vessels

Infrapopliteal Single focal stenosis 5 cm inlength in the target tibialartery with occlusion orstenosis of similar orworse severity in the othertibial arteries

Multiple stenoses each 5cm in length or totallength 10 cm or singleocclusion 3 cm in lengthin the target tibial arterywith occlusion or stenosisof similar or worse severityin the other tibial arteries

Multiple stenoses in thetarget tibial artery andorsingle occlusion with totallesion length gt10 cm withocclusion or stenosis of similar or worse severity inthe other tibial arteries

Multiple occlusions involvingthe target tibial artery withtotal lesion length gt10 cmor dense lesion calci1047297cationor nonvisualization of collaterals the other tibialarteries occluded or withdense calci1047297cation

Reprinted with permission from Norgren et al (4) and Jaff et al (5)

AAA frac14

abdominal aortic aneurysm CFA frac14

common femoral artery CIA frac14

common iliac artery EIA frac14

external iliac artery SFA frac14

super1047297

cial femoral arteryTASC frac14 Trans-Atlantic Inter-Society Consensus

T A B L E 2 Classi1047297cations of Severity of PAD

Fontaine Rutherford

Stage Clinical Grade Category Clinical

I Asymptomatic 0 0 AsymptomaticIIa Mild claudication I 1 Mild claudication

IIb Moderate-severeclaudication

I 2 Moderate claudication

I 3 Severe claudication

III Ischemic rest pain II 4 Ischemic rest pain

IV Ulceration organgrene

III 5 Minor tissue loss

IV 6 Ulceration or gangrene




1348



Treatment of TASC A B C and D Iliac Lesions) re-

ported 100 technical success in 325 patients with

aortoiliac lesions with a 24-month primary patency

rate of 879 (96) Neither TASC category nor lesion

length was predictive of restenosis These data

further support the endovascular-1047297rst strategy

regardless of TASC classi1047297cation and take into

consideration the evolution of devices (ie 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 super1047297cial femoral

artery (SFA) but also proximal to the deep femoralartery (profunda femoris) which is the major collat-

eral artery supplying blood to the lower limb when

there is SFA obstruction Traditionally common

femoral endarterectomy has been the CFA revascu-

larization procedure of choice (23) although

advances in endovascular therapy have shown some

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

gical Quality Improvement Program database for 2005

to 2010 found a combined mortality and morbidity

rate of 15 for common femoral endarterectomy

which was higher than expected (98) Patients

requiring CFA revascularization who are at increasedsurgical risk may be considered for less invasive

endovascular options

FEMORAL-POPLITEAL DISEASE

This segment begins at the bifurcation of the CFA into

the SFA and the deep femoral (profunda femoris)

artery The SFA is subject to 1047298exion elongation

compression and torsion unlike any other lower-

extremity artery This complexity leads to many

challenges for endovascular technology but despite

this an endovascular-1047297rst approach is currently thestandard of therapy for the majority of lesions

becau se of the very high proce dural success rate and

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

lesions (TASC D) are more approachable because of

the re-entry and crossing devices more experienced

operators drug-eluting stents (DES) (99100) and

drug-coated balloons (DCBs) (101ndash107) that promise

improved long-term patency for patients with clau-

dication (99100103105)


GUIDELINES) The ACCAHA (2006 2011) and ESC

(2011) PAD guidelines and the AUC documentfrom the SCAI recommend revascularization in

femoral-popliteal lesions for patients with CLI or for

patients with claudication who have had a suboptimal

r espon se to a tr ial of e xer cise (Tab le 5) An

endovascular-1047297rst approach is recommended for

TASC A through C lesions and is a reasonable option

for TASC D lesions depending on the experience of

the operator the patientrsquos comorbidities and proce-

dure safety (Table 5) (2395)

The 2 guidelines are in con1047298ict over the use of

primary stent placement in the femoral-popliteal ar-

teries with the ACCAHA guideline giving it a Class III

recommendation (do not do) and the ESC guideline

making primary femoral stenting reasonable 1047297rst-line

therapy (Class IIa) for intermediate-length lesions

(108109) The current evidence from several ran-

domized controlled trials supports primary stenting

in intermediate-length femoral stenoses and occlu-

sions (108ndash110) The soon-to-be-published updatedACCAHA guidelines will readdress this issue In

current practice the standard is to primarily stent

intermediate to long SFA lesions

The ACCAHA guideline broadly lump stents

togetherwith atherectomy devicescryotherapy laser

and cutting balloons stating they may be useful as

salvage therapy (Class IIa) but also stating that their

effectiveness remains to proven (Class IIb) Stents

should be removed from this group because their

effectiveness has been established in intermediate-

length femoral lesions Other than the use of the cut-

ting balloon and rotational atherectomy in lesions thatare resistant to dilation there is no comparative

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

Stable Limb Ischemia (Claudication)

A CC A HA P AD G ui de li ne s ( 20 06 2 01 1) E SC P AD G ui de li ne s ( 20 11 )

Endovascular procedures are indicated forpatients with a vocational or lifestyle-limiting disability due to intermittentclaudication when clinical features suggesta reasonable likelihood of symptomaticimprovement with endovascularintervention and 1) there has been aninadequate response to exercise orpharmacological therapy andor 2) there isa very favorable risk-bene1047297t ratio (egfocal aortoiliac occlusive disease) (Class I

Level of Evidence A)

When revascularization is indicated anendovascular-1047297rst strategy isrecommended in all aortoiliac TASC AndashClesions (Class I Level of Evidence C)

Translesional pressure gradients (with andwithout vasodilation) should be obtained toevaluate the signi1047297cance of angiographiciliac arterial stenoses of 50 to 75diameter before intervention (Class I Level

of Evidence C)

A primary endovascular approach may beconsidered in aortoiliac TASC D lesions inpatients with severe comorbidities if done by an experienced team (Class IIb

Level of Evidence C)

Stenting is effective as primary therapy forcommon iliac artery stenosis and occlusions(Class I Level of Evidence B)

Primary stent implantation rather thanprovisional stenting may be consideredfor aortoiliac lesions (Class IIb Level of

Evidence C)

ACC frac14 American College of Cardiology AHA frac14 American Heart Association ESC frac14 European Society of

Cardiology PAD frac14 peripheral artery disease TASC frac14 Trans-Atlantic Inter-Society Consensus



1349



evidence suggesting that the more expensive athe-

rectomy devices cryoplasty or laser angioplasty

should be preferred over conventional therapy

(percutaneous transluminal angioplasty [PTA] and

bare- metal stents [BMS] ) The ESC guideline disti n-

guishes bare-metal self-expanding stents from

adjunctive devices such as atherectomy devices cit-

i ng the p roven bene1047297t of BMS over PTA in

intermediate-length femoral-popliteal lesions

CLINICAL TRIAL UPDATE Three randomized controlledtrials of self-expanding BMS compared with PTA have

shown that the advantage for primary stenting is

related to lesion length For relatively discrete lesions

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

mary stent placement however 2 other trials

(108109) with longer lesions (gt70 mm) showed a

signi1047297cant patency and functional bene1047297t for primary

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

dural success rate of endovascular therapy in

femoral-popliteal lesions is very high but in stable

limb ischemia durable patency remains a barrier

Cilostazol has been shown to reduce 1-year restenosis by more than one-half (20 vs 49 p frac14 00001) in

intermediate-length (128 mm) femoral lesions treated

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

be con1047297rmed before this can be recommended as

standard therapy

Recent randomized controlled trials demonstrating

bene1047297t f or DE S (99100) DC B (103105106) and

covered stents (115ndash117) in femoral-popliteal arteries

will likely result in a change in the guidelines and

indications (Table 6 Figure 3)

There hasbeen some enthusiasm for self-expanding

covered (expanded polytetra1047298uoroethylene) stent

grafts in complex or lengthy femoral-popliteal seg-

ments Two randomized trials comparing covered

stents to BMS had divergent results One showed a

bene1047297t for 2-year primary patency but no difference in

target-lesion revascularization (TLR) or clinical out-

comes (116) whereas the other in longer (gt8 cm) le-

sions found no difference for primary patency (115ndash

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

patency between the 2 options (118)

The Zilver paclitaxel-eluting self-expanding DES

was superior to PTA in a randomized femoral-

popliteal trial with 1-year patency rates of 831 for

primary DES and 328 for PTA (p lt 0001) (Figure 3

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

advantage for provisional DES after failed PTA

(899) compared with provisional BMS (730

p frac14 001) The bene1047297t was sustained at 2 years with

primary patency for the DES (748) signi1047297cantly

better t han PTA (265 p lt 001) (100) To date there

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

to either BMS or DCB in femoral-popliteal arteries

but Zelle r et al (104) published a propensity scorendash

based compar ison of DES and DCB in conse cutive

patients with TASC C and D long (gt10 cm) lesions and

found no signi1047297cant differences in 1-year patency

(Figure 3 Table 6)

DCBs offer the promise of improved patency with areduced need for stents This is particularly important

in the dynamic environment of the super1047297cial femoral

and popliteal arteries where mechanical fatigue may

lead to stent fracture and increased risk of in-stent

restenosis Each DCB is unique with respect to the

paclitaxel dose (varying from 2 to 35 mgmm2) the

carrier molecule (excipient) the balloon material and

the coating technology used Superiority for paclitaxel

DCB over PTA was 1047297rst reported in 2008 (101102)

(Figure 3 Table 6) Subsequently new DCBs have

emerged including the INPACT (105106111113) and

the Lutonix (103106) balloons both of which showedclinical superiority to PTA in femoral-popliteal lesions

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



Endovascular procedures are indicated for patientswith a vocational or lifestyle-limiting disabilitydue to intermittent claudication when clinicalfeatures suggest a reasonable likelihood of symptomatic improvement with endovascularintervention and 1) there has been aninadequate response to exercise orpharmacological therapy andor 2) there is avery favorable risk-bene1047297t ratio (eg focalstenosis) (Class I Level of Evidence A)

When revascularization is indicated anendovascular-1047297rst strategy isrecommended in all femoropoplitealTASC AndashC lesions (Class I Level of

Evidence C)

Stents (and other adjunctive techniques such aslasers cutting balloons atherectomy devicesand thermal devices) can be useful in thefemoral popliteal and tibial arteries as salvagetherapy for a suboptimal or failed result fromballoon dilation (eg persistent translesionalgradient residual diameter stenosis gt50 or1047298ow-limiting dissection) (Class IIa Level of

Evidence C)

Primary stent implantation should beconsidered in femoropopliteal TASCB lesions (Class IIa Level of

Evidence A)

The effectiveness of stents atherectomy cuttingballoons thermal devices and lasers for thetreatment of femoral-popliteal arterial lesions isnot well established (except to salvage asuboptimal result from balloon dilation) (Class

IIb Level of Evidence A)

A primary endovascular approach mayalso be considered in TASC D lesionsin patients with severe comorbiditiesif an experienced interventionist isavailable (Class IIb Level of

Evidence C)

Primary stent placement is not recommended in thefemoral popliteal or tibial arteries (Class III


Endovascular intervention is not indicated asprophylactic therapy in an asymptomatic patientwith lower-extremity PAD (Class III Level of

Evidence C)

Abbreviations as in Table 4



1350



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

100

90

80

70

60

50

40

30

20

10

R e s t e n o s i s ( )

0 50 100 150 200

Lesion Length (in MM)

FAST PTA

Lesion length 445Restenosis 386

FAST BMS


FEMPAC PTA


PACIFIER PTA

Lesion length 66

Restenosis 324

FEMPAC DCB


ZILVER DES

Lesion length 664Restenosis 169 PACIFIER DCB


THUNDER DCB


INPACT SFA DCB


ZILVER PTA


ASTRON PTA


THUNDER PTA


INPACT SFA PTA


ASTRON BMS


ABSOLUTE PTA


ABSOLUTE BMS


VIASTAR BMS


VIASTAR CS


ZELLER DCBLesion length 194Restenosis 239

ZELLER DES


T A B L E 6 Comparative Femoral-Popliteal Trials

Clinical Trial Nam e (Ref ) Device N Lesion length (m m) Restenosis () ICCLI () TLR () De Novo ( ) Occlusions () RVD (mm )

FAST (110) PTA 121 45 28 386 96535 183 595 248 51

BMS 123 45 27 317 97525 149 659 366 53

ABSOLUTE (108) PTA 53 92 75 630 8713 31 100 32 NR

BMS 51 101 75 370 8812 28 100 37 NR

ASTRON (109) PTA 39 65 46 611 973 NR 100 39 NR

BMS 34 82 67 344 919 NR 100 38 NR

ZILVER (100) PTA 238 63 41 672 90785 175 247 NR NR

DES 241 66 39 169 90289 95 296 NR NR

Zeller (104) DES 97 195 65 304 91772 215 557 629 NR

DCB 131 194 86 239 81168 193 481 527 NR

THUNDER (111) PTA 54 74 67 440 NR 48 30 26 47

DCB 48 75 62 170 NR 10 38 27 52

FEMPAC (102) PTA 42 47

42 470 937 17 34 19 51DCB 45 40 44 190 964 7 35 13 52

INPACT SFA (112) PTA 111 88 51 476 93763 206 946 195 468

DCB 220 89 48 178 9550 24 95 258 50

LEVANT-2 (106) PTA 160 63 40 474 91981 375 875 219 48

DCB 316 63 41 348 92179 38 839 206 48

PACIFIER (113) PTA 47 66 55 324 95743 214 829 383 49

DCB 41 70 53 86 95545 71 682 227 496

p lt 005

ABSOLUTE frac14 Balloon Angioplasty Versus Stenting With Nitinol Stents in the Super1047297cial Femoral Artery ASTRON frac14 Balloon angioplasty versus stenting with nitinol stents

in intermediate length super1047297cial femoral artery lesions BMS frac14 bare-metal stent CLI frac14 critical limb ischemia CS frac14 covered stent DCB frac14 drug-coated balloon DES frac14 drug-

eluting stent FAST frac14 The Femoral Artery Stenting Trial FEMPAC frac14 Femoral Paclitaxel Trial IC frac14 intermittent claudication INPACT SFA frac14 Randomized Trial of INPACT

(Paclitaxel) Admiral Drug-Coated Balloon (DCB) vs Standard Percutaneous Transluminal Angioplasty (PTA) for the Treatment of Atherosclerotic Lesions in the Super 1047297cial

