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THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Peripheral Artery Disease
Evolving Role of Exercise, Medical Therapy, andEndovascular Options
Jeffrey W. Olin, DO,a Christopher J. White, MD,b Ehrin J. Armstrong, MD, MSC,c Daniella Kadian-Dodov, MD,a

William R. Hiatt, MDd

JACC JOURNAL CME

This article has been selected as the month’s JACC Journal CME activity,

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

CME tab on the top navigation bar.

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provide continuing medical education for physicians.

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

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commensurate with the extent of their participation in the activity.

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To obtain credit for JACC CME, you must:

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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

From the aZena and Michael A. Wiener Cardiovascular Institute & Marie-Jo

Health, Icahn School of Medicine at Mount Sinai, New York, New York; bDep

Orleans, Louisiana; cDepartment of Medicine, Division of Cardiology, Unive

rado, and Veterans Affairs Eastern Colorado Health Care System, Denver, Col

Cardiology, University of Colorado School of Medicine, and CPC Clinical

steering committee and scientific advisory board for Merck for the TRAP2 tria

the EUCLID Trial; and is a site investigator for AstraZeneca. Dr. White serv

Surmodics. Dr. Armstrong is a consultant/advisory board member for Ab

tranetics. Dr. Hiatt has received grant support for clinical trial research fr

ReNeuron, and the National Institutes of Health. Dr. Kadian-Dodov has no r

disclose. Michael Jaff, DO, served as Guest Editor for this paper.

Manuscript received October 8, 2015; revised manuscript received Decembe

peripheral artery disease so as to decrease the likelihood of experiencing

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

patients with claudication, counsel on lifestyle modifications to improve

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

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

scientific 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, Pfizer,

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

seé and Henry R. Kravis Center for Cardiovascular

artment of Cardiology, Ochsner Clinical School, New

rsity of Colorado School of Medicine, Denver, Colo-

orado; and the dDepartment of Medicine, Division of

Research, Aurora, Colorado. Dr. Olin serves on the

l; serves on the international steering committee for

es on the research advisory board for Lutonix and

bott Vascular, Medtronic, Merck, Pfizer, and Spec-

om AstraZeneca, Bayer, Janssen, GlaxoSmithKline,

elationships relevant to the contents of this paper to

r 14, 2015, accepted December 15, 2015.

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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 – 5 7 Management of Patients With Peripheral Artery Disease

1339

Peripheral Artery Disease

Evolving Role of Exercise, Medical Therapy, andEndovascular Options

ABSTRACT

The prevalence of peripheral artery disease (PAD) continues to increase worldwide. It is important to identify patients

with PAD because of the increased risk of myocardial infarction, stroke, and cardiovascular death and impaired quality of

life because of a profound limitation in exercise performance and the potential to develop critical limb ischemia. Despite

effective therapies to lower the cardiovascular risk and prevent progression to critical limb ischemia, patients with PAD

continue to be under-recognized and undertreated. The management of PAD patients should include an exercise

program, guideline-based medical therapy to lower the cardiovascular risk, and, when revascularization is indicated,

an “endovascular first” approach. The indications and strategic choices for endovascular revascularization will vary

depending on the clinical severity of the PAD and the anatomic distribution of the disease. In this review, we

discuss an evidence-based approach to the management of patients with PAD. (J Am Coll Cardiol 2016;67:1338–57)

© 2016 by the American College of Cardiology Foundation.

P eripheral artery disease (PAD) refers to athero-sclerosis involving the aorta, iliac, and lower-extremity arteries and is associated with

significant morbidity and mortality (1,2). Since thelast iteration of the guidelines focused on PAD (2–4),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 managementof PAD patients, highlighting the roles of exercise,optimal medical management, and endovasculartherapy. Surgical revascularization will not be dis-cussed because current expert consensus documentsrecommend an “endovascular first” approach for themajority of PAD patients requiring revascularization(2,3).

Despite initiatives to improve on the identificationand management of PAD (2,5), the number of peopleaffected and disease morbidity continues to rise. Asof 2010, more than 200 million people worldwide areliving with PAD, which represents a 28.7% increasedprevalence in low- and middle-income countries anda 13.1% increase in high-income countries over a10-year period (6,7). Prevalence studies in the UnitedStates estimate that 5.9% of Americans over 40 yearsof age have PAD (8). When specific high-risk pop-ulations are evaluated, estimates of PAD prevalenceare as high as 30% (9). The prevalence and severity ofPAD is increased in African Americans and Hispanics(10). A recent retrospective cohort study evaluatingnearly 12 million insured American adults reportedmean annual incidence rates of PAD and critical limbischemia (CLI) of 2.35% and 0.35%, 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 (5,9,10,12,13). Smoking and diabetes areparticularly virulent and are associated with worseoutcomes, independent of other risk factors (14).

Identification of patients with PAD is importantbecause there is a 3- to 4-fold increased risk of car-diovascular events, even in the setting of asymp-tomatic disease (15). At 5 years, approximately 1 of 5patients with PAD will experience a nonfatal cardio-vascular event, and 15% to 20% will die (most ofcardiovascular causes) (8,16).

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%). Formaltesting to assess functional capacity and enduranceshows significant impairment in patients with PAD,even if asymptomatic. Although the majority of pa-tients report leg symptoms other than classic claudi-cation, greater functional decline is associated withgreater severity of disease, lower baseline ankle-brachial index (ABI), and increased numbers ofcardiovascular events (17–20). In patients with CLI,outcomes are dire: at 1 year, 10% will experience afatal cardiovascular event, and 25% will undergo limbamputation (2).