Femoral Artery (SFA) andor Proximal Popliteal Artery (PPA) LEVANT-2 frac14 The Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis NR frac14 not

reported PACIFIER frac14 Paclitaxel-coated Balloons in Femoral Indication to Defeat Restenosis PTA frac14 percutaneous transluminal (balloon) angioplasty RVD frac14 reference vessel

diameter THUNDER frac14 Local Taxan With Short Time Contact for Reduction of Restenosis in Distal Arteries TLR frac14 target-lesion revascularization ZELLER frac14 Drug-coatedballoons vs drug-eluting stents for treatment of long femoropopliteal lesions ZILVER frac14 PTX Randomized Trial



1351



and excellent safety pro1047297

les (Figure 3 Table 6) Thedurability of a paclitaxel-eluting DCB in the SFA has

been demonstra ted at 2 and 5 years (107111)At2years

patients treated with DCB showed signi1047297cantly higher

primary patency than those treated with PTA (789

vs 501 p lt 0001) including lower clinically driven

TLR and similar functional status improvement with

fewer repeat interventions Five-year follow-up

demonstrated thatTLR remainedsigni1047297cantlylower in

the DCB group (21) than for PTA (56 p frac14 00005)

(117) The TLR bene1047297t in femoral-popliteal arterieswas

independent of lesion length There have been no

safety concerns raised for DCB regarding aneurysmformation or 1047297 brotic constr iction

TIBIAL-PERONEAL DISEASE

Infrapopliteal or below-the-knee disease begins with

the popliteal artery at the knee joint and continues

to the tibial and peroneal arteries to the ankle

Revascularization is indicated in patients with CLI

and rarely for those with claudication The BASIL

(Bypass Versus Angioplasty in Severe Ischaemia

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

surgery in 452 CLI patients and found no difference

for amputation-free survival but a lower cost withPTA (119)

In general nonambulatory patients with a short-

ened life expectancy and extensive lower-extremity

tissue necrosis should undergo amputation Patients

who have the opportunity to regain ambulatory

function should undergo magnetic resonance angi-

ography computed tomography angiography or

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 1047298ow from the hip to the foot



(2011) PAD guidelines agree that an endovascular-1047297rst

approach is reasonable in patients with CLI and

infrapopliteal arterial disease (Table 7) (23) In can-

didates for endovascular treatment both guidelinessupport PTA as the initial approach with the use of

BMS as needed for bailout lesions (Table 7) (23) The

guidelines however have lagged behind the most

recent evidence demonstrating that DES and DCBs are

superior to angioplasty alone and BMS for infrapo-

pliteal disease (Table 8)

The expert consensus infrapopliteal AUC document

from the SCAI supports endovascular intervention

for patients with severe claudication and focal target

lesions as well as for anatomically suitable lesions

in patients with CLI (RC 4 to 6) (126) Endovascular

therapy may be appropriate in patients with moderateto severe claudication with occlusions or diffuse dis-

ease of 2 or 3 infrapopliteal vessels and for ischemic

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

infrapopliteal disease It would rarely be appropriate

to perform infrapopliteal intervention for mild clau-

dication (RC 1) or for moderate to severe claudication

with major tissue loss for single-vessel infrapopliteal

obstruction (ie 2 vessels are patent to the foot)

CLINICAL TRIAL UPDATES There have been 4 ran-

domized trials (Table 8) (120ndash122125127) demon-

strating superiority for infrapopliteal DES versus

either PTA BMS or DCB These data provideconvincing evidence favoring infrapopliteal DES over

PTA BMS or DCB for 1) patency 2) reduced rein-

terventions 3) reduced amputation and 4) improved

event-free survival These results are not limited to

patients with CLI because most trials have included

patients with severe claudication It would be

appropriate to revise the guideline statements in

favor of DES for infrapopliteal lesions at this time

The evidence supporting the use of DCB for infra-

popliteal lesions is less certain The DEBATE-BTK

(Drug-Eluting Balloon in Peripheral Intervention for

Below the Knee Angioplasty Evaluation) trial ran-domized 158 infrapopliteal lesions in diabetic

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

for CLI

ACCAHA P AD Guidelines (2006 2011) ESC P AD Guidelines (2011)

For individuals with combined in1047298ow andout1047298ow disease with CLI in1047298ow lesionsshould be addressed 1047297rst (Class I Level

of Evidence C)

For patients with limb-threatening lower-extremity ischemia and an estimated lifeexpectancy 2 years in whom anautogenous vein conduit is not availableballoon angioplasty is reasonable toperform when possible as the initialprocedure to improve distal blood 1047298ow(Class IIa Level of Evidence B)

For infrapopliteal lesionsangioplasty is the preferredtechnique and stentimplantation should beconsidered only in the caseof insuf 1047297cient PTA (Class IIa


The effectiveness of uncoateduncoveredstents atherectomy cutting balloonsthermal devices and lasers for thetreatment of infrapopliteal lesions(except to salvage a suboptimal resultfrom balloon dilation) is not wellestablished (Class IIb Level of

Evidence C)

When revascularization in theinfrapopliteal segment isindicated the endovascular-1047297rst strategy should beconsidered (Class IIa Level

of Evidence C)

Primary stent placement is not recommendedin the femoral popliteal or tibial arteries(Class III Level of Evidence C)

Surgical and endovascular intervention is notindicated in patients with severedecrements in limb perfusion (egABI lt04) in the absence of clinicalsymptoms of CLI (Class III Level of

Evidence C)

ABI frac14 ankle-brachial index other abbreviations as in Table 6



1352



patients with CLI to either DCB (InPact Amphirion

Medtronic Minneapolis Minnesota) or PTA (123) The

mean lesion length was 129 83 mm signi1047297cantly

(w100 mm) longer than those in the infrapopliteal

DES randomized trials The primary endpoint reste-

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

gr ou p and 743 of t ho se in th e P TA g rou p

(p lt 0001) Twelve-month major adverse events

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

PTA (51) group (p frac14 002) driven mainly by a

reduction in TLR and better ulcer healing However

there was no difference in the rate of amputation

limb salvage or mortality between the groups

In contrast the results of the InPact Deep CLI trial

resulted in the DCB (InPact Amphirion) being with-

drawn from the market worldwide by the sponsor

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

popliteal lesions and randomized them 21 to DCB and

PTA respectively The restenosis rate and TLR were

not different between the 2 groups There was anonsigni1047297cant trend toward higher amputation rates

in the DEB (88) compared with the PTA group

(36 p frac14 008) It seems clear that more data and

more experience are needed to understand the rela-

tive bene1047297ts of DEB for infrapopliteal lesions (124)

In practical terms an endovascular-1047297rst approach

is the current standard of care for symptomatic

infrainguinal atherosclerotic disease Adverse peri-

procedural events with endovascular therapy for

the treatment of infrapopliteal disease appear to be

low with mortality rates in observational series lt1

The recent technological advances of DES and DEBswill strengthen this consensus recommendation The

BEST-CLI (Best Endovascular Versus Best Surgical

Therapy in Patients With CLI) trial has just been

launched and will answer the question of whether

surgery in selected patients with CLI and with

good-quality saphenous veins is a better choice than

endovascular therapy (128)

THE FUTURE OF ENDOVASCULAR THERAPY

The emphasis on value-based care that offers the

right procedure for the right patient at the right time

requires justi1047297cation of expensive devices in the

context of cost-conscious medical care Unfortu-

nately we often lack head-to-head comparative data

to determine which device or strategy is preferred for

speci1047297c clinical situations It is reasonable to choose

lower-cost strategies unless there is evidence justi-

fying a more expensive choice

AUC have been introduced in a variety of cardio-

vascular subspecialties AUC are intended to aidclinicians in improving patient quality and safety by

reducing (but not eliminating) variation in clinical

practice Essentially AUC offer care pathways that

are meant to offer guidance It is recognized that

deviation from the care pathway will be the right

thing to do in speci1047297c cases Responsible clinicians

should be able to articulate their reasons for deviating

from the ldquoappropriaterdquo care pathway thereby navi-

gating the Scylla and Charybdis of cost-effectiveness

and clinical necessity

Independent accreditation of hospital facilities

such as noninvasive and invasive laboratories is avaluable tool for benchmarking quality of care and

T A B L E 8 Comparative Tibial-Peroneal Trials

Clinical Trial Nam e (Ref ) Device N Lesion length (mm ) Restenosis () ICCLI ( ) TLR ( ) De Novo () Occlusions () RVD (mm )

ACHILLES (120) PTA 101 27 21 429 NR 165 982 754 26

DES 99 27 21 224 NR 100 947 813 26DESTINY (121) BMS 66 19 10 360 0100 350 100 170 29

DES 74 16 10 170 0100 80 100 150 30

YUKON-BTX (122) BMS 79 31 9 444 582418 175 100 215 30

DES 82 30 8 194 488512 97 100 232 30

DEBATE-BTK (123) PTA 67 131 79 740 0100 430 NR 821 29

DCB 65 129 83 270 0100 180 NR 775 29

INPACT DEEP CLI (124) PTA 1 19 129 95 355 08992 131 882 459 129

DCB 239 102 91 410 0100 92 772 386 102

IDEAS (125) DCB 25 148 57 579 NR 136 NR 120 NR

DES 27 127 47 280 NR 77 NR 230 NR

p lt 005

ACHILLES frac14 Comparing Angioplasty and DES in the Treatment of Subjects With Ischemic Infrapopliteal Arterial Disease DEBATE-BTK frac14 Drug-Eluting Balloon in Peripheral

Intervention for Below the Knee Angioplasty Evaluation trial DESTINY frac14 Drug Eluting Stents in the Critically Ischemic Lower Leg IDEAS frac14 Infrapopliteal Drug Eluting An-

gioplasty Versus Stenting for the Treatment of Long-segment Arterial Disease The IDEAS-I Randomized Controlled Trial INPACT DEEP CLI frac14 Randomized Study of INPACT

Amphirion Drug Eluting Balloon vs Standard PTA (Percutaneous Transluminal Angioplasty) for the Treatment of Below the Knee Critical Limb Ischemia YUKON-BTX frac14

YUKON-drug-eluting Stent Below The Knee - Prospective Randomized Double-blind Multicenter Study other abbreviations as in Table 6



1353



reducing variation Accreditation for Cardiovascular

Excellence (ACE) offers on-site reviews for cardiac

peripheral carotid electrophysiology and congenital

heart disease Importantly accreditation must be

independent of professional societies regulators

and payers to avoid bias The value of accreditation

is in establishing ongoing procedures to ensure

quality and safety When done properly independent

accreditation functions more like a coach than a

policeman to promote a culture of continuous

improvement Payers and regulators should require

or reward independent accreditation to support

value-based health care

CONCLUSIONS

Despite the increased prevalence over the past 20

years PAD continues to be underdiagnosed and

undertreated compared with CAD Because most

deaths in patients with PAD are attributable to car-

diovascular disease patients with PAD (even those

who are asymptomatic) who are not diagnosed or

treated will needlessly experience MACE There are

effective therapies to prevent cardiovascular events

yet they are still not offered to a large percentage of

patients with PAD Additionally there have been

many advances in minimally invasive techniques to

improve the circulation to the lower extremities and

in the past decade more physicians have become

competent to provide high-level care to patients with

claudication and CLI The endovascular arena has

changed so dramatically over the past 5 years that it is

dif 1047297cult for the guidelines to keep up with these

changes The goal for the future should be early

identi1047297cation of the PAD patient so that progression to

CLI and amputation can be prevented and appropriate

therapy to prevent MACE can be implemented The

optimal treatment of an individual patient involves a

combination of exercise pharmacological therapy

and revascularization (endovascular or open surgery)

REPRINT REQUESTS AND CORRESPONDENCE Dr Jeffrey

W Olin Vascular Medicine and Vascular Diagnostic

Laboratory Zena and Michael A Wiener Cardiovascular

Institute and Marie-Joseeacute and Henry R Kravis Center for

Cardiovascular Health Icahn School of Medicine at

Mount Sinai One Gustave L Levy Place New York New

York 10029 E-mail jeffreyolinmountsinaiorg

R E F E R E N C E S

1 Patel MR Conte MS Cutlip DE et al Evaluation

and treatment of patients with lower extremityperipheral artery disease consensus de1047297nitions

from Peripheral Academic Research Consortium

(PARC) [published correction appears in J Am Coll

Cardiol 2015652578ndash2579] J Am Coll Cardiol

201565931ndash41

2 Rooke TW Hirsch AT Misra S et al Manage-

ment of patients with peripheral artery disease

(compilation of 2005 and 2011 ACCFAHA guide-

line recommendations) a report of the American

College of Cardiology FoundationAmerican Heart

Association Task Force on Practice Guidelines

J Am Coll Cardiol 2013611555ndash70

3 Tendera M Aboyans V Bartelink M et al ESC

guidelines on the diagnosis and treatment of pe-

ripheral artery disease Eur Heart J 2011322851ndash906

4 NorgrenL Hiatt WRDormandyJA etal TASC II

Working Group Inter-society Consensus for the

Managementof PeripheralArterial Disease (TASCII)

Eur J Vasc Endovasc Surg 200733 Suppl 1S1ndash75

5 TASC Steering Committee Jaff MR White CJ

et al An update on methods for revascularization

and expansion of the TASC lesion classi1047297cation to

include below-the-knee arteries a supplement to

the Inter-Society Consensus for the Management

of Peripheral Arterial Disease (TASC II) Vasc Med

201520465ndash78

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 system-atic review and analysisLancet 20133821329ndash40

7 Sampson U Fowkes F McDermott M et al

Global and regional burden of death and disabilityfrom peripheral artery disease 21 world regions

1990-2010 Glob Heart 20149145ndash58e21

8 Pande RL Perlstein TS Beckman JA et al Sec-

ondary preventionand mortality in peripheralartery

disease National Health and Nutrition Examination

Study 1999 to 2004 Circulation 201112417ndash23

9 Hirsch AT Criqui MH Treat-Jacobson D et al

Peripheral arterialdiseasedetectionawarenessand

treatment in primarycare JAMA 20012861317ndash24

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 1999ndash2000 Circu-

lation 2004110738ndash43

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 201460686ndash95e2

12 Armstrong EJ Chen DC Westin GG et al

Adherence to guideline-recommended therapy is

associated with decreased major adverse cardio-

vascular events and major adverse limb events

among patients with peripheral artery disease

J Am Heart Assoc 20143e000697

13 Criqui MH Aboyans V Epidemiology of pe-

ripheral artery disease Circ Res 20151161509ndash26

14 Joosten MM Pai JK Bertoia ML et al Asso-

ciations between conventional cardiovascular risk

factors and risk of peripheral artery disease inmen JAMA 20123081660ndash7

15 Leng GC Fowkes FG Lee AJ Dunbar J

Housley E Ruckley CV Use of ankle brachialpressure index to predict cardiovascular events

and death a cohort study BMJ 19963131440ndash4

16 Criqui MH Langer RD Fronek A et al Mor-

tality over a period of 10 years in patients with

peripheral arterial disease N Engl J Med 1992

326381ndash6

17 McDermott MM Greenland P Liu K et al Leg

symptoms in peripheral arterial disease associated

clinical characteristics and functional impairment

JAMA 20012861599ndash606

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 2004292453ndash61

19 McDermott MM Guralnik JM Tian L et al

Associations of borderline and low normal ankle-

brachial index values with functional decline at

5-year follow-up the WALCS (Walking and Leg Cir-

culation Study)J Am CollCardiol 2009531056ndash62

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 20154e001846

21 Aboyans V Criqui MH Abraham P et al for

the American Heart Association Council on Pe-

ripheral Vascular Disease Council on Epidemi-

ology and Prevention Council on Clinical

Cardiology Council on Cardiovascular Nursing

Council on Cardiovascular Radiology and Inter-vention and Council on Cardiovascular Surgery



1354



and Anesthesia Measurement and interpretation

of the ankle-brachial index a scienti1047297c statement

from the American Heart Association [published

correction appears in Circulation 2013127e264]

Circulation 20121262890ndash909

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 2004109733ndash9

23 Ankle Brachial Index Collaboration Ankle

brachial index combined with Framingham risk

score to predict cardiovascular events and mor-

tality a meta-analysis JAMA 2008300197ndash208

24 Lee JY Lee SW Lee WS et al Prevalence and

clinical implications of newly revealed asymp-

tomatic abnormal ankle-brachial index in patients

with signi1047297cant coronary artery disease J Am Coll

Cardiol Intv 201361303ndash13

25 Diehm C Schuster A Allenberg JR et al High

prevalence of peripheral arterial disease and co-

morbidity in 6880 primary care patients cross-

sectional study Atherosclerosis 200417295ndash105

26 Cooke JP Wilson AM Biomarkers of peripheral

arterialdisease J AmColl Cardiol2010552017ndash23

27 Hiatt WR Zakharyan A Fung ET et al

A validated biomarker panel to identify peripheral

artery disease Vasc Med 201217386ndash93

28 McDermottMM LiuK GreenD et alChangesin

D-dimer and in1047298ammatory biomarkers before

ischemic events in patients with peripheral artery

diseaseThe BRAVOStudy VascMed 20162112ndash20

29 Hiatt WR Armstrong EJ Larson CJ Brass EP

Pathogenesis of the limb manifestations and ex-

ercise limitations in peripheral artery disease Circ

Res 20151161527ndash39

30 McDermott MM Mehta S Greenland P Exer-

tional leg symptoms other than intermittent

claudication are common in peripheral artery dis-

ease Arch Intern Med 1999159387ndash92

31 GorelyT Crank H HumphreysL NawazS TewGA

ldquoStanding still in the streetrdquo experiences knowledge

andbeliefs of patientswith intermittent claudicationa

qualitative study J Vasc Nurs 2015334ndash9

32 Cunningham MA Swanson V Pappas E

OrsquoCarroll RE Holdsworth RJ Illness beliefs and

walking behavior after revascularization for inter-

mittent claudication a qualitative study

J Cardiopulm Rehabil Prev 201434195ndash201

33 Hiatt WR Regensteiner JG Hargarten ME

Wolfel EE Brass EP Bene1047297t of exercise condi-

tioning for patients with peripheral arterial dis-

ease Circulation 199081602ndash9

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

mechanism of the training response Circulation

1994901866ndash74

35 Hiatt WR Regensteiner JG Wolfel EE

Carry MR Brass EP Effect of exercise training on

skeletal muscle histology and metabolism in pe-

ripheral arterial disease J Appl Physiol (1985)

199681780ndash8

36 Mays R Rogers R Hiatt WR Regensteiner JGCommunity walking programs for treatment of

peripheral artery disease J Vasc Surg 201358

1678ndash87

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 201590339ndash45

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 cardiovas-

cular mortality and morbidity Circ J 200973

167ndash73

39 Gardner AW Montgomery PS Parker DE

Optimal exercise program length for patients with

claudication J Vasc Surg 2012551346ndash54

40 Popplewell MA Bradbury AW Why do health

systems not fund supervised exercise programmes

for intermittent claudication Eur J Vasc Endovasc

Surg 201448608ndash10

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 2011342174ndash9

42 Mays RJ Hiatt WR Casserly IP et al

Community-based walking exercise for peripheral

artery disease an exploratory pilot study Vasc

Med 201520339ndash47

43 Gardner AW Parker DE Montgomery PS

Scott KJ Blevins SM Ef 1047297cacy of quanti1047297ed home-

based exercise and supervised exercise in patients

with intermittent claudication a randomized

controlled trial Circulation 2011123491ndash8


Blevins SM Step-monitored home exerciseimproves ambulation vascular function and

in1047298ammation in symptomatic patients with pe-

ripheral artery disease a randomized controlled

trial J Am Heart Assoc 20143e001107

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

2012331311ndash20

46 McDermott MM Liu K Guralnik JM et al

Home-based walking exercise intervention in

peripheral artery disease a randomized control

trial JAMA 201331057ndash65

47 McDermott MM Guralnik JM Criqui MH et al

Home-based exercise in peripheral artery disease

12-month follow-up of the GOALS randomized



Unsupervised exercise and mobility loss in

peripheral artery disease a randomized controlled


49 Weinberg MD Lau JF Rosen1047297eld K Olin JW

Peripheral artery disease part 2 medical and endo-

vascular treatment Nat Rev Cardiol 20118429ndash41

50 Bronas UG Hirsch AT Murphy T et al for the

CLEVER Research Group Design of the multi-

center standardized supervised exercise training

intervention for the CLaudication Exercise Vs

Endoluminal Revascularization (CLEVER) studyVasc Med 200914313ndash21

51 Hamburg NM Balady GJ Exercise rehabilitation

in peripheral artery disease functional impact and

mechanismsof bene1047297ts Circulation 201112387ndash97

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 Exer-

cise Versus Endoluminal Revascularization

(CLEVER) study Circulation 2012125130ndash9

53 Nordanstig J Taft C Hensaumlter M Perlander A

Osterberg K Jivegaringrd 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 Inter-

mittent Claudication (IRONIC) Trial Circulation

2014130939ndash47

54 Lundgren F Dahlloumlf A Lundholm K

Schersteacuten T Volkmann R Intermittent claudica-

tion surgical reconstruction or physical training

A prospective randomized trial of treatment ef 1047297-

ciency Ann Surg 1989209346ndash55


Supervised exercise stent revascularization or med-

ical therapy for claudication due to aortoiliac periph-

eral artery disease the CLEVER study [published

correction appears in J Am Coll Cardiol 201565

2055] J Am Coll Cardiol 201565999ndash1009

56 Fakhry F Spronk S van der Laan L et al

Endovascular revascularization and supervised

exercise for peripheral artery disease and inter-

mittent claudication a randomized clinical trial

JAMA 20153141936ndash44

57 Spronk S Bosch JL den Hoed PT Veen HF

Pattynama PM Hunink MG Cost-effectiveness of endovascular revascularization compared to super-

vised hospital-based exercise training in patients


controlled trial J Vasc Surg 2008481472ndash80

58 Fokkenrood HJ Scheltinga MR Koelemay MJ

et al Signi1047297cant savings with a stepped care model

for treatment of patients with intermittent claudi-

cation Eur J Vasc Endovasc Surg 201448423ndash9

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 under-

use remains Circulation 20121261345ndash54

60 Olin JW Allie DE Belkin M et al ACCFAHA

ACRSCAISIRSVMSVNSVS 2010 performancemeasures for adults with peripheral artery disease

a report of the American College of Cardiology

FoundationAmericanHeart Association TaskForce

on Performance Measuresthe AmericanCollegeof

Radiologythe Society forCardiacAngiography and

Interventions the Society for Interventional Radi-

ology the Society for Vascular Medicine the Soci-

ety for Vascular Nursing and the Society for

Vascular Surgery (Writing Committee to Develop

ClinicalPerformance Measuresfor PeripheralArtery

Disease) J Am Coll Cardiol 2010562147ndash81

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 dis-

ease J Vasc Surg 2014601565ndash71



1355



62 Dartmouth-Hitchcock Medical Center Vascular

Physician Offer and Report (VAPOR) Trial 2015

Available at httpsclinicaltrialsgovct2show

NCT02220686termfrac14NCTthorn02220686amprankfrac141

Accessed January 7 2016

63 Dawson DL Cutler BS Meissner MH

Strandness DE Jr Cilostazol has bene1047297cial effects

in treatment of intermittent claudication results

from a multicenter randomized prospective

double-blind trial Circulation 199898678ndash86

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 201015181ndash8

65 Hiatt WR Money SR Brass EP Long-term

safety of cilostazol in patients with peripheral ar-

tery disease the CASTLE study (Cilostazol A

Study in Long-Term Effects) J Vasc Surg 2008

47330ndash6

66 De Backer T Vander Stichele R Lehert P Van

Bortel L Naftidrofuryl for intermittent claudica-

tion meta-analysis based on individual patient

data BMJ 2009338b603

67 Heart Outcomes Prevention Evaluation Study

Investigators Effects of an angiotensin-

converting enzyme inhibitor ramipril on cardio-

vascular events in high-risk patients [published

corrections appear in N Engl J Med 2000342

1376 and N Engl J Med 2000342748] N Engl J

Med 2000342145ndash53

68 Oumlstergren J Sleight P Dagenais G et al

Impact of ramipril in patients with evidence of

clinical or subclinical peripheral arterial disease

Eur Heart J 20042517ndash24

69 ONTARGET Investigators Telmisartan ram-

ipril or both in patients at high risk for vascular

events N Engl J Med 20083581547ndash59

70 Arms tron g EJ Che n DC S ingh G D

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 201520237ndash44

71 Stone NJ Robinson JG Lichtenstein AH et al

2013ACCAHAguideline on thetreatment of blood

cholesterol to reduce atherosclerotic cardiovascu-

larriskinadultsa reportof theAmericanCollegeof

CardiologyAmerican Heart Association Task Force

on Practice Guidelines [published correction ap-

pearsin J AmCollCardiol20146325pt B3024ndash5]


72 Heart Protection Study Collaborative Group

Randomized trial of the effects of cholesterol-

lowering with simvastatin on peripheral vascular

and other major vascular outcomes in 20536

people with peripheral arterial disease and other

high-risk conditions J Vasc Surg 200745645ndash54

73 Westin GG Armstrong EJ Bang H et al As-

sociation between statin medications and mortal-

ity major adverse cardiovascular event and

amputation-free survival in patients with critical

limb ischemia J Am Coll Cardiol 201463682ndash90

74 Kumbhani DJ Steg PG Cannon CP et al on

behalf of the REACH Registry Investigators Statintherapy and long-term adverse limb outcomes in

patientswith peripheral arterydiseaseinsights from

the REACH registry Eur Heart J 2014352864ndash72

75 Vogel TR Dombrovskiy VY Galintildeanes EL

KruseRL Preoperativestatins andlimb salvage after

lower extremity revascularization in the Medicare

population Circ Cardiovasc Interv20136694ndash700

76 Berger JS Krantz MJ Kittelson JM Hiatt WR

Aspirin for the prevention of cardiovascular events

in a general population screened for a low ankle-

brachial index a randomized controlled trial

JAMA 20093011909ndash19

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


JAMA 2010303841ndash8

78 Belch J MacCuish A Campbell I et alon behalf

of the Prevention of Progression of Arterial Disease

and Diabetes (POPADAD) trial factorial randomisedplacebocontrolled trialof aspirinand antioxidantsin

patientswith diabetes and asymptomatic peripheral

arterial disease BMJ 2008337a1840

79 Morrow DA Braunwald E Bonaca MP et al

for the TRA 2P-TIMI 50 Steering Committee and

Investigators Vorapaxar in the secondary pre-

vention of atherothrombotic events N Engl J Med

20123661404ndash13

80 CAPRIE Steering Committee A randomised

blinded trial of clopidogrel versus aspirin in pa-

tients at risk of ischaemic events (CAPRIE) Lancet

19963481329ndash39

81 Bhatt DL Fox KAA Hacke W et al for the

CHARISMA Investigators Clopidogrel and aspirin

versus aspirin alone for the prevention of athero-thrombotic events N EnglJ Med20063541706ndash17

82 Cacoub PP Bhatt DL Steg PG Topol EJ

Creager MA for the CHARISMA Investigators Pa-

tients with peripheral arterial disease in the

CHARISMA Trial Eur Heart J 200930192ndash201

83 Armstrong EJ Anderson DR Yeo KK et al

Association of dual-antiplatelet therapy with

reduced major adverse cardiovascular events in

patients with symptomatic peripheral arterial dis-

ease J Vasc Surg 201562157ndash65e1

84 Belch JJF Dormandy J for the CASPAR

Writing Committee Results of the randomized

placebo-controlled clopidogrel and acetylsalicylic

acid in bypass surgery for peripheral arterial dis-ease (CASPAR) Trial [published correction appears

in J Vasc Surg 201153564] J Vasc Surg 201052

825ndash33 833e1ndash2

85 University of Texas Southwestern Medical

Center Antiplatelet Strategy For Peripheral Arte-

rial Interventions for Revascularization of Lower

Extremities (ASPIRE PAD) 2014 Available at

httpsclinicaltrialsgovct2showNCT02317822

termfrac14NCTthorn02317822amprankfrac141 Accessed January

7 2016

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

in Acute Coronary Syndrome (TRACER) Am Heart

J 2014168588ndash96

87 Bonaca MP Scirica BM Creager MA et al

Vorapaxar in patients with peripheral artery dis-

ease results from TRA2P-TIMI 50 Circulation

20131271522ndash9

88 Cooke JP Losordo DW Modulating the

vascular response to limb ischemia angiogenicand cell therapies Circ Res 20151161561ndash78