Patient-reported symptoms underestimate PADprevalence, and the physical examination is not areliable tool for the identification of disease. Diag-nosis and prevention of adverse outcomes may

ABBR EV I A T I ON S

AND ACRONYMS

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 = superficial 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 – 5 7

1340

therefore be elusive, unless patients areidentified with targeted diagnostic testing(i.e., ankle-brachial index [ABI]) (21). Thetreatment of underlying cardiovascular riskfactors results in reduced morbidity andmortality for patients with PAD, although thispopulation continues to be under-recognizedand undertreated for their cardiovascular risk(2,8). Among 7,458 participants with PAD inthe 1999 to 2004 NHANES (National Healthand Nutrition Examination Survey) data, only30.5% of subjects were taking statins, 24.9%were taking angiotensin-converting enzymeinhibitors (ACEI) or angiotensin receptorblockers, and 35.8% were administeredaspirin. Among patients with PAD (and noother clinical cardiovascular disease), use ofmultiple preventive therapies was associated

with a 65% lower all-cause mortality (hazard ratio[HR]: 0.35; p ¼ 0.02) (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 the2 systolic pressures in the dorsalis pedis and posteriortibial artery in each leg and dividing by the higher ofthe brachial artery systolic blood pressures in eacharm. An abnormal ABI is diagnostic for PAD (21).A normal ABI is between 1.00 and 1.40. An ABI #0.90demonstrates 90% sensitivity and 95% specificity forPAD and is the accepted threshold for diagnosis (2,21).Values between 0.91 and 1.00 are considered border-line; however, the cardiovascular event rate for an ABIin this range is increased by 10% to 20% (21). At levels>1.40, the identification of PAD is not accuratebecause of the presence of arterial calcification andnoncompressibility of the blood vessels, a findingfrequently encountered in the very elderly and inthose with diabetes and chronic kidney disease. In thissetting, the toe-brachial index is used and consideredabnormal when <0.70 (4,21). There is a strong andconsistent relationship between an abnormal ABI andthe presence of coronary or cerebrovascular disease(5,16,22). In addition, the ABI is a predictor of cardio-vascular morbidity and mortality independent ofclinical risk prediction scores such as the FraminghamRisk Score and other surrogate markers of systemicatherosclerosis such as the coronary calcium score andcarotid artery intimal-medial thickness (23). There isalso a higher cardiovascular event rate in patients withPAD (even in asymptomatic patients) with knowncoronary 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 orsmoking (2–4,9,25). The goal is to identify and treatpatients with increased cardiovascular risk. Despitethese recommendations and the fact that nearly one-half of all PAD patients are asymptomatic, there is noreimbursement for the performance of an ABI in theabsence of clinical symptoms of PAD. Alternativediagnostic methods for PAD are beyond the scope ofthis review.

Serum biomarkers have been used for risk predic-tion and the detection of PAD (26). A combinedbiomarker profile that includes fasting glucose, high-sensitivity C-reactive protein, b2-microglobulin, andcystatin C demonstrated efficacy in the identificationof PAD and reclassification of cardiovascular riskassessment by Framingham Risk Score in patients whowould have otherwise been misidentified (27). TheBRAVO (Biomarker Risk Assessment in VulnerableOutcomes) study evaluated 595 patients with PAD andfollowed them for 3 years. The primary outcome wasischemic heart disease events (myocardial infarction,unstable angina, or ischemic heart disease death). Ofthe 50 participants who had an event, the D-dimer washigher 2 months before the event than the values 10months, 12 months, 16 months 20 months, 26 months,and 32 months before the event. There was no changein the serum amyloid A or CRP 2 months before anevent (28). Although there is a clear associationbetween various biomarkers and PAD, the overallclinical value related to patient outcomes remainsunclear, and thus, there is no clinical benefit inmeasuring biomarkers at this time.

THE ROLE OF EXERCISE

Patients with PAD have a profound limitation inexercise performance that is related to a complexpathophysiology (29). Although reduced exerciseperformance is a hallmark of PAD, the symptomaticmanifestations are quite varied, as described previ-ously (30). Not surprisingly, patients with claudica-tion slow their walking pace and often avoid walkingaltogether. Thus, patients with PAD present with acomplex array of symptoms, health beliefs, andexercise limitations in their daily lives (31,32). Theseperceptions and attitudes must be addressed if atreatment plan is to be successful.

The overall goal in treating the exercise limitationfrom PAD is to improve exercise performance with acorollary improvement in quality of life (QOL) andfunctional status. In this regard, treatments thatimprove treadmill exercise performance, 6-minwalking distance, and patient-related QOL can serveas a basis for obtaining regulatory approval of a


1341

claudication therapy. In contrast, changes in limbhemodynamics, such as an improvement in the ABI orimaging after a successful revascularization, serveonly as surrogate measures of clinical benefit.

Exercise training has been a mainstay of treatmentfor symptomatic PAD, with a well-established benefitafter a typical 12-week exercise training program(33,34). Exercise training directly modifies severalpathophysiological mechanisms in PAD, includingimproved skeletal muscle metabolism, endothelialfunction, and gait biomechanics (35).

SUPERVISED EXERCISE TRAINING IMPROVES MORBIDITY

AND MORTALITY IN PAD. Individual single-site studiesand a meta-analysis of those studies demonstrate thata 12-week intervention of supervised exercise (SE)improves exercise performance and QOL in PAD (34).Supervised exercise is also more effective than anonstructured community exercise program (36).Physical activity in patients with PAD is associatedwith decreased all-cause and cardiovascular mortality(37,38). Standardized supervised training methodshave been published previously (39).

On the basis of current evidence, supervisedwalking exercise gets a Class Ia recommendation andunsupervised exercise a Class IIb recommendation(2). Despite clear evidence of benefit, SE programshave not been accepted by payers, providers, orpatients for a variety of reasons, including questionsof long-term adherence and the benefit of exercise as alifestyle intervention, coupled with the desire by mostpatients and vascular physicians for a more immedi-ate approach to relieving claudication with endovas-cular therapy (40). Therefore, SE training programsfor claudication are very limited and not reimbursed.

HOME-BASED EXERCISE DATA AND GENERALIZABILITY

OF THE FINDINGS. The methodology to provide acommunity (home)-based exercise intervention hasimproved considerably over the past decade, andthese exercise training methods have providedencouraging results.