89 Gupta NK Armstrong EJ Parikh SA The cur-

rent state of stem cell therapy for peripheral

artery disease Curr Cardiol Rep 201416447

90 AstraZeneca A Study Comparing Cardiovas-

cular Effects of Ticagrelor and Clopidogrel in Pa-

tients with Peripheral Artery Disease (EUCLID)

2015 Available at httpsclinicaltrialsgovct2

showNCT01732822termfrac14NCT01732822amprankfrac141

wwwclinicaltrialsgov Accessed January 7 2016

91 Bayer Rivaroxaban for the Prevention of Major

Adverse Cardiovascular Events in Coronary or Pe-

ripheral Artery Disease (COMPASS) 2016 Available

at httpsclinicaltrialsgovct2showNCT01776424

termfrac14NCT01776424amprankfrac141 Accessed January 7

2016

92 Beckman JA Creager MA Critical limb

ischemia and intermediate-term survival J Am

Coll Cardiol Intv 201471450ndash2

93 Iida O Soga Y Kawasaki D et al Long-term

results of direct and indirect endovascular revas-

cularization based on the angiosome concept in

patients with critical limb ischemia presenting with

isolated below-the-knee lesions J Vasc Surg 2012

55363ndash70e5

94 Jongkind V Akkersdijk GJ Yeung KK

Wisselink W A systematic review of endovascular

treatment of extensive aortoiliac occlusive dis-


95 Klein AJ Feldman DN Aronow HD et al SCAI

expert consensus statement for aorto-iliac arterial

intervention appropriate use Catheter Cardiovasc

Interv 201484520ndash8

96 de Donato G Bosiers M Setacci F et al

24-Month data from the BRAVISSIMO a large-

scale prospective registry on iliac stenting for

TASC A amp B and TASC C amp D lesions Ann Vasc Surg

201529738ndash50

97 Bonvini RF Rastan A Sixt S et al Endovas-

cular treatment of common femoral artery dis-

ease medium-term outcomes of 360 consecutive

procedures J Am Coll Cardiol 201158792ndash8

98 Nguyen BN Amdur RL Abugideiri M

Rahbar R Neville RF Sidawy AN Postoperativecomplications after common femoral endarterec-

tomy J Vasc Surg 2015611489ndash94e1

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 re-

sults Circ Cardiovasc Interv 20114495ndash504

100 Dake MD Ansel GM Jaff MR et al for the

Zilver PTX Investigators Sustained safety and

effectiveness of paclitaxel-eluting stents for fem-

oropopliteal lesions 2-year follow-up from the

Zilver PTX randomized and single-arm clinical

studies [published correction appears in J Am Coll

Cardiol 201362666] J Am Coll Cardiol 2013612417ndash27



1356



101 Tepe GZellerT Albrecht Tet alLocaldelivery

of paclitaxel to inhibit restenosis during angioplasty

of the leg N Engl J Med 2008358689ndash99

102 Werk M Langner S Reikensmeier B et al

Inhibition of restenosis in femoropopliteal arteries

paclitaxel-coated versus uncoated balloonfemoral paclitaxel randomized pilot trial [pub-

lished correction appears in Circulation 2008118

e670] Circulation 20081181358ndash65

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 1047297rst-in-

human randomized trial of low-dose drug-coated

balloon versus uncoated balloon angioplasty

J Am Coll Cardiol Intv 2014710ndash9

104 Zeller T Rastan A Macharzina R et al Drug-

coated balloons vs drug-eluting stents for treat-

ment of long femoropopliteal lesions J Endovasc

Ther 201421359ndash68

105 Scheinert D Schulte KL Zeller T Lammer J

Tepe G Paclitaxel-releasing balloon in femo-

ropopliteal lesions using a BTHC excipient

twelve-month results from the BOLUX P-I ran-

domized trial J Endovasc Ther 20152214ndash21

106 Rosen1047297eld K Jaff MR White CJ et al for the

LEVANT 2 Investigators Trial of a paclitaxel-

coated balloon for femoropopliteal artery dis-

ease N Engl J Med 2015373145ndash53

107 Laird JR Schneider PA Tepe G et al for the

INPACT SFA Investigators Durability of treatment

effect using a drug-coated balloon for femo-

ropopliteal lesions 24-month results of INPACT

SFA J Am Coll Cardiol 2015662329ndash38

108 Schillinger M Sabeti S Loewe C et alBalloon angioplasty versus implantation of nitinol

stents in the super1047297cial femoral artery N Engl J

Med 20063541879ndash88

109 Dick P Wallner H Sabeti S et al Balloon

angioplasty versus stenting with nitinol stents in

intermediate length super1047297cial femoral artery le-

sions Catheter Cardiovasc Interv 2009741090ndash5

110 Krakenberg H Schluumlter M Steinkamp HJet al

Nitinol stent implantation versus percutaneous

transluminal angioplasty in super1047297cial femoral ar-

terylesionsupto10cminlengththeFemoralArtery

Stenting Trial (FAST) Circulation 2007116285ndash92

111 Tepe G Schnorr B Albrecht T et al Angio-

plasty of femoral-popliteal arteries with drug

coated balloons 5-year follow-up of the THUN-DER trial J Am Coll Cardiol Intv 20158102ndash8

112 Tepe G Laird J Schneider P et al for the IN

PACT SFA Trial Investigators Drug-coated balloon

versus standard percutaneous transluminal an-

gioplasty for the treatment of super1047297cial femoral

and popliteal peripheral artery disease 12-month

results from the INPACT SFA randomized trial


113 Werk M Albrecht T Meyer DR et al Paclitaxel-

coated balloons reduce restenosis after femoro-

popliteal angioplasty evidence from the randomized

PACIFIERtrial Circ Cardiovasc Interv 20125831ndash40

114 Iida O Yokoi H Soga Y et al for the STOP-IC

investigators Cilostazol reduces angiographic

restenosis after endovascular therapy for femo-

ropopliteal lesions in the Suf 1047297cient Treatment of

Peripheral Intervention by Cilostazol Study Cir-

culation 20131272307ndash15

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 endo-

prosthesis with PROPATEN bioactive surface [VIA]

versus bare nitinol stent in the treatment of longlesions in super1047297cial femoral artery occlusive dis-

ease) J Am Coll Cardiol 2013621320ndash7


Sustained bene1047297t at 2 years for covered stents

versus bare-metal stents in long SFA lesions the

VIASTAR trial [published correction appears in

Cardiovasc Intervent Radiol 201538779ndash80]

Cardiovasc Intervent Radiol 20153825ndash32

117 Geraghty PJ Mewissen MW Jaff MR

Ansel GM for the VIBRANT Investigators Three-

year results of the VIBRANT Trial of VIABAHN

endoprosthesis versus bare nitinol stent implan-

tation for complex super1047297cial femoral artery

occlusive disease J Vasc Surg 201358386ndash95e4

118 McQuade K Gable D Pearl G Theune B

Black S Four-year randomized prospective

comparison of percutaneous ePTFEnitinol self-

expanding stent graft versus prosthetic femoral-

popliteal bypass in the treatment of super1047297cial

femoral artery occlusive disease J Vasc Surg

201052584ndash90 discussion 590ndash1 591e1ndashe7

119 Bradbury AW Adam DJ Bell J et al for the

BASILTrial Participants Bypass Versus Angioplasty

inSevereIschaemia ofthe Leg(BASIL)trialanalysis

of amputation free and overall survival by treat-

ment received [published correction appears in J

Vasc Surg 2010521751] J Vasc Surg 201051

18Sndash31S

120 ScheinertD KatsanosK Zeller Tet al forthe

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


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 occlusivedisease J Vasc Surg 201255390ndash8

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 2011322274ndash81

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 2013128615ndash21

124 Zeller T Baumgartner I Scheinert D et al for

the INPACT DEEP Trial Investigators Drug-eluting

balloon versus standard balloon angioplasty for

infrapopliteal revascularization in critical limb

ischemia 12-month results from the INPACT DEEP

randomized trial J Am Coll Cardiol 201464

1568ndash76

125 SiablisD KitrouPM Spiliopoulos S Katsanos K

Karnabatidis D Paclitaxel-coated balloon angio-

plastyversus dug-eluting stenting for the treatment

of infrapopliteal long-segment arterial occlusive

disease theIDEASrandomizedcontrolledtrialJ Am


126 GrayBH Diaz-SandovalLJ Dieter RSJaff MR

White CJ SCAI expert consensus statement for

infrapoplitealarterialinterventionappropriate use

Catheter Cardiovasc Interv 201484539ndash45

127 Rastan A Brechtel K Krakenberg H et al

Sirolimus-eluting stents for treatment of infrapo-

pliteal arteries reduce clinical event rate compared

to bare-metal stents long-term results from a ran-

domized trial J Am Coll Cardiol201260587ndash91

128 Farber A Rosen1047297eld K Menard M The BEST-

CLI Trial a multidisciplinary effort to assess which

therapy is best for patients with critical limb

ischemia Tech Vasc Interv Radiol 201417221ndash4

KEY WORDS ankle-brachial index

claudication drug-eluting stents

endovascular therapy exercise therapy

vascular diseases

Go to httpwwwaccorgjacc-

journals-cme to take the CME

quiz for this article



1357






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 ldquoendovascular 1047297rstrdquo 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 2016671338ndash57)

copy 2016 by the American College of Cardiology Foundation

Peripheral artery disease (PAD) refers to athero-

sclerosis involving the aorta iliac and lower-

extremity arteries and is associated with

signi1047297cant morbidity and mortality (12) Since the

last iteration of the guidelines focused on PAD ( 2ndash4)

published data have emerged that may alter the stan-

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

view will delve in great detail into the management

of PAD patients highlighting the roles of exercise

optimal medical management and endovascular

therapy Surgical revascularization will not be dis-

cussed because current expert consensus documents

recommend an ldquoendovascular 1047297rstrdquo approach for the

majority of PAD patients requiring revascularization

(23)

Despite initiatives to improve on the identi1047297cation

and management of PAD (25) the number of people

affected and disease morbidity continues to rise As

of 2010 more than 200 million people worldwide areliving with PAD which represents a 287 increased

prevalence in low- and middle-income countries and

a 131 increase in high-income countries over a

10-year period (67) Prevalence studies in the United

States estimate that 59 of Americans over 40 years

of age have PAD (8) When speci1047297c high-risk pop-

ulations are evaluated estimates of PAD prevalence

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

PAD is increased in African Americans and Hispanics

(10) A recent retrospective cohort study evaluating

nearly 12 million insured American adults reported

mean annual incidence rates of PAD and critical limbischemia (CLI) of 235 and 035 respectively (11)

The risk factors for PAD mirror those of cerebrovas-

cular and coronary atherosclerosis including a posi-

tive family history diabetes mellitus smoking

chronic kidney disease hypertension and hyperlip-

idemia (59101213) Smoking and diabetes are

particularly virulent and are associated with worse

outcomes independent of other risk factors (14)

Identi1047297cation of patients with PAD is important

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

diovascular events even in the setting of asymp-

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

patients with PAD will experience a nonfatal cardio-

vascular event and 15 to 20 will die (most of

cardiovascular causes) (816)

Most patients with PAD fall into 1 of 3 groups

classic claudication (10 to 30) atypical leg pain

(20 to 40) or asymptomatic (nearly 50) Formal

testing to assess functional capacity and endurance

shows signi1047297cant impairment in patients with PADeven if asymptomatic Although the majority of pa-

tients report leg symptoms other than classic claudi-

cation greater functional decline is associated with

greater severity of disease lower baseline ankle-

brachial index (ABI) and increased numbers of

cardiovascular events (17ndash20) In patients with CLI

outcomes are dire at 1 year 10 will experience a

fatal cardiovascular event and 25 will undergo limb

amputation (2)

Patient-reported symptoms underestimate PAD

prevalence and the physical examination is not a

reliable tool for the identi1047297cation of disease Diag-nosis and prevention of adverse outcomes may



1339






















[HR] 035 p frac14 002) (8)









































this review















































therapy






disease



artery


Society Consensus



1340










































































































1341









































































With PAD

Frequency

3-5 days per week

Modality


Method









Duration


Tips for success











1342

















PATIENTS WITH PAD















SMOKING CESSATION
























bull Cilostazol











1343































States

ACEIs






















STATINS





Outcomes in PAD

0 6 12 18 24 30 36Follow-Up (Months)

0 6 12 18 24 30 36

Follow-Up (Months)

0

1 0

2 0

3 0

4 0


0

1 0

2 0

3 0

4 0

M a j o r A


Hazard ratio 064 95 CI 045-089 P=0009

Hazard ratio 055 95 CI 037-083 P=0005


4 Guideline502237

450222

391207

355180

322156

288143

256123


4 Guideline502237

306155

240133

201102

17594

14276

12564



A

B








1344
















CLI (73)












































and 095 in AAA) (7778)


















tice guidelines

CLOPIDOGREL AND





























1345




















patients with CLI




























VORAPAXAR




















93 vs 105 HR 087 95 CI 080 to 094







































1346































































45

40

35

30

25

20

15

10

05

00


0 180 360 540 720 900 1080


0 180 360 540 720 900 1080


250

200

150

100

50

00


23 vs 39HR 058 (039 ndash 086)

P=0006

184 vs 222HR 084 (073 ndash 097)

P=0017


Placebo Vorapaxar


Placebo Vorapaxar

A

B






1347























































length


Single stenosis or













AAA frac14





super1047297



Fontaine Rutherford













1348













































dication (99100103105)








































of Evidence C)





Evidence C)





1349



























standard therapy




































(Figure 3 Table 6)


















Evidence C)


Evidence C)


Evidence A)




Evidence C)




Evidence C)




1350




100

90

80

70

60

50

40

30

20

10


0 50 100 150 200


FAST PTA


FAST BMS


FEMPAC PTA


PACIFIER PTA

Lesion length 66

Restenosis 324

FEMPAC DCB


ZILVER DES



THUNDER DCB


INPACT SFA DCB


ZILVER PTA


ASTRON PTA


THUNDER PTA


INPACT SFA PTA


ASTRON BMS


ABSOLUTE PTA


ABSOLUTE BMS


VIASTAR BMS


VIASTAR CS



ZELLER DES




FAST (110) PTA 121 45 28 386 96535 183 595 248 51

BMS 123 45 27 317 97525 149 659 366 53

ABSOLUTE (108) PTA 53 92 75 630 8713 31 100 32 NR

BMS 51 101 75 370 8812 28 100 37 NR

ASTRON (109) PTA 39 65 46 611 973 NR 100 39 NR

BMS 34 82 67 344 919 NR 100 38 NR

ZILVER (100) PTA 238 63 41 672 90785 175 247 NR NR

DES 241 66 39 169 90289 95 296 NR NR

Zeller (104) DES 97 195 65 304 91772 215 557 629 NR

DCB 131 194 86 239 81168 193 481 527 NR

THUNDER (111) PTA 54 74 67 440 NR 48 30 26 47

DCB 48 75 62 170 NR 10 38 27 52


42 470 937 17 34 19 51DCB 45 40 44 190 964 7 35 13 52

INPACT SFA (112) PTA 111 88 51 476 93763 206 946 195 468

DCB 220 89 48 178 9550 24 95 258 50

LEVANT-2 (106) PTA 160 63 40 474 91981 375 875 219 48

DCB 316 63 41 348 92179 38 839 206 48

PACIFIER (113) PTA 47 66 55 324 95743 214 829 383 49

DCB 41 70 53 86 95545 71 682 227 496

p lt 005










1351












































































for CLI



of Evidence C)





Evidence C)


of Evidence C)



Evidence C)




1352

































































ACHILLES (120) PTA 101 27 21 429 NR 165 982 754 26


DES 74 16 10 170 0100 80 100 150 30

YUKON-BTX (122) BMS 79 31 9 444 582418 175 100 215 30

DES 82 30 8 194 488512 97 100 232 30

DEBATE-BTK (123) PTA 67 131 79 740 0100 430 NR 821 29

DCB 65 129 83 270 0100 180 NR 775 29


DCB 239 102 91 410 0100 92 772 386 102

IDEAS (125) DCB 25 148 57 579 NR 136 NR 120 NR

DES 27 127 47 280 NR 77 NR 230 NR

p lt 005








1353
















CONCLUSIONS
































R E F E R E N C E S






201565931ndash41





















201520465ndash78








































326381ndash6




JAMA 20012861599ndash606























1354





































Res 20151161527ndash39























1994901866ndash74





199681780ndash8



1678ndash87










167ndash73






























2012331311ndash20





































2014130939ndash47
















JAMA 20153141936ndash44


































1355

















Med 201015181ndash8





47330ndash6











Med 2000342145ndash53













































JAMA 20093011909ndash19
















20123661404ndash13




19963481329ndash39

























7 2016






J 2014168588ndash96




20131271522ndash9

















2016









55363ndash70e5













201529738ndash50























1356






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357






















[HR] 035 p frac14 002) (8)









































this review















































therapy






disease



artery


Society Consensus



1340










































































































1341









































































With PAD

Frequency

3-5 days per week

Modality


Method









Duration


Tips for success











1342

















PATIENTS WITH PAD















SMOKING CESSATION
























bull Cilostazol











1343































States

ACEIs






















STATINS





Outcomes in PAD

0 6 12 18 24 30 36Follow-Up (Months)

0 6 12 18 24 30 36

Follow-Up (Months)

0

1 0

2 0

3 0

4 0


0

1 0

2 0

3 0

4 0

M a j o r A


Hazard ratio 064 95 CI 045-089 P=0009

Hazard ratio 055 95 CI 037-083 P=0005


4 Guideline502237

450222

391207

355180

322156

288143

256123


4 Guideline502237

306155

240133

201102

17594

14276

12564



A

B








1344
















CLI (73)












































and 095 in AAA) (7778)


















tice guidelines

CLOPIDOGREL AND





























1345




















patients with CLI




























VORAPAXAR




















93 vs 105 HR 087 95 CI 080 to 094







































1346































































45

40

35

30

25

20

15

10

05

00


0 180 360 540 720 900 1080


0 180 360 540 720 900 1080


250

200

150

100

50

00


23 vs 39HR 058 (039 ndash 086)

P=0006

184 vs 222HR 084 (073 ndash 097)

P=0017


Placebo Vorapaxar


Placebo Vorapaxar

A

B






1347























































length


Single stenosis or













AAA frac14





super1047297



Fontaine Rutherford













1348













































dication (99100103105)








































of Evidence C)





Evidence C)





1349



























standard therapy




































(Figure 3 Table 6)


















Evidence C)


Evidence C)


Evidence A)




Evidence C)




Evidence C)




1350




100

90

80

70

60

50

40

30

20

10


0 50 100 150 200


FAST PTA


FAST BMS


FEMPAC PTA


PACIFIER PTA

Lesion length 66

Restenosis 324

FEMPAC DCB


ZILVER DES



THUNDER DCB


INPACT SFA DCB


ZILVER PTA


ASTRON PTA


THUNDER PTA


INPACT SFA PTA


ASTRON BMS


ABSOLUTE PTA


ABSOLUTE BMS


VIASTAR BMS


VIASTAR CS



ZELLER DES




FAST (110) PTA 121 45 28 386 96535 183 595 248 51

BMS 123 45 27 317 97525 149 659 366 53

ABSOLUTE (108) PTA 53 92 75 630 8713 31 100 32 NR

BMS 51 101 75 370 8812 28 100 37 NR

ASTRON (109) PTA 39 65 46 611 973 NR 100 39 NR

BMS 34 82 67 344 919 NR 100 38 NR

ZILVER (100) PTA 238 63 41 672 90785 175 247 NR NR

DES 241 66 39 169 90289 95 296 NR NR

Zeller (104) DES 97 195 65 304 91772 215 557 629 NR

DCB 131 194 86 239 81168 193 481 527 NR

THUNDER (111) PTA 54 74 67 440 NR 48 30 26 47

DCB 48 75 62 170 NR 10 38 27 52


42 470 937 17 34 19 51DCB 45 40 44 190 964 7 35 13 52

INPACT SFA (112) PTA 111 88 51 476 93763 206 946 195 468

DCB 220 89 48 178 9550 24 95 258 50

LEVANT-2 (106) PTA 160 63 40 474 91981 375 875 219 48

DCB 316 63 41 348 92179 38 839 206 48

PACIFIER (113) PTA 47 66 55 324 95743 214 829 383 49

DCB 41 70 53 86 95545 71 682 227 496

p lt 005










1351












































































for CLI



of Evidence C)





Evidence C)


of Evidence C)



Evidence C)




1352

































































ACHILLES (120) PTA 101 27 21 429 NR 165 982 754 26


DES 74 16 10 170 0100 80 100 150 30

YUKON-BTX (122) BMS 79 31 9 444 582418 175 100 215 30

DES 82 30 8 194 488512 97 100 232 30

DEBATE-BTK (123) PTA 67 131 79 740 0100 430 NR 821 29

DCB 65 129 83 270 0100 180 NR 775 29


DCB 239 102 91 410 0100 92 772 386 102

IDEAS (125) DCB 25 148 57 579 NR 136 NR 120 NR

DES 27 127 47 280 NR 77 NR 230 NR

p lt 005








1353
















CONCLUSIONS
































R E F E R E N C E S






201565931ndash41





















201520465ndash78








































326381ndash6




JAMA 20012861599ndash606























1354





































Res 20151161527ndash39























1994901866ndash74





199681780ndash8



1678ndash87










167ndash73






























2012331311ndash20





































2014130939ndash47
















JAMA 20153141936ndash44


































1355

















Med 201015181ndash8





47330ndash6











Med 2000342145ndash53













































JAMA 20093011909ndash19
















20123661404ndash13




19963481329ndash39

























7 2016






J 2014168588ndash96




20131271522ndash9

















2016









55363ndash70e5













201529738ndash50























1356






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357










































































































1341









































































With PAD

Frequency

3-5 days per week

Modality


Method









Duration


Tips for success











1342

















PATIENTS WITH PAD















SMOKING CESSATION
























bull Cilostazol











1343































States

ACEIs






















STATINS





Outcomes in PAD

0 6 12 18 24 30 36Follow-Up (Months)

0 6 12 18 24 30 36

Follow-Up (Months)

0

1 0

2 0

3 0

4 0


0

1 0

2 0

3 0

4 0

M a j o r A


Hazard ratio 064 95 CI 045-089 P=0009

Hazard ratio 055 95 CI 037-083 P=0005


4 Guideline502237

450222

391207

355180

322156

288143

256123


4 Guideline502237

306155

240133

201102

17594

14276

12564



A

B








1344
















CLI (73)












































and 095 in AAA) (7778)


















tice guidelines

CLOPIDOGREL AND





























1345




















patients with CLI




























VORAPAXAR




















93 vs 105 HR 087 95 CI 080 to 094







































1346































































45

40

35

30

25

20

15

10

05

00


0 180 360 540 720 900 1080


0 180 360 540 720 900 1080


250

200

150

100

50

00


23 vs 39HR 058 (039 ndash 086)

P=0006

184 vs 222HR 084 (073 ndash 097)

P=0017


Placebo Vorapaxar


Placebo Vorapaxar

A

B






1347























































length


Single stenosis or













AAA frac14





super1047297



Fontaine Rutherford













1348













































dication (99100103105)








































of Evidence C)





Evidence C)





1349



























standard therapy




































(Figure 3 Table 6)


















Evidence C)


Evidence C)


Evidence A)




Evidence C)




Evidence C)




1350




100

90

80

70

60

50

40

30

20

10


0 50 100 150 200


FAST PTA


FAST BMS


FEMPAC PTA


PACIFIER PTA

Lesion length 66

Restenosis 324

FEMPAC DCB


ZILVER DES



THUNDER DCB


INPACT SFA DCB


ZILVER PTA


ASTRON PTA


THUNDER PTA


INPACT SFA PTA


ASTRON BMS


ABSOLUTE PTA


ABSOLUTE BMS


VIASTAR BMS


VIASTAR CS



ZELLER DES




FAST (110) PTA 121 45 28 386 96535 183 595 248 51

BMS 123 45 27 317 97525 149 659 366 53

ABSOLUTE (108) PTA 53 92 75 630 8713 31 100 32 NR

BMS 51 101 75 370 8812 28 100 37 NR

ASTRON (109) PTA 39 65 46 611 973 NR 100 39 NR

BMS 34 82 67 344 919 NR 100 38 NR

ZILVER (100) PTA 238 63 41 672 90785 175 247 NR NR

DES 241 66 39 169 90289 95 296 NR NR

Zeller (104) DES 97 195 65 304 91772 215 557 629 NR

DCB 131 194 86 239 81168 193 481 527 NR

THUNDER (111) PTA 54 74 67 440 NR 48 30 26 47

DCB 48 75 62 170 NR 10 38 27 52


42 470 937 17 34 19 51DCB 45 40 44 190 964 7 35 13 52

INPACT SFA (112) PTA 111 88 51 476 93763 206 946 195 468

DCB 220 89 48 178 9550 24 95 258 50

LEVANT-2 (106) PTA 160 63 40 474 91981 375 875 219 48

DCB 316 63 41 348 92179 38 839 206 48

PACIFIER (113) PTA 47 66 55 324 95743 214 829 383 49

DCB 41 70 53 86 95545 71 682 227 496

p lt 005










1351












































































for CLI



of Evidence C)





Evidence C)


of Evidence C)



Evidence C)




1352

































































ACHILLES (120) PTA 101 27 21 429 NR 165 982 754 26


DES 74 16 10 170 0100 80 100 150 30

YUKON-BTX (122) BMS 79 31 9 444 582418 175 100 215 30

DES 82 30 8 194 488512 97 100 232 30

DEBATE-BTK (123) PTA 67 131 79 740 0100 430 NR 821 29

DCB 65 129 83 270 0100 180 NR 775 29


DCB 239 102 91 410 0100 92 772 386 102

IDEAS (125) DCB 25 148 57 579 NR 136 NR 120 NR

DES 27 127 47 280 NR 77 NR 230 NR

p lt 005








1353
















CONCLUSIONS
































R E F E R E N C E S






201565931ndash41





















201520465ndash78








































326381ndash6




JAMA 20012861599ndash606























1354





































Res 20151161527ndash39























1994901866ndash74





199681780ndash8



1678ndash87










167ndash73






























2012331311ndash20





































2014130939ndash47
















JAMA 20153141936ndash44


































1355

















Med 201015181ndash8





47330ndash6











Med 2000342145ndash53













































JAMA 20093011909ndash19
















20123661404ndash13




19963481329ndash39

























7 2016






J 2014168588ndash96




20131271522ndash9

















2016









55363ndash70e5













201529738ndash50























1356






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357









































































With PAD

Frequency

3-5 days per week

Modality


Method









Duration


Tips for success











1342

















PATIENTS WITH PAD















SMOKING CESSATION
























bull Cilostazol











1343































States

ACEIs






















STATINS





Outcomes in PAD

0 6 12 18 24 30 36Follow-Up (Months)

0 6 12 18 24 30 36

Follow-Up (Months)

0

1 0

2 0

3 0

4 0


0

1 0

2 0

3 0

4 0

M a j o r A


Hazard ratio 064 95 CI 045-089 P=0009

Hazard ratio 055 95 CI 037-083 P=0005


4 Guideline502237

450222

391207

355180

322156

288143

256123


4 Guideline502237

306155

240133

201102

17594

14276

12564



A

B








1344
















CLI (73)












































and 095 in AAA) (7778)


















tice guidelines

CLOPIDOGREL AND





























1345




















patients with CLI




























VORAPAXAR




















93 vs 105 HR 087 95 CI 080 to 094







































1346































































45

40

35

30

25

20

15

10

05

00


0 180 360 540 720 900 1080


0 180 360 540 720 900 1080


250

200

150

100

50

00


23 vs 39HR 058 (039 ndash 086)

P=0006

184 vs 222HR 084 (073 ndash 097)

P=0017


Placebo Vorapaxar


Placebo Vorapaxar

A

B






1347























































length


Single stenosis or













AAA frac14





super1047297



Fontaine Rutherford













1348













































dication (99100103105)








































of Evidence C)





Evidence C)