The least resource-intensive home-based programcan employ education and behavioral interventionsthat prepare patients for exercise training (41).Notably, adherence to a community program may bepoor without proper motivation and engagement.

There are a number of new devices that monitorthe intensity and duration of an exercise sessionperformed in the home environment. A pilot studythat used a program of training, monitoring, andcoaching had encouraging results in a subgroup ofsubjects but was too small to definitively establish thebenefits of the interventions (42). Two larger trialsused a step activity monitor to record the duration

and intensity of the walking exercise to inform theresearch staff and patient as to the patient’s exerciseprescription. One randomized trial combined theactivity monitor with a home-based program thatused the principles of a hospital-based supervisedprogram (43). Adherence to the home program was>80%, and the results on improvements in treadmillexercise performance were comparable betweenhome and supervised programs. A follow-up studydemonstrated similar results (44).

McDermott et al. (45) have developed a coordinatedexercise program (group-mediated cognitive behav-ioral therapy) that includes weekly group sessions runby a trained facilitator. In a randomized controlledtrial of 194 patients, subjects in the intervention groupimproved their 6-minwalking distance, peak treadmillexercise performance, and several measures of QOLand accelerometer-measured physical activity (46).In addition, after 6 months, the intervention groupgained self-efficacy, satisfaction with functioning,pain acceptance, and social functioning, and thesebenefits were sustained at the 12-month endpoint (47).At 12 months, fewer treated patients experiencedmobility loss, and treated patients also improved inwalking velocity and QOL (48).

It is apparent that many of the exercise methodsdiscussed are effective in improving walking distancewith less discomfort and improved QOL; however,they all require resources that are not available inmany communities, especially those in the lowestsocioeconomic class. Although a simple recommen-dation between the physician and the patient to exer-cise is usually ineffective, the physician can providea comprehensive exercise prescription (Table 1) onhow to structure a home exercise program (50,51).This is not a 1-time recommendation but an ongoingdiscussion between the physician and the patientin an attempt to change patient behavior. Patientswho are compliant with such a program often experi-ence considerable improvement in walking distanceand QOL.STUDIES ON EXERCISE VERSUS ENDOVASCULAR

THERAPY: ARE WE ASKING THE RIGHT QUESTIONS?

Several studies have compared an SE program torevascularization in patients with PAD andexercise-limiting claudication (52,53). Given thetremendous expansion and effectiveness of endovas-cular treatments for symptomatic PAD, as well aspatient reluctance to enter an exercise-lifestyle treat-ment program (as discussed previously), the mostprudent approach would be to include both modalitiesin the treatment plan: exercise and revascularization.In fact, both exercise training and revascularizationcan greatly improve patient exercise performance

TABLE 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 (flat)

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

3. Stop the treadmill completely when pain is 3–4 on claudicationdiscomfort scale*

4. When the discomfort has ceased, resume exercise at the sameintensity

5. Repeat rest/exercise cycles

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

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

b) Once you are able to walk at 3.4 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 3–4 on claudication pain/discomfortscale. This way the pain/discomfort should go away in 2–5 min. Ifyou 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 3–4 on pain/discomfort scale, stop walking completely.Do 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 yourquality of life, this type of program is also beneficial for yourheart, blood pressure, and lipid (cholesterol and triglyceride)levels.

*Claudication pain scale: 1 ¼ no pain or discomfort; 2 ¼ onset of claudication;3 ¼ mild pain or discomfort; 4 ¼ moderate pain or discomfort; 5 ¼ severe pain ordiscomfort. Adapted from Weinberg et al. (49).

PAD ¼ peripheral artery disease.



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and QOL, but by very different mechanisms. Revascu-larization primarily improves exercise blood flow,whereas exercise training does not (29). In contrast,exercise training induces a variety of adaptive re-sponses, including improved skeletal muscle mito-chondrial oxidativemetabolism, improvedendothelialfunction, and more efficient biomechanics of walking.Thus, the obvious “best” treatment strategy wouldappear to be the combined program, utilizing endo-vascular revascularization and an optimal home-basedand long-term exercise program. This hypothesiswas initially tested more than 25 years ago, and thecombination of bypass surgery and exercise trainingwas superior to either treatment alone (54).

The CLEVER (Claudication: Exercise Versus Endo-luminal Revascularization) study was an importantand well-designed comparative effectiveness trialthat compared the outcomes for stenting of aortoiliacdisease with SE on a background of optimal medical

therapy in both groups (52). At the initial 6-monthfollow up, the primary endpoint of peak walkingtime on a graded treadmill test was significantlyimproved in both the exercise and stent groupscompared with optimal medical management, but thepeak walking time was significantly higher in theexercise group than in the stent group (52). The sec-ondary endpoints were changes in responses to QOLquestionnaires. Both of these patient-reported out-comes were improved with exercise or stenting overoptimal medical management; however, improve-ments tended to be greater in the stenting group. Thesame endpoints were measured at 18 months offollow-up (55). In 79 of 119 patients who completedthe study, improvements in treadmill peak walkingtime remained for both the exercise and stentinggroups over optimal medical therapy, but the differ-ences in peak walking time between the exercise andstenting groups were no longer statistically signifi-cant. Improved patient-reported outcomes remainedfor both the exercise and stent groups.

CLEVER clearly established the independent, long-term, and broad-based benefits of both exercisetraining and stent revascularization in symptomaticPAD. Similar to many such trials, of the nearly 1,000patients evaluated, only 11% were randomized, andfewer were available for 18-month follow-up. Unfor-tunately, the arm of CLEVER that would have testedthe combination of exercise plus stenting was drop-ped because of poor enrollment.

In the recently published ERASE (EndovascularRevascularization and Supervised Exercise) trial,106 patients were randomized to both endovasculartherapy and SE and 106 patients to SE alone (56). After1 year, the combination group had greater improve-ment in maximum walking distance (MWD) andhealth-related QOL scores than the group randomizedto SE alone; however, both groups demonstrateddramatic improvement in MWD, pain-free walkingdistance, and QOL. The supervised exercise groupincreased MWD from 285 m to 1,240 m, for animprovement of 955 m. The combination groupincreased MWD from 264 m to 1,501 m, for animprovement of 1,237 m. This study illustrates2 important points: 1) the combination of endovasculartherapy and SE is the most effective therapy for manypatients with claudication; and 2) even the grouprandomized to SE alone showed marked improvementin MWD, pain-free walking distance, and QOL (56).

The cost of therapy must also be considered whenplanning a particular strategy to treat symptomaticPAD. In a single-center Dutch randomized trial,endovascular revascularization had similar benefitbut higher total mean cumulative costs per patient

CENTRAL ILLUSTRATION The Peripheral Artery Disease Prescription

• Control Blood Pressure to Goal -ACE Inhibitor

• High-Dose Statin Therapy • Good Foot Care

• Antiplatelet Therapy • Revascularization

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

• Discontinue Tobacco Use

• Cilostazol

• Discontinue Tobacco Use

• Walking Program • Walking Program

Decrease the Risk of MI, Stroke, and CV Death

Improve Symptoms, Quality of Life, and Prevent Amputation

Olin, J.W. et al. J Am Coll Cardiol. 2016; 67(11):1338–57.

Management of patients with peripheral artery disease: recommendations for improving outcomes and quality of life. ACE ¼ angiotensin-converting

enzyme; CV ¼ cardiovascular; MI ¼ myocardial infarction.


1343

compared with a hospital-based exercise program(57). Another study from a Dutch health-care databaseof 4,954 patients demonstrated that a steppedapproach of exercise therapy followed by endovas-cular revascularization was more cost-effective thanrevascularization only (58).

Thus, future studies should address not only theclinical benefits but also the effectiveness of thecombination of an exercise program and limb revas-cularization. In this context, effectiveness pertains tothe ability of a treatment program to be utilized by amajority of appropriate patients in a community andto achieve high adherence to the program, as well asthat the desired improvements in functional out-comes are obtained.

OPTIMAL MEDICAL THERAPY FOR

PATIENTS WITH PAD

Medical therapy for PAD should address treatment forlimb-related outcomes (improve claudication symp-toms and prevent CLI and amputation) and treatmentto prevent major adverse cardiovascular events(MACE; myocardial infarction, stroke, and cardio-vascular death) (Central Illustration).

Despite the recommendations from societalguidelines on the management of patients with PAD(2), these patients continue to be undertreated

compared with patients with CAD (8,59). Adherenceto these guidelines in real-world practice is associatedwith improved outcomes (Figure 1), which empha-sizes the benefit of multifactorial risk reduction inthis high-risk population (12). Performance measuresfor PAD will help improve quality of care and may beincorporated into future quality metrics (60).

SMOKING CESSATION

Smoking is a major risk factor for the development andprogression of PAD. A multidisciplinary approach tosmoking cessation should be used, including group-based programs and cognitive behavioral therapy.

A recent study evaluated the association betweensuccessful quitting after endovascular interventionand long-term outcomes (61). Among 739 patientsundergoing lower-extremity angiography, 28% wereactive smokers at the time of endovascular interven-tion. In the subsequent year, 30% of active smokerssuccessfully quit. Those who remained off tobaccohad significantly lower 5-year mortality (14% vs. 31%)and improved amputation-free survival (81% vs.60%). Discontinuation of smoking is the mostimportant lifestyle modification in preventing CLI,amputation, and MACE in patients with PAD. Thisneeds to be conveyed to the patient in an empatheticand nonjudgmental way during every office visit. The

FIGURE 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 36Follow-Up (Months)

010

2030

40M

ajor

Adv

erse

Car

diov

ascu

lar E

vent

s, %

010

2030

40M

ajor

Adv

erse

Lim

b Ev

ents

, %

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

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

Number at risk<4 Guideline

4 Guideline502237

450222

391207

355180

322156

288143

256123

Number at risk<4 Guideline

4 Guideline502237

306155

240133

201102

17594

14276

12564

<4 Guideline Therapies 4 Guideline Therapies

<4 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 significant reduction in (A) major adverse cardiovascular

events and (B) major adverse limb events. Reproduced with permission from Armstrong

et al. (12). CI ¼ confidence interval; PAD ¼ peripheral artery disease.



1344

VAPOR (Vascular Physician Offer and Report) trial iscurrently evaluating methods to improve physician-patient interactions to encourage patients with PADto 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 randomizedtrials shows an improvement in absolute claudica-tion distance of approximately 50% compared withplacebo (64). Although cilostazol appears to be safefor long-term administration, adherence is low (>60%discontinuation at 3 years) because of adverse effectsincluding headache, palpitations, and diarrhea (65).Because of its mechanistic similarity to other type IIIphosphodiesterase inhibitors, such as milrinone, cil-ostazol is contraindicated in patients with a history ofheart failure. The optimal dose of cilostazol is 100 mgtwice daily, and it may take up to 4 months to derivemaximum benefit from this drug (63).

Pentoxifylline is rarely used today to treat claudi-cation because of a lack of efficacy compared withcilostazol. Naftidrofuryl is a 5-HT2 antagonist that isapproved in Europe. In a pooled analysis involving888 patients randomized to naftidrofuryl, there was a26% increase in pain-free walking compared withplacebo (66). It is not available for use in the UnitedStates.