1349



























standard therapy




































(Figure 3 Table 6)


















Evidence C)


Evidence C)


Evidence A)




Evidence C)




Evidence C)




1350




100

90

80

70

60

50

40

30

20

10


0 50 100 150 200


FAST PTA


FAST BMS


FEMPAC PTA


PACIFIER PTA

Lesion length 66

Restenosis 324

FEMPAC DCB


ZILVER DES



THUNDER DCB


INPACT SFA DCB


ZILVER PTA


ASTRON PTA


THUNDER PTA


INPACT SFA PTA


ASTRON BMS


ABSOLUTE PTA


ABSOLUTE BMS


VIASTAR BMS


VIASTAR CS



ZELLER DES




FAST (110) PTA 121 45 28 386 96535 183 595 248 51

BMS 123 45 27 317 97525 149 659 366 53

ABSOLUTE (108) PTA 53 92 75 630 8713 31 100 32 NR

BMS 51 101 75 370 8812 28 100 37 NR

ASTRON (109) PTA 39 65 46 611 973 NR 100 39 NR

BMS 34 82 67 344 919 NR 100 38 NR

ZILVER (100) PTA 238 63 41 672 90785 175 247 NR NR

DES 241 66 39 169 90289 95 296 NR NR

Zeller (104) DES 97 195 65 304 91772 215 557 629 NR

DCB 131 194 86 239 81168 193 481 527 NR

THUNDER (111) PTA 54 74 67 440 NR 48 30 26 47

DCB 48 75 62 170 NR 10 38 27 52


42 470 937 17 34 19 51DCB 45 40 44 190 964 7 35 13 52

INPACT SFA (112) PTA 111 88 51 476 93763 206 946 195 468

DCB 220 89 48 178 9550 24 95 258 50

LEVANT-2 (106) PTA 160 63 40 474 91981 375 875 219 48

DCB 316 63 41 348 92179 38 839 206 48

PACIFIER (113) PTA 47 66 55 324 95743 214 829 383 49

DCB 41 70 53 86 95545 71 682 227 496

p lt 005










1351












































































for CLI



of Evidence C)





Evidence C)


of Evidence C)



Evidence C)




1352

































































ACHILLES (120) PTA 101 27 21 429 NR 165 982 754 26


DES 74 16 10 170 0100 80 100 150 30

YUKON-BTX (122) BMS 79 31 9 444 582418 175 100 215 30

DES 82 30 8 194 488512 97 100 232 30

DEBATE-BTK (123) PTA 67 131 79 740 0100 430 NR 821 29

DCB 65 129 83 270 0100 180 NR 775 29


DCB 239 102 91 410 0100 92 772 386 102

IDEAS (125) DCB 25 148 57 579 NR 136 NR 120 NR

DES 27 127 47 280 NR 77 NR 230 NR

p lt 005








1353
















CONCLUSIONS
































R E F E R E N C E S






201565931ndash41





















201520465ndash78








































326381ndash6




JAMA 20012861599ndash606























1354





































Res 20151161527ndash39























1994901866ndash74





199681780ndash8



1678ndash87










167ndash73






























2012331311ndash20





































2014130939ndash47
















JAMA 20153141936ndash44


































1355

















Med 201015181ndash8





47330ndash6











Med 2000342145ndash53













































JAMA 20093011909ndash19
















20123661404ndash13




19963481329ndash39

























7 2016






J 2014168588ndash96




20131271522ndash9

















2016









55363ndash70e5













201529738ndash50























1356






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357

















PATIENTS WITH PAD















SMOKING CESSATION
























bull Cilostazol











1343































States

ACEIs






















STATINS





Outcomes in PAD

0 6 12 18 24 30 36Follow-Up (Months)

0 6 12 18 24 30 36

Follow-Up (Months)

0

1 0

2 0

3 0

4 0


0

1 0

2 0

3 0

4 0

M a j o r A


Hazard ratio 064 95 CI 045-089 P=0009

Hazard ratio 055 95 CI 037-083 P=0005


4 Guideline502237

450222

391207

355180

322156

288143

256123


4 Guideline502237

306155

240133

201102

17594

14276

12564



A

B








1344
















CLI (73)












































and 095 in AAA) (7778)


















tice guidelines

CLOPIDOGREL AND





























1345




















patients with CLI




























VORAPAXAR




















93 vs 105 HR 087 95 CI 080 to 094







































1346































































45

40

35

30

25

20

15

10

05

00


0 180 360 540 720 900 1080


0 180 360 540 720 900 1080


250

200

150

100

50

00


23 vs 39HR 058 (039 ndash 086)

P=0006

184 vs 222HR 084 (073 ndash 097)

P=0017


Placebo Vorapaxar


Placebo Vorapaxar

A

B






1347























































length


Single stenosis or













AAA frac14





super1047297



Fontaine Rutherford













1348













































dication (99100103105)








































of Evidence C)





Evidence C)





1349



























standard therapy




































(Figure 3 Table 6)


















Evidence C)


Evidence C)


Evidence A)




Evidence C)




Evidence C)




1350




100

90

80

70

60

50

40

30

20

10


0 50 100 150 200


FAST PTA


FAST BMS


FEMPAC PTA


PACIFIER PTA

Lesion length 66

Restenosis 324

FEMPAC DCB


ZILVER DES



THUNDER DCB


INPACT SFA DCB


ZILVER PTA


ASTRON PTA


THUNDER PTA


INPACT SFA PTA


ASTRON BMS


ABSOLUTE PTA


ABSOLUTE BMS


VIASTAR BMS


VIASTAR CS



ZELLER DES




FAST (110) PTA 121 45 28 386 96535 183 595 248 51

BMS 123 45 27 317 97525 149 659 366 53

ABSOLUTE (108) PTA 53 92 75 630 8713 31 100 32 NR

BMS 51 101 75 370 8812 28 100 37 NR

ASTRON (109) PTA 39 65 46 611 973 NR 100 39 NR

BMS 34 82 67 344 919 NR 100 38 NR

ZILVER (100) PTA 238 63 41 672 90785 175 247 NR NR

DES 241 66 39 169 90289 95 296 NR NR

Zeller (104) DES 97 195 65 304 91772 215 557 629 NR

DCB 131 194 86 239 81168 193 481 527 NR

THUNDER (111) PTA 54 74 67 440 NR 48 30 26 47

DCB 48 75 62 170 NR 10 38 27 52


42 470 937 17 34 19 51DCB 45 40 44 190 964 7 35 13 52

INPACT SFA (112) PTA 111 88 51 476 93763 206 946 195 468

DCB 220 89 48 178 9550 24 95 258 50

LEVANT-2 (106) PTA 160 63 40 474 91981 375 875 219 48

DCB 316 63 41 348 92179 38 839 206 48

PACIFIER (113) PTA 47 66 55 324 95743 214 829 383 49

DCB 41 70 53 86 95545 71 682 227 496

p lt 005










1351












































































for CLI



of Evidence C)





Evidence C)


of Evidence C)



Evidence C)




1352

































































ACHILLES (120) PTA 101 27 21 429 NR 165 982 754 26


DES 74 16 10 170 0100 80 100 150 30

YUKON-BTX (122) BMS 79 31 9 444 582418 175 100 215 30

DES 82 30 8 194 488512 97 100 232 30

DEBATE-BTK (123) PTA 67 131 79 740 0100 430 NR 821 29

DCB 65 129 83 270 0100 180 NR 775 29


DCB 239 102 91 410 0100 92 772 386 102

IDEAS (125) DCB 25 148 57 579 NR 136 NR 120 NR

DES 27 127 47 280 NR 77 NR 230 NR

p lt 005








1353
















CONCLUSIONS
































R E F E R E N C E S






201565931ndash41





















201520465ndash78








































326381ndash6




JAMA 20012861599ndash606























1354





































Res 20151161527ndash39























1994901866ndash74





199681780ndash8



1678ndash87










167ndash73






























2012331311ndash20





































2014130939ndash47
















JAMA 20153141936ndash44


































1355

















Med 201015181ndash8





47330ndash6











Med 2000342145ndash53













































JAMA 20093011909ndash19
















20123661404ndash13




19963481329ndash39

























7 2016






J 2014168588ndash96




20131271522ndash9

















2016









55363ndash70e5













201529738ndash50























1356






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357































States

ACEIs






















STATINS





Outcomes in PAD

0 6 12 18 24 30 36Follow-Up (Months)

0 6 12 18 24 30 36

Follow-Up (Months)

0

1 0

2 0

3 0

4 0


0

1 0

2 0

3 0

4 0

M a j o r A


Hazard ratio 064 95 CI 045-089 P=0009

Hazard ratio 055 95 CI 037-083 P=0005


4 Guideline502237

450222

391207

355180

322156

288143

256123


4 Guideline502237

306155

240133

201102

17594

14276

12564



A

B








1344
















CLI (73)












































and 095 in AAA) (7778)


















tice guidelines

CLOPIDOGREL AND





























1345




















patients with CLI




























VORAPAXAR




















93 vs 105 HR 087 95 CI 080 to 094







































1346































































45

40

35

30

25

20

15

10

05

00


0 180 360 540 720 900 1080


0 180 360 540 720 900 1080


250

200

150

100

50

00


23 vs 39HR 058 (039 ndash 086)

P=0006

184 vs 222HR 084 (073 ndash 097)

P=0017


Placebo Vorapaxar


Placebo Vorapaxar

A

B






1347























































length


Single stenosis or













AAA frac14





super1047297



Fontaine Rutherford













1348













































dication (99100103105)








































of Evidence C)





Evidence C)





1349



























standard therapy




































(Figure 3 Table 6)


















Evidence C)


Evidence C)


Evidence A)




Evidence C)




Evidence C)




1350




100

90

80

70

60

50

40

30

20

10


0 50 100 150 200


FAST PTA


FAST BMS


FEMPAC PTA


PACIFIER PTA

Lesion length 66

Restenosis 324

FEMPAC DCB


ZILVER DES



THUNDER DCB


INPACT SFA DCB


ZILVER PTA


ASTRON PTA


THUNDER PTA


INPACT SFA PTA


ASTRON BMS


ABSOLUTE PTA


ABSOLUTE BMS


VIASTAR BMS


VIASTAR CS



ZELLER DES




FAST (110) PTA 121 45 28 386 96535 183 595 248 51

BMS 123 45 27 317 97525 149 659 366 53

ABSOLUTE (108) PTA 53 92 75 630 8713 31 100 32 NR

BMS 51 101 75 370 8812 28 100 37 NR

ASTRON (109) PTA 39 65 46 611 973 NR 100 39 NR

BMS 34 82 67 344 919 NR 100 38 NR

ZILVER (100) PTA 238 63 41 672 90785 175 247 NR NR

DES 241 66 39 169 90289 95 296 NR NR

Zeller (104) DES 97 195 65 304 91772 215 557 629 NR

DCB 131 194 86 239 81168 193 481 527 NR

THUNDER (111) PTA 54 74 67 440 NR 48 30 26 47

DCB 48 75 62 170 NR 10 38 27 52


42 470 937 17 34 19 51DCB 45 40 44 190 964 7 35 13 52

INPACT SFA (112) PTA 111 88 51 476 93763 206 946 195 468

DCB 220 89 48 178 9550 24 95 258 50

LEVANT-2 (106) PTA 160 63 40 474 91981 375 875 219 48

DCB 316 63 41 348 92179 38 839 206 48

PACIFIER (113) PTA 47 66 55 324 95743 214 829 383 49

DCB 41 70 53 86 95545 71 682 227 496

p lt 005










1351












































































for CLI



of Evidence C)





Evidence C)


of Evidence C)



Evidence C)




1352

































































ACHILLES (120) PTA 101 27 21 429 NR 165 982 754 26


DES 74 16 10 170 0100 80 100 150 30

YUKON-BTX (122) BMS 79 31 9 444 582418 175 100 215 30

DES 82 30 8 194 488512 97 100 232 30

DEBATE-BTK (123) PTA 67 131 79 740 0100 430 NR 821 29

DCB 65 129 83 270 0100 180 NR 775 29


DCB 239 102 91 410 0100 92 772 386 102

IDEAS (125) DCB 25 148 57 579 NR 136 NR 120 NR

DES 27 127 47 280 NR 77 NR 230 NR

p lt 005








1353
















CONCLUSIONS
































R E F E R E N C E S






201565931ndash41





















201520465ndash78








































326381ndash6




JAMA 20012861599ndash606























1354





































Res 20151161527ndash39























1994901866ndash74





199681780ndash8



1678ndash87










167ndash73






























2012331311ndash20





































2014130939ndash47
















JAMA 20153141936ndash44


































1355

















Med 201015181ndash8





47330ndash6











Med 2000342145ndash53













































JAMA 20093011909ndash19
















20123661404ndash13




19963481329ndash39

























7 2016






J 2014168588ndash96




20131271522ndash9

















2016









55363ndash70e5













201529738ndash50























1356






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357
















CLI (73)












































and 095 in AAA) (7778)


















tice guidelines

CLOPIDOGREL AND





























1345




















patients with CLI




























VORAPAXAR




















93 vs 105 HR 087 95 CI 080 to 094







































1346































































45

40

35

30

25

20

15

10

05

00


0 180 360 540 720 900 1080


0 180 360 540 720 900 1080


250

200

150

100

50

00


23 vs 39HR 058 (039 ndash 086)

P=0006

184 vs 222HR 084 (073 ndash 097)

P=0017


Placebo Vorapaxar


Placebo Vorapaxar

A

B






1347























































length


Single stenosis or













AAA frac14





super1047297



Fontaine Rutherford













1348













































dication (99100103105)








































of Evidence C)





Evidence C)





1349



























standard therapy




































(Figure 3 Table 6)


















Evidence C)


Evidence C)


Evidence A)




Evidence C)




Evidence C)