ACEIs

ACEIs are associated with a significant reduction inMACE among patients with PAD. These data arederived primarily from the HOPE (Heart OutcomesPrevention Evaluation) trial, which randomized 9,297high-risk patients with vascular disease or diabetesplus 1 other risk factor to ramipril 10 mg dailyor placebo. Among these, 1,966 patients with PAD(42.3%) were randomized to ramipril and 2,085(44.8%) to placebo. The primary outcome (myocardialinfarction, stroke, cardiovascular death) occurred in14.3% of those without PAD versus 22.0% of thosewith PAD (67). In the 5,231 patients without PAD, theprimary outcome was observed in 12.6% in the ram-ipril group and 14.9% in the placebo arm. In those withan ABI<0.6, the primary outcome occurred in 16.4% inthe ramipril arm versus 22% in the placebo arm. Thecardiovascular benefit of ramipril applies to patientswith both asymptomatic and symptomatic PAD acrossa broad range of ABI values (68). Similar results havealso been observed with telmisartan, which suggests apossible class effect of ACEI/angiotensin receptorblockade among patients with PAD (69,70).

STATINS

High-intensity statin medications are recommendedfor all patients with PAD on the basis of themost recent American College of Cardiology (ACC)/American Heart Association (AHA) guidelines, which


1345

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 derivedfrom subset analysis of larger clinical trials. TheMedical Research Council/British Heart Foundation’sHeart Protection Study randomized 20,536 high-riskpatients to simvastatin 40 mg daily or placebo (72).All-cause mortality occurred in 12.9% of patientsrandomized to simvastatin and 14.7% randomized toplacebo (22% relative risk reduction; p ¼ 0.0003).Observational studies have also confirmed the car-diovascular and overall mortality benefit of statinsamong patients with more advanced PAD, includingCLI (73).

Recent data suggest that statin use is also associ-ated with a reduction in adverse limb outcomes,including amputation. In the REACH (Reduction ofAtherothrombosis for Continued Health) registry,statin therapy was associated with a significantreduction in the combined endpoint of worseningclaudication, new CLI, new revascularization, oramputation (74). The absolute 4-year event rates were22.0% versus 26.2%, which emphasizes the high rate ofadverse limb events among patients with symptom-atic PAD. Importantly, statin therapy was also associ-ated with a significant reduction in 4-year rates ofischemic amputation (3.8% vs. 5.6%). In an analysis ofMedicare 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 observationaldata among patients with CLI suggest that statintherapy is also associated with improved 1-year ratesof primary patency, secondary patency, and improvedlimb salvage after endovascular intervention (73).

Patients with PAD should be prescribed a high-intensity statin to reduce the risk of cardiovascularevents. In most studies, the rates of statin prescrip-tion were <75%, which emphasizes the importance ofmaximizing medical therapy among this high-riskgroup of patients with advanced atheroscleroticdisease (59).

ANTIPLATELET THERAPY

ASPIRIN. Aspirin has been a mainstay of drug ther-apy among patients with PAD; however, the datasupporting aspirin use in patients with PAD have notbeen well substantiated (76,77).

Recent studies investigating the benefit of aspirinamong patients with asymptomatic PAD have yieldednegative results. Both the POPADAD (Prevention ofProgression of Arterial Disease and Diabetes) trial andthe AAA (Aspirin for Asymptomatic Atherosclerosis)

trial compared low-dose aspirin with placebo inpatients with a low ABI. Neither study demonstrateda reduction in fatal and nonfatal cardiovascularevents or revascularization with aspirin mono-therapy, although both notably included low-riskpatients with borderline ABI (#0.99 in POPADADand #0.95 in AAA) (77,78).

Consistent with these results, a meta-analysisspecifically examined aspirin for PAD in 18 trialsinvolving 5,269 patients. In patients taking aspirinmonotherapy, there was a nonsignificant reductionin cardiovascular events (absolute event rate 8.2%vs. 9.6%; relative risk: 0.75; 95% confidence inter-val [CI]: 0.48 to 1.18); however, there was a sig-nificant reduction in nonfatal stroke (HR: 0.64; 95%CI: 0.42 to 0.99; p ¼ 0.04) (76). In the last iterationof 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 PADand an ABI <0.90, and a Class IIb indication amongasymptomatic patients with an ABI of 0.90 to 0.99(2). Some of these recommendations may change inthe upcoming revision of the ACC/AHA PAD prac-tice guidelines.

CLOPIDOGREL AND

DUAL-ANTIPLATELET THERAPY

Clopidogrel is indicated as an alternative to aspirinfor antiplatelet monotherapy among patients withPAD, although recent studies suggest that <20% ofpatients with PAD are prescribed clopidogrel in clin-ical practice (79). The data supporting clopidogrel useare primarily based on the CAPRIE (ClopidogrelVersus Aspirin in Patients at Risk of IschaemicEvents) study, in which clopidogrel monotherapy wasassociated with a small benefit compared with aspirin325 mg daily in the overall population, but there was a23.8% relative risk reduction among the subgroup ofpatients with symptomatic PAD (n ¼ 6,452; absoluteevent rate 3.7% vs. 4.9% per year) (80).

Dual-antiplatelet therapy (DAPT) with low-doseaspirin (75 to 162 mg daily) and clopidogrel 75 mgdaily was studied in the CHARISMA (Clopidogrel forHigh Atherothrombotic Risk and Ischemic Stabiliza-tion, Management, and Avoidance) trial, whichincluded patients at high risk for atherothromboticevents. The overall results of this trial were not sig-nificant, although in subgroup analyses, there was abenefit of DAPT among patients with symptomaticatherothrombosis (81). In an analysis of the 3,096 pa-tients in the trial with PAD, DAPT was associated witha lower rate of myocardial infarction (2.3% vs. 3.7%;



1346

HR: 0.63; 95% CI: 0.42 to 0.96; p ¼ 0.02) and hospital-ization for ischemic events (16.5% vs. 20.1%; HR: 0.81;95% CI: 0.68 to 0.95; p ¼ 0.011) but not the overallcomposite primary endpoint (82). There was no dif-ference between the groups in moderate, severe, orfatal bleeding, but there was an increase in minorbleeding in the DAPT group.

In a recent propensity-matched observationalstudy among patients undergoing endovascularintervention, there was a significant reduction inMACE among patients taking DAPT (adjusted HR:0.65; 95% CI: 0.44 to 0.96; p ¼ 0.03) compared withthose taking aspirin monotherapy (83). The discor-dant findings between this study and the CHARISMAtrial may be explained by inclusion of a cohortwith more advanced atherosclerotic disease under-going endovascular intervention, including >50% ofpatients with CLI.

The CASPAR (Clopidogrel and Acetylsalicylic Acidin Bypass Surgery for Peripheral Arterial Disease) trialstudied DAPT versus aspirin 75 to 100 mg daily amongpatients undergoing below-knee surgical bypass fortreatment of CLI (84). The primary endpoint of death,major amputation, index-graft occlusion, or revascu-larization was not different for DAPT versusacetylsalicylic acid (ASA) monotherapy. In a pre-specified subgroup analysis, there was a significantbenefit of DAPT in patients treated with prostheticgrafts (HR: 0.65; 95% CI: 0.45 to 0.95; p ¼ 0.025) butnot in those treated with vein grafts. A similar trial,the CAMPER study (Clopidogrel and Aspirin in theManagement of peripheral Endovascular Revascular-ization), tested DAPT versus aspirin in patients un-dergoing infrainguinal endovascular therapy. Thestudy was never completed because of poor enroll-ment (doctors would not randomize patients to ASAalone); continued funding could not be justified.

DAPT is often prescribed after endovascular inter-vention, although the data supporting duration ofDAPT are sparse. In practice,most physicians prescribeDAPT for a time period ranging from 1 to 3months post-intervention. The ASPIRE-PAD study (AntiplateletStrategy for Peripheral Arterial Interventions forRevascularization of Lower Extremities) is currentlyevaluating comparative outcomes of 1 versus 12months 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 onthe platelet surface, leads to receptor activationand increased intracellular Ca2þ; cyclic adenosine

monophosphate (cAMP) levels subsequently decrease,which leads to increased platelet aggregation andrelease of further activating factors. Vorapaxar inhibitsPAR-1, thereby significantly reducing thrombin-mediated platelet activation.

The TRA 2�P-TIMI 50 trial (Thrombin ReceptorAntagonist for Secondary Prevention–Thrombolysisin Myocardial Infarction Study Group) studied vor-apaxar sulfate 2.5 mg daily versus placebo (ASA and/or clopidogrel therapy, at the investigators’ discre-tion) among 26,449 patients with a recent myocardialinfarction, recent ischemic stroke, or symptomaticPAD. At 3 years, there was a significant reduction inthe primary endpoint of MACE (absolute event rates:9.3% vs. 10.5%; HR: 0.87; 95% CI: 0.80 to 0.94;p < 0.001) (79). After 2 years, the data and safetymonitoring board recommended stopping the studydrug in the patient subgroup entered with priorischemic stroke because of an increased risk ofintracranial hemorrhage. Among the 3,787 patientswith PAD, the majority were treated with aspirinmonotherapy plus vorapaxar or placebo. The reduc-tion in MACE was not statistically significant in thoseassigned to vorapaxar (absolute event rates: 11.3% vs.11.9%; HR: 0.94; 95% CI: 0.78 to 1.14). Similarlynegative results were observed among patients withPAD who were enrolled in the TRACER (ThrombinReceptor Antagonist for Clinical Event Reduction inAcute Coronary Syndrome) trial (86). Additionally,vorapaxar is associated with a significantly increasedrisk of major bleeding. However, in both of thesetrials, there were relatively few MACE in the PADsubgroup. The PAD group was underpowered to drawany conclusions on efficacy.

Pre-specified analysis of limb-related outcomes inthe TRA 2�P-TIMI 50 trial demonstrated that patientsassigned to vorapaxar had significantly reduced ratesof acute limb ischemia (2.3% vs. 3.9%; HR: 0.58; 95%CI: 0.39 to 0.86; p ¼ 0.006), as well as peripheralartery revascularization (18.4% vs. 22.2%; HR: 0.84;95% CI: 0.73 to 0.97; p ¼ 0.017) during the 3-yearfollow-up (Figure 2) (87). These efficacy endpointsmust be balanced by a significantly increased rate ofmajor bleeding among patients prescribed vorapaxar.Further research into the mechanism by whichvorapaxar led to improved limb outcomes is requiredto fully understand these effects.

CELL-BASED AND ANGIOGENIC THERAPIES

Modulation and enhancement of lower-extremityblood flow via angiogenesis, arteriogenesis, or vas-culogenesis could provide a promising breakthroughtherapy for patients with PAD (88). Additionally,

FIGURE 2 Limb-Related Events in Patients Treated With Vorapaxar

4.5%

4.0%

3.5%

3.0%

2.5%

2.0%

1.5%

1.0%

0.5%

0.0%Ev

ent R

ate

(%)

0 180 360 540 720 900 1080Days Since Randomization

0 180 360 540 720 900 1080Days Since Randomization

25.0%

20.0%

15.0%

10.0%

5.0%

0.0%

Even

t Rat

e (%

)

2.3% vs. 3.9%HR 0.58 (0.39 – 0.86)

P=0.006

18.4% vs. 22.2%HR 0.84 (0.73 – 0.97)

P=0.017

Hospitalization for Acute Limb IschemiaPlacebo Vorapaxar

Peripheral RevascularizationPlacebo Vorapaxar

A

B

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

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

permission from Bonaca et al. (87). HR ¼ hazard ratio.


1347

there has been much interest in the use of stem cell–derived endothelial cells or modification of residentstem cells (89). Potential benefits of these therapiesinclude improved wound healing and limb salvageamong patients with CLI, as well as improved clau-dication distance. To date, numerous cell-based andangiogenic therapies have been tested, and despitepromising results in early clinical trials, none of theseagents have shown benefit in larger trials.