1350




100

90

80

70

60

50

40

30

20

10


0 50 100 150 200


FAST PTA


FAST BMS


FEMPAC PTA


PACIFIER PTA

Lesion length 66

Restenosis 324

FEMPAC DCB


ZILVER DES



THUNDER DCB


INPACT SFA DCB


ZILVER PTA


ASTRON PTA


THUNDER PTA


INPACT SFA PTA


ASTRON BMS


ABSOLUTE PTA


ABSOLUTE BMS


VIASTAR BMS


VIASTAR CS



ZELLER DES




FAST (110) PTA 121 45 28 386 96535 183 595 248 51

BMS 123 45 27 317 97525 149 659 366 53

ABSOLUTE (108) PTA 53 92 75 630 8713 31 100 32 NR

BMS 51 101 75 370 8812 28 100 37 NR

ASTRON (109) PTA 39 65 46 611 973 NR 100 39 NR

BMS 34 82 67 344 919 NR 100 38 NR

ZILVER (100) PTA 238 63 41 672 90785 175 247 NR NR

DES 241 66 39 169 90289 95 296 NR NR

Zeller (104) DES 97 195 65 304 91772 215 557 629 NR

DCB 131 194 86 239 81168 193 481 527 NR

THUNDER (111) PTA 54 74 67 440 NR 48 30 26 47

DCB 48 75 62 170 NR 10 38 27 52


42 470 937 17 34 19 51DCB 45 40 44 190 964 7 35 13 52

INPACT SFA (112) PTA 111 88 51 476 93763 206 946 195 468

DCB 220 89 48 178 9550 24 95 258 50

LEVANT-2 (106) PTA 160 63 40 474 91981 375 875 219 48

DCB 316 63 41 348 92179 38 839 206 48

PACIFIER (113) PTA 47 66 55 324 95743 214 829 383 49

DCB 41 70 53 86 95545 71 682 227 496

p lt 005










1351












































































for CLI



of Evidence C)





Evidence C)


of Evidence C)



Evidence C)




1352

































































ACHILLES (120) PTA 101 27 21 429 NR 165 982 754 26


DES 74 16 10 170 0100 80 100 150 30

YUKON-BTX (122) BMS 79 31 9 444 582418 175 100 215 30

DES 82 30 8 194 488512 97 100 232 30

DEBATE-BTK (123) PTA 67 131 79 740 0100 430 NR 821 29

DCB 65 129 83 270 0100 180 NR 775 29


DCB 239 102 91 410 0100 92 772 386 102

IDEAS (125) DCB 25 148 57 579 NR 136 NR 120 NR

DES 27 127 47 280 NR 77 NR 230 NR

p lt 005








1353
















CONCLUSIONS
































R E F E R E N C E S






201565931ndash41





















201520465ndash78








































326381ndash6




JAMA 20012861599ndash606























1354





































Res 20151161527ndash39























1994901866ndash74





199681780ndash8



1678ndash87










167ndash73






























2012331311ndash20





































2014130939ndash47
















JAMA 20153141936ndash44


































1355

















Med 201015181ndash8





47330ndash6











Med 2000342145ndash53













































JAMA 20093011909ndash19
















20123661404ndash13




19963481329ndash39

























7 2016






J 2014168588ndash96




20131271522ndash9

















2016









55363ndash70e5













201529738ndash50























1356






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357




















patients with CLI




























VORAPAXAR




















93 vs 105 HR 087 95 CI 080 to 094







































1346































































45

40

35

30

25

20

15

10

05

00


0 180 360 540 720 900 1080


0 180 360 540 720 900 1080


250

200

150

100

50

00


23 vs 39HR 058 (039 ndash 086)

P=0006

184 vs 222HR 084 (073 ndash 097)

P=0017


Placebo Vorapaxar


Placebo Vorapaxar

A

B






1347























































length


Single stenosis or













AAA frac14





super1047297



Fontaine Rutherford













1348













































dication (99100103105)








































of Evidence C)





Evidence C)





1349



























standard therapy




































(Figure 3 Table 6)


















Evidence C)


Evidence C)


Evidence A)




Evidence C)




Evidence C)




1350




100

90

80

70

60

50

40

30

20

10


0 50 100 150 200


FAST PTA


FAST BMS


FEMPAC PTA


PACIFIER PTA

Lesion length 66

Restenosis 324

FEMPAC DCB


ZILVER DES



THUNDER DCB


INPACT SFA DCB


ZILVER PTA


ASTRON PTA


THUNDER PTA


INPACT SFA PTA


ASTRON BMS


ABSOLUTE PTA


ABSOLUTE BMS


VIASTAR BMS


VIASTAR CS



ZELLER DES




FAST (110) PTA 121 45 28 386 96535 183 595 248 51

BMS 123 45 27 317 97525 149 659 366 53

ABSOLUTE (108) PTA 53 92 75 630 8713 31 100 32 NR

BMS 51 101 75 370 8812 28 100 37 NR

ASTRON (109) PTA 39 65 46 611 973 NR 100 39 NR

BMS 34 82 67 344 919 NR 100 38 NR

ZILVER (100) PTA 238 63 41 672 90785 175 247 NR NR

DES 241 66 39 169 90289 95 296 NR NR

Zeller (104) DES 97 195 65 304 91772 215 557 629 NR

DCB 131 194 86 239 81168 193 481 527 NR

THUNDER (111) PTA 54 74 67 440 NR 48 30 26 47

DCB 48 75 62 170 NR 10 38 27 52


42 470 937 17 34 19 51DCB 45 40 44 190 964 7 35 13 52

INPACT SFA (112) PTA 111 88 51 476 93763 206 946 195 468

DCB 220 89 48 178 9550 24 95 258 50

LEVANT-2 (106) PTA 160 63 40 474 91981 375 875 219 48

DCB 316 63 41 348 92179 38 839 206 48

PACIFIER (113) PTA 47 66 55 324 95743 214 829 383 49

DCB 41 70 53 86 95545 71 682 227 496

p lt 005










1351












































































for CLI



of Evidence C)





Evidence C)


of Evidence C)



Evidence C)




1352

































































ACHILLES (120) PTA 101 27 21 429 NR 165 982 754 26


DES 74 16 10 170 0100 80 100 150 30

YUKON-BTX (122) BMS 79 31 9 444 582418 175 100 215 30

DES 82 30 8 194 488512 97 100 232 30

DEBATE-BTK (123) PTA 67 131 79 740 0100 430 NR 821 29

DCB 65 129 83 270 0100 180 NR 775 29


DCB 239 102 91 410 0100 92 772 386 102

IDEAS (125) DCB 25 148 57 579 NR 136 NR 120 NR

DES 27 127 47 280 NR 77 NR 230 NR

p lt 005








1353
















CONCLUSIONS
































R E F E R E N C E S






201565931ndash41





















201520465ndash78








































326381ndash6




JAMA 20012861599ndash606























1354





































Res 20151161527ndash39























1994901866ndash74





199681780ndash8



1678ndash87










167ndash73






























2012331311ndash20





































2014130939ndash47
















JAMA 20153141936ndash44


































1355

















Med 201015181ndash8





47330ndash6











Med 2000342145ndash53













































JAMA 20093011909ndash19
















20123661404ndash13




19963481329ndash39

























7 2016






J 2014168588ndash96




20131271522ndash9

















2016









55363ndash70e5













201529738ndash50























1356






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357































































45

40

35

30

25

20

15

10

05

00


0 180 360 540 720 900 1080


0 180 360 540 720 900 1080


250

200

150

100

50

00


23 vs 39HR 058 (039 ndash 086)

P=0006

184 vs 222HR 084 (073 ndash 097)

P=0017


Placebo Vorapaxar


Placebo Vorapaxar

A

B






1347























































length


Single stenosis or













AAA frac14





super1047297



Fontaine Rutherford













1348













































dication (99100103105)








































of Evidence C)





Evidence C)





1349



























standard therapy




































(Figure 3 Table 6)


















Evidence C)


Evidence C)


Evidence A)




Evidence C)




Evidence C)




1350




100

90

80

70

60

50

40

30

20

10


0 50 100 150 200


FAST PTA


FAST BMS


FEMPAC PTA


PACIFIER PTA

Lesion length 66

Restenosis 324

FEMPAC DCB


ZILVER DES



THUNDER DCB


INPACT SFA DCB


ZILVER PTA


ASTRON PTA


THUNDER PTA


INPACT SFA PTA


ASTRON BMS


ABSOLUTE PTA


ABSOLUTE BMS


VIASTAR BMS


VIASTAR CS



ZELLER DES




FAST (110) PTA 121 45 28 386 96535 183 595 248 51

BMS 123 45 27 317 97525 149 659 366 53

ABSOLUTE (108) PTA 53 92 75 630 8713 31 100 32 NR

BMS 51 101 75 370 8812 28 100 37 NR

ASTRON (109) PTA 39 65 46 611 973 NR 100 39 NR

BMS 34 82 67 344 919 NR 100 38 NR

ZILVER (100) PTA 238 63 41 672 90785 175 247 NR NR

DES 241 66 39 169 90289 95 296 NR NR

Zeller (104) DES 97 195 65 304 91772 215 557 629 NR

DCB 131 194 86 239 81168 193 481 527 NR

THUNDER (111) PTA 54 74 67 440 NR 48 30 26 47

DCB 48 75 62 170 NR 10 38 27 52


42 470 937 17 34 19 51DCB 45 40 44 190 964 7 35 13 52

INPACT SFA (112) PTA 111 88 51 476 93763 206 946 195 468

DCB 220 89 48 178 9550 24 95 258 50

LEVANT-2 (106) PTA 160 63 40 474 91981 375 875 219 48

DCB 316 63 41 348 92179 38 839 206 48

PACIFIER (113) PTA 47 66 55 324 95743 214 829 383 49

DCB 41 70 53 86 95545 71 682 227 496

p lt 005










1351












































































for CLI



of Evidence C)





Evidence C)


of Evidence C)



Evidence C)




1352

































































ACHILLES (120) PTA 101 27 21 429 NR 165 982 754 26


DES 74 16 10 170 0100 80 100 150 30

YUKON-BTX (122) BMS 79 31 9 444 582418 175 100 215 30

DES 82 30 8 194 488512 97 100 232 30

DEBATE-BTK (123) PTA 67 131 79 740 0100 430 NR 821 29

DCB 65 129 83 270 0100 180 NR 775 29


DCB 239 102 91 410 0100 92 772 386 102

IDEAS (125) DCB 25 148 57 579 NR 136 NR 120 NR

DES 27 127 47 280 NR 77 NR 230 NR

p lt 005








1353
















CONCLUSIONS
































R E F E R E N C E S






201565931ndash41





















201520465ndash78








































326381ndash6




JAMA 20012861599ndash606























1354





































Res 20151161527ndash39























1994901866ndash74





199681780ndash8



1678ndash87










167ndash73






























2012331311ndash20





































2014130939ndash47
















JAMA 20153141936ndash44


































1355

















Med 201015181ndash8





47330ndash6











Med 2000342145ndash53













































JAMA 20093011909ndash19
















20123661404ndash13




19963481329ndash39

























7 2016






J 2014168588ndash96




20131271522ndash9

















2016









55363ndash70e5













201529738ndash50























1356






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357























































length


Single stenosis or













AAA frac14





super1047297



Fontaine Rutherford













1348













































dication (99100103105)








































of Evidence C)





Evidence C)





1349



























standard therapy




































(Figure 3 Table 6)


















Evidence C)


Evidence C)


Evidence A)




Evidence C)




Evidence C)




1350




100

90

80

70

60

50

40

30

20

10


0 50 100 150 200


FAST PTA


FAST BMS


FEMPAC PTA


PACIFIER PTA

Lesion length 66

Restenosis 324

FEMPAC DCB


ZILVER DES



THUNDER DCB


INPACT SFA DCB


ZILVER PTA


ASTRON PTA


THUNDER PTA


INPACT SFA PTA


ASTRON BMS


ABSOLUTE PTA


ABSOLUTE BMS


VIASTAR BMS


VIASTAR CS



ZELLER DES




FAST (110) PTA 121 45 28 386 96535 183 595 248 51

BMS 123 45 27 317 97525 149 659 366 53

ABSOLUTE (108) PTA 53 92 75 630 8713 31 100 32 NR

BMS 51 101 75 370 8812 28 100 37 NR

ASTRON (109) PTA 39 65 46 611 973 NR 100 39 NR

BMS 34 82 67 344 919 NR 100 38 NR

ZILVER (100) PTA 238 63 41 672 90785 175 247 NR NR

DES 241 66 39 169 90289 95 296 NR NR

Zeller (104) DES 97 195 65 304 91772 215 557 629 NR

DCB 131 194 86 239 81168 193 481 527 NR

THUNDER (111) PTA 54 74 67 440 NR 48 30 26 47

DCB 48 75 62 170 NR 10 38 27 52


42 470 937 17 34 19 51DCB 45 40 44 190 964 7 35 13 52

INPACT SFA (112) PTA 111 88 51 476 93763 206 946 195 468

DCB 220 89 48 178 9550 24 95 258 50

LEVANT-2 (106) PTA 160 63 40 474 91981 375 875 219 48

DCB 316 63 41 348 92179 38 839 206 48

PACIFIER (113) PTA 47 66 55 324 95743 214 829 383 49

DCB 41 70 53 86 95545 71 682 227 496

p lt 005










1351












































































for CLI



of Evidence C)





Evidence C)


of Evidence C)



Evidence C)




1352

































































ACHILLES (120) PTA 101 27 21 429 NR 165 982 754 26


DES 74 16 10 170 0100 80 100 150 30

YUKON-BTX (122) BMS 79 31 9 444 582418 175 100 215 30

DES 82 30 8 194 488512 97 100 232 30

DEBATE-BTK (123) PTA 67 131 79 740 0100 430 NR 821 29

DCB 65 129 83 270 0100 180 NR 775 29


DCB 239 102 91 410 0100 92 772 386 102

IDEAS (125) DCB 25 148 57 579 NR 136 NR 120 NR

DES 27 127 47 280 NR 77 NR 230 NR

p lt 005








1353
















CONCLUSIONS
































R E F E R E N C E S






201565931ndash41





















201520465ndash78








































326381ndash6




JAMA 20012861599ndash606























1354





































Res 20151161527ndash39























1994901866ndash74





199681780ndash8



1678ndash87










167ndash73






























2012331311ndash20





































2014130939ndash47
















JAMA 20153141936ndash44


































1355

















Med 201015181ndash8





47330ndash6











Med 2000342145ndash53













































JAMA 20093011909ndash19
















20123661404ndash13




19963481329ndash39

























7 2016






J 2014168588ndash96




20131271522ndash9

















2016









55363ndash70e5













201529738ndash50























1356






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357













































dication (99100103105)








































of Evidence C)





Evidence C)