ONGOING CLINICAL TRIALS

There are currently 2 clinical trials studying novelantiplatelet and anticoagulant agents to reduce MACEand potentially modify limb-related outcomes.EUCLID (Study Comparing Cardiovascular Effects ofTicagrelor and Clopidogrel in Patients With Periph-eral Artery Disease) is a randomized, blinded, double-dummy trial comparing ticagrelor 90 mg twice dailyto clopidogrel monotherapy among 13,500 patientswith PAD (90). All patients are tested for clopidogrelresistance before randomization. The primaryendpoint is a composite of MACE, and results areexpected in late 2016. The COMPASS (Rivaroxaban forthe Prevention of Major Cardiovascular Events inCoronary or Peripheral Artery Disease) trial is evalu-ating low-dose rivaroxaban alone versus placebo,aspirin alone, or rivaroxaban and aspirin among21,400 patients with a history of myocardial infarc-tion or PAD; the primary endpoint of this trial is acomposite of MACE (91).

ENDOVASCULAR THERAPY

Endovascular revascularization plays a key role in themanagement of patients with PAD. Patients with sta-ble claudication have a low risk of limb loss but may beseverely limited by their symptoms. In most circum-stances, patients with claudication should be offered atrial of cilostazol and an exercise program as initialtherapy. If the patient is not satisfied after a trial ofmedical therapy, endovascular revascularization canbe considered. Patients with CLI require more urgentrevascularization because of an increased risk of tissueloss and amputation, as well as an extremely high riskof cardiovascular events (92).

There are 2 well-established classification schemesto describe the severity of PAD. The first is a func-tional assessment (Fontaine or Rutherford classifica-tion [RC]) (Table 2), and the second is an anatomiclesion classification (Trans-Atlantic Inter-SocietyConsensus [TASC]) (Table 3) (4,5). In addition, therehas been recent interest in the angiosome concept, inhelping to influence 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 fedby a source artery and drained by specific veins.

If the patient is a candidate for either endovascularor open surgery, the less invasive option (i.e., anendovascular-first strategy) is the current standard ofcare. The selection of a complex lesion (TASC D), forendovascular therapy will vary with the skill andexperience of the interventionalist. The goal intreating a patient who has functional impairmentbecause of claudication is durable relief of symptoms.In patients with CLI and a threatened limb or tissueloss, the goal is rapid reperfusion of the ischemic

TABLE 2 Classifications of Severity of PAD

Fontaine Rutherford

Stage Clinical Grade Category Clinical

I Asymptomatic 0 0 Asymptomatic

IIa 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

PAD ¼ peripheral artery disease.



1348

tissue to relieve the ischemia, prevent amputation,and restore ambulation.

AORTOILIAC OCCLUSIVE DISEASE

There has been a practice shift over the past 25 yearsas the treatment of aortoiliac disease transitionedfrom open surgery with aortobiiliac or aortobifemoralbypass to endovascular treatments for complex and

TABLE 3 TASC Classification

TASC A TASC B

Aortoiliac Unilateral or bilateralstenoses of CIA

Unilateral or bilateral singleshort (#3 cm) stenosisof EIA

Short (#3 cm) stenosisinfrarenal aorta

Unilateral CIA occlusionSingle or multiple steno

totaling 3–10 cm invthe EIA, not extendinthe CFA

Unilateral EIA occlusioninvolving the originsinternal iliac or CFA

Femoral-popliteal Single stenosis #10 cm inlength

Single occlusion #5 cm inlength

Multiple lesions (stenosocclusions), each #5

Single stenosis orocclusion #15 cm, ninvolving theinfrageniculate poplartery

Heavily calcified occlusi#5 cm in length

Single popliteal stenosi

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

Multiple stenoses, eachcm in length, or totlength #10 cm, or socclusion #3 cm in lin the target tibial awith occlusion or stof similar or worse sein the other tibial ar

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

AAA ¼ abdominal aortic aneurysm; CFA ¼ common femoral artery; CIA ¼ comTASC ¼ Trans-Atlantic Inter-Society Consensus.

diffuse disease (TASC D). This preference for lessinvasive therapy is evidence based and driven byshorter length of stay (or treatment as an outpatiententirely) and lower periprocedural morbidity andmortality rates, while achieving comparable patencyrates (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 ACC/AHA PAD guidelines (2)recommended an endovascular-first approach foraortoiliac lesions, recommended that borderlinelesions be assessed with hemodynamic gradients, andsupported primary stent placement in the aortoiliacarteries (Table 4). The current expert consensusdocument from the Society for Cardiac Angiographyand Interventions (SCAI) on appropriate use criteria(AUC) for aortoiliac intervention are similar to thecurrent guidelines (95).

CLINICAL TRIAL UPDATE. The results of the CLEVERtrial were discussed previously in the section onexercise. BRAVISSIMO (Belgian-Italian-Dutch TrialInvestigating Abbott Vascular Iliac Stents in the

TASC C TASC D

of

sesolvingg into

notof

Bilateral CIA occlusionsBilateral EIA stenoses 3–10 cm

long, not extending intothe CFA

Unilateral EIA stenosisextending into the CFA

Unilateral EIA occlusion thatinvolves the origins ofinternal iliac and/or CFA

Heavily calcified unilateral EIAocclusion with or without

involvement of origins ofinternal iliac and/or CFA

Infrarenal aortoiliac occlusionDiffuse disease involving the

aorta and both iliac arteriesDiffuse multiple stenoses

involving the unilateral CIA,EIA, and CFA

Unilateral occlusions of both CIAand EIA

Bilateral occlusions of EIAIliac stenoses in patients with

AAA not amenable toendograft placement

es orcm

ot

iteal

on

s

Multiple stenoses orocclusions totaling>15 cm, with or withoutheavy calcification

Recurrent stenoses orocclusions after failingtreatment

Chronic total occlusions of CFAor SFA (>20 cm, involvingthe popliteal artery)