1349



























standard therapy




































(Figure 3 Table 6)


















Evidence C)


Evidence C)


Evidence A)




Evidence C)




Evidence C)




1350




100

90

80

70

60

50

40

30

20

10


0 50 100 150 200


FAST PTA


FAST BMS


FEMPAC PTA


PACIFIER PTA

Lesion length 66

Restenosis 324

FEMPAC DCB


ZILVER DES



THUNDER DCB


INPACT SFA DCB


ZILVER PTA


ASTRON PTA


THUNDER PTA


INPACT SFA PTA


ASTRON BMS


ABSOLUTE PTA


ABSOLUTE BMS


VIASTAR BMS


VIASTAR CS



ZELLER DES




FAST (110) PTA 121 45 28 386 96535 183 595 248 51

BMS 123 45 27 317 97525 149 659 366 53

ABSOLUTE (108) PTA 53 92 75 630 8713 31 100 32 NR

BMS 51 101 75 370 8812 28 100 37 NR

ASTRON (109) PTA 39 65 46 611 973 NR 100 39 NR

BMS 34 82 67 344 919 NR 100 38 NR

ZILVER (100) PTA 238 63 41 672 90785 175 247 NR NR

DES 241 66 39 169 90289 95 296 NR NR

Zeller (104) DES 97 195 65 304 91772 215 557 629 NR

DCB 131 194 86 239 81168 193 481 527 NR

THUNDER (111) PTA 54 74 67 440 NR 48 30 26 47

DCB 48 75 62 170 NR 10 38 27 52


42 470 937 17 34 19 51DCB 45 40 44 190 964 7 35 13 52

INPACT SFA (112) PTA 111 88 51 476 93763 206 946 195 468

DCB 220 89 48 178 9550 24 95 258 50

LEVANT-2 (106) PTA 160 63 40 474 91981 375 875 219 48

DCB 316 63 41 348 92179 38 839 206 48

PACIFIER (113) PTA 47 66 55 324 95743 214 829 383 49

DCB 41 70 53 86 95545 71 682 227 496

p lt 005










1351












































































for CLI



of Evidence C)





Evidence C)


of Evidence C)



Evidence C)




1352

































































ACHILLES (120) PTA 101 27 21 429 NR 165 982 754 26


DES 74 16 10 170 0100 80 100 150 30

YUKON-BTX (122) BMS 79 31 9 444 582418 175 100 215 30

DES 82 30 8 194 488512 97 100 232 30

DEBATE-BTK (123) PTA 67 131 79 740 0100 430 NR 821 29

DCB 65 129 83 270 0100 180 NR 775 29


DCB 239 102 91 410 0100 92 772 386 102

IDEAS (125) DCB 25 148 57 579 NR 136 NR 120 NR

DES 27 127 47 280 NR 77 NR 230 NR

p lt 005








1353
















CONCLUSIONS
































R E F E R E N C E S






201565931ndash41





















201520465ndash78








































326381ndash6




JAMA 20012861599ndash606























1354





































Res 20151161527ndash39























1994901866ndash74





199681780ndash8



1678ndash87










167ndash73






























2012331311ndash20





































2014130939ndash47
















JAMA 20153141936ndash44


































1355

















Med 201015181ndash8





47330ndash6











Med 2000342145ndash53













































JAMA 20093011909ndash19
















20123661404ndash13




19963481329ndash39

























7 2016






J 2014168588ndash96




20131271522ndash9

















2016









55363ndash70e5













201529738ndash50























1356






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357



























standard therapy




































(Figure 3 Table 6)


















Evidence C)


Evidence C)


Evidence A)




Evidence C)




Evidence C)




1350




100

90

80

70

60

50

40

30

20

10


0 50 100 150 200


FAST PTA


FAST BMS


FEMPAC PTA


PACIFIER PTA

Lesion length 66

Restenosis 324

FEMPAC DCB


ZILVER DES



THUNDER DCB


INPACT SFA DCB


ZILVER PTA


ASTRON PTA


THUNDER PTA


INPACT SFA PTA


ASTRON BMS


ABSOLUTE PTA


ABSOLUTE BMS


VIASTAR BMS


VIASTAR CS



ZELLER DES




FAST (110) PTA 121 45 28 386 96535 183 595 248 51

BMS 123 45 27 317 97525 149 659 366 53

ABSOLUTE (108) PTA 53 92 75 630 8713 31 100 32 NR

BMS 51 101 75 370 8812 28 100 37 NR

ASTRON (109) PTA 39 65 46 611 973 NR 100 39 NR

BMS 34 82 67 344 919 NR 100 38 NR

ZILVER (100) PTA 238 63 41 672 90785 175 247 NR NR

DES 241 66 39 169 90289 95 296 NR NR

Zeller (104) DES 97 195 65 304 91772 215 557 629 NR

DCB 131 194 86 239 81168 193 481 527 NR

THUNDER (111) PTA 54 74 67 440 NR 48 30 26 47

DCB 48 75 62 170 NR 10 38 27 52


42 470 937 17 34 19 51DCB 45 40 44 190 964 7 35 13 52

INPACT SFA (112) PTA 111 88 51 476 93763 206 946 195 468

DCB 220 89 48 178 9550 24 95 258 50

LEVANT-2 (106) PTA 160 63 40 474 91981 375 875 219 48

DCB 316 63 41 348 92179 38 839 206 48

PACIFIER (113) PTA 47 66 55 324 95743 214 829 383 49

DCB 41 70 53 86 95545 71 682 227 496

p lt 005










1351












































































for CLI



of Evidence C)





Evidence C)


of Evidence C)



Evidence C)




1352

































































ACHILLES (120) PTA 101 27 21 429 NR 165 982 754 26


DES 74 16 10 170 0100 80 100 150 30

YUKON-BTX (122) BMS 79 31 9 444 582418 175 100 215 30

DES 82 30 8 194 488512 97 100 232 30

DEBATE-BTK (123) PTA 67 131 79 740 0100 430 NR 821 29

DCB 65 129 83 270 0100 180 NR 775 29


DCB 239 102 91 410 0100 92 772 386 102

IDEAS (125) DCB 25 148 57 579 NR 136 NR 120 NR

DES 27 127 47 280 NR 77 NR 230 NR

p lt 005








1353
















CONCLUSIONS
































R E F E R E N C E S






201565931ndash41





















201520465ndash78








































326381ndash6




JAMA 20012861599ndash606























1354





































Res 20151161527ndash39























1994901866ndash74





199681780ndash8



1678ndash87










167ndash73






























2012331311ndash20





































2014130939ndash47
















JAMA 20153141936ndash44


































1355

















Med 201015181ndash8





47330ndash6











Med 2000342145ndash53













































JAMA 20093011909ndash19
















20123661404ndash13




19963481329ndash39

























7 2016






J 2014168588ndash96




20131271522ndash9

















2016









55363ndash70e5













201529738ndash50























1356






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357




100

90

80

70

60

50

40

30

20

10


0 50 100 150 200


FAST PTA


FAST BMS


FEMPAC PTA


PACIFIER PTA

Lesion length 66

Restenosis 324

FEMPAC DCB


ZILVER DES



THUNDER DCB


INPACT SFA DCB


ZILVER PTA


ASTRON PTA


THUNDER PTA


INPACT SFA PTA


ASTRON BMS


ABSOLUTE PTA


ABSOLUTE BMS


VIASTAR BMS


VIASTAR CS



ZELLER DES




FAST (110) PTA 121 45 28 386 96535 183 595 248 51

BMS 123 45 27 317 97525 149 659 366 53

ABSOLUTE (108) PTA 53 92 75 630 8713 31 100 32 NR

BMS 51 101 75 370 8812 28 100 37 NR

ASTRON (109) PTA 39 65 46 611 973 NR 100 39 NR

BMS 34 82 67 344 919 NR 100 38 NR

ZILVER (100) PTA 238 63 41 672 90785 175 247 NR NR

DES 241 66 39 169 90289 95 296 NR NR

Zeller (104) DES 97 195 65 304 91772 215 557 629 NR

DCB 131 194 86 239 81168 193 481 527 NR

THUNDER (111) PTA 54 74 67 440 NR 48 30 26 47

DCB 48 75 62 170 NR 10 38 27 52


42 470 937 17 34 19 51DCB 45 40 44 190 964 7 35 13 52

INPACT SFA (112) PTA 111 88 51 476 93763 206 946 195 468

DCB 220 89 48 178 9550 24 95 258 50

LEVANT-2 (106) PTA 160 63 40 474 91981 375 875 219 48

DCB 316 63 41 348 92179 38 839 206 48

PACIFIER (113) PTA 47 66 55 324 95743 214 829 383 49

DCB 41 70 53 86 95545 71 682 227 496

p lt 005










1351












































































for CLI



of Evidence C)





Evidence C)


of Evidence C)



Evidence C)




1352

































































ACHILLES (120) PTA 101 27 21 429 NR 165 982 754 26


DES 74 16 10 170 0100 80 100 150 30

YUKON-BTX (122) BMS 79 31 9 444 582418 175 100 215 30

DES 82 30 8 194 488512 97 100 232 30

DEBATE-BTK (123) PTA 67 131 79 740 0100 430 NR 821 29

DCB 65 129 83 270 0100 180 NR 775 29


DCB 239 102 91 410 0100 92 772 386 102

IDEAS (125) DCB 25 148 57 579 NR 136 NR 120 NR

DES 27 127 47 280 NR 77 NR 230 NR

p lt 005








1353
















CONCLUSIONS
































R E F E R E N C E S






201565931ndash41





















201520465ndash78








































326381ndash6




JAMA 20012861599ndash606























1354





































Res 20151161527ndash39























1994901866ndash74





199681780ndash8



1678ndash87










167ndash73






























2012331311ndash20





































2014130939ndash47
















JAMA 20153141936ndash44


































1355

















Med 201015181ndash8





47330ndash6











Med 2000342145ndash53













































JAMA 20093011909ndash19
















20123661404ndash13




19963481329ndash39

























7 2016






J 2014168588ndash96




20131271522ndash9

















2016









55363ndash70e5













201529738ndash50























1356






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357












































































for CLI



of Evidence C)





Evidence C)


of Evidence C)



Evidence C)




1352

































































ACHILLES (120) PTA 101 27 21 429 NR 165 982 754 26


DES 74 16 10 170 0100 80 100 150 30

YUKON-BTX (122) BMS 79 31 9 444 582418 175 100 215 30

DES 82 30 8 194 488512 97 100 232 30

DEBATE-BTK (123) PTA 67 131 79 740 0100 430 NR 821 29

DCB 65 129 83 270 0100 180 NR 775 29


DCB 239 102 91 410 0100 92 772 386 102

IDEAS (125) DCB 25 148 57 579 NR 136 NR 120 NR

DES 27 127 47 280 NR 77 NR 230 NR

p lt 005








1353
















CONCLUSIONS
































R E F E R E N C E S






201565931ndash41





















201520465ndash78








































326381ndash6




JAMA 20012861599ndash606























1354





































Res 20151161527ndash39























1994901866ndash74





199681780ndash8



1678ndash87










167ndash73






























2012331311ndash20





































2014130939ndash47
















JAMA 20153141936ndash44


































1355

















Med 201015181ndash8





47330ndash6











Med 2000342145ndash53













































JAMA 20093011909ndash19
















20123661404ndash13




19963481329ndash39

























7 2016






J 2014168588ndash96




20131271522ndash9

















2016









55363ndash70e5













201529738ndash50























1356






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357

































































ACHILLES (120) PTA 101 27 21 429 NR 165 982 754 26


DES 74 16 10 170 0100 80 100 150 30

YUKON-BTX (122) BMS 79 31 9 444 582418 175 100 215 30

DES 82 30 8 194 488512 97 100 232 30

DEBATE-BTK (123) PTA 67 131 79 740 0100 430 NR 821 29

DCB 65 129 83 270 0100 180 NR 775 29


DCB 239 102 91 410 0100 92 772 386 102

IDEAS (125) DCB 25 148 57 579 NR 136 NR 120 NR

DES 27 127 47 280 NR 77 NR 230 NR

p lt 005








1353
















CONCLUSIONS
































R E F E R E N C E S






201565931ndash41





















201520465ndash78








































326381ndash6




JAMA 20012861599ndash606























1354





































Res 20151161527ndash39























1994901866ndash74





199681780ndash8



1678ndash87










167ndash73






























2012331311ndash20





































2014130939ndash47
















JAMA 20153141936ndash44


































1355

















Med 201015181ndash8





47330ndash6











Med 2000342145ndash53













































JAMA 20093011909ndash19
















20123661404ndash13




19963481329ndash39

























7 2016






J 2014168588ndash96




20131271522ndash9

















2016









55363ndash70e5













201529738ndash50























1356






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357
















CONCLUSIONS
































R E F E R E N C E S






201565931ndash41





















201520465ndash78








































326381ndash6




JAMA 20012861599ndash606























1354





































Res 20151161527ndash39























1994901866ndash74





199681780ndash8



1678ndash87










167ndash73






























2012331311ndash20





































2014130939ndash47
















JAMA 20153141936ndash44


































1355

















Med 201015181ndash8





47330ndash6











Med 2000342145ndash53













































JAMA 20093011909ndash19
















20123661404ndash13




19963481329ndash39

























7 2016






J 2014168588ndash96




20131271522ndash9

















2016









55363ndash70e5













201529738ndash50























1356






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357





































Res 20151161527ndash39























1994901866ndash74





199681780ndash8



1678ndash87










167ndash73






























2012331311ndash20





































2014130939ndash47
















JAMA 20153141936ndash44


































1355

















Med 201015181ndash8





47330ndash6











Med 2000342145ndash53













































JAMA 20093011909ndash19
















20123661404ndash13




19963481329ndash39

























7 2016






J 2014168588ndash96




20131271522ndash9

















2016









55363ndash70e5













201529738ndash50























1356






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357

















Med 201015181ndash8





47330ndash6











Med 2000342145ndash53













































JAMA 20093011909ndash19
















20123661404ndash13




19963481329ndash39

























7 2016






J 2014168588ndash96




20131271522ndash9

















2016









55363ndash70e5













201529738ndash50























1356






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357






































Med 20063541879ndash88






























































18Sndash31S




























1568ndash76























vascular diseases






1357

2016-peripheral artery disease

Documents