Chronic total occlusion ofpopliteal artery andproximal trifurcation vessels

#5alingleength,rteryenosisverityteries

Multiple stenoses in thetarget tibial artery and/orsingle occlusion with totallesion length >10 cm withocclusion or stenosis ofsimilar or worse severity inthe other tibial arteries

Multiple occlusions involvingthe target tibial artery withtotal lesion length >10 cm,or dense lesion calcificationor nonvisualization ofcollaterals; the other tibialarteries occluded or withdense calcification

mon iliac artery; EIA ¼ external iliac artery; SFA ¼ superficial femoral artery;

TABLE 4 Aortoiliac Guideline-Based Recommendations for

Stable Limb Ischemia (Claudication)

ACC/AHA PAD Guidelines (2006, 2011) ESC PAD Guidelines (2011)

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; and/or 2) there isa very favorable risk-benefit ratio (e.g.,focal aortoiliac occlusive disease) (Class I,Level of Evidence: A)

When revascularization is indicated, anendovascular-first strategy isrecommended in all aortoiliac TASC A–Clesions (Class I, Level of Evidence: C)

Translesional pressure gradients (with andwithout vasodilation) should be obtained toevaluate the significance of angiographiciliac arterial stenoses of 50% to 75%diameter before intervention (Class I, Levelof Evidence: C)

A primary endovascular approach may beconsidered in aortoiliac TASC D lesions inpatients with severe comorbidities, ifdone 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 ofEvidence: C)

ACC ¼ American College of Cardiology; AHA ¼ American Heart Association; ESC ¼ European Society ofCardiology; PAD ¼ peripheral artery disease; TASC ¼ Trans-Atlantic Inter-Society Consensus.


1349

Treatment of TASC A, B, C, and D Iliac Lesions) re-ported 100% technical success in 325 patients withaortoiliac lesions with a 24-month primary patencyrate of 87.9% (96). Neither TASC category nor lesionlength was predictive of restenosis. These datafurther support the endovascular-first strategy,regardless of TASC classification, and take intoconsideration the evolution of devices (i.e., re-entrycatheters, crossing devices, and stents), whichimprove success rates for the most complex lesions.

COMMON FEMORAL DISEASE

Patients with common femoral artery (CFA) diseaseare particularly symptomatic because the obstructionnot only occurs proximal to the superficial femoralartery (SFA) but also proximal to the deep femoralartery (profunda femoris), which is the major collat-eral artery supplying blood to the lower limb whenthere is SFA obstruction. Traditionally, commonfemoral endarterectomy has been the CFA revascu-larization procedure of choice (2,3), althoughadvances in endovascular therapy have shown somepromising results (97). A review of the National Sur-gical Quality Improvement Program database for 2005to 2010 found a combined mortality and morbidityrate of 15% for common femoral endarterectomy,which was higher than expected (98). Patientsrequiring CFA revascularization who are at increasedsurgical risk may be considered for less invasiveendovascular options.

FEMORAL-POPLITEAL DISEASE

This segment begins at the bifurcation of the CFA intothe SFA and the deep femoral (profunda femoris)artery. The SFA is subject to flexion, elongation,compression, and torsion unlike any other lower-extremity artery. This complexity leads to manychallenges for endovascular technology, but despitethis, an endovascular-first approach is currently thestandard of therapy for the majority of lesionsbecause of the very high procedural success rate andlow risk (3). Some of the most lengthy and complexlesions (TASC D) are more approachable because ofthe re-entry and crossing devices, more experiencedoperators, drug-eluting stents (DES) (99,100), anddrug-coated balloons (DCBs) (101–107) that promiseimproved long-term patency for patients with clau-dication (99,100,103,105).


GUIDELINES). The ACC/AHA (2006, 2011) and ESC(2011) PAD guidelines and the AUC documentfrom the SCAI recommend revascularization in

femoral-popliteal lesions for patients with CLI or forpatients with claudication who have had a suboptimalresponse to a trial of exercise (Table 5). Anendovascular-first approach is recommended forTASC A through C lesions and is a reasonable optionfor TASC D lesions, depending on the experience ofthe operator, the patient’s comorbidities, and proce-dure safety (Table 5) (2,3,95).

The 2 guidelines are in conflict over the use ofprimary stent placement in the femoral-popliteal ar-teries, with the ACC/AHA guideline giving it a Class IIIrecommendation (do not do) and the ESC guidelinemaking primary femoral stenting reasonable first-linetherapy (Class IIa) for intermediate-length lesions(108,109). The current evidence from several ran-domized controlled trials supports primary stentingin intermediate-length femoral stenoses and occlu-sions (108–110). The soon-to-be-published updatedACC/AHA guidelines will readdress this issue. Incurrent practice, the standard is to primarily stentintermediate to long SFA lesions.

The ACC/AHA guideline broadly lump stentstogetherwith atherectomydevices, cryotherapy, laser,and cutting balloons, stating they may be useful assalvage therapy (Class IIa), but also stating that theireffectiveness remains to proven (Class IIb). Stentsshould be removed from this group, because theireffectiveness 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

TABLE 5 Femoral-Popliteal Guideline Based Recommendations for

Stable Limb Ischemia (Claudication)


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

When revascularization is indicated, anendovascular-first strategy isrecommended in all femoropoplitealTASC A–C lesions (Class I, Level ofEvidence: C)

Stents (and other adjunctive techniques such aslasers, cutting balloons, atherectomy devices,and thermal devices) can be useful in thefemoral, popliteal, and tibial arteries as salvagetherapy for a suboptimal or failed result fromballoon dilation (e.g., persistent translesionalgradient, residual diameter stenosis >50%, orflow-limiting dissection) (Class IIa, Level ofEvidence: C)

Primary stent implantation should beconsidered in femoropopliteal TASCB lesions (Class IIa, Level ofEvidence: 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) (ClassIIb, 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 ofEvidence: C)

Primary stent placement is not recommended in thefemoral, popliteal, or tibial arteries (Class III,Level of Evidence: C)

Endovascular intervention is not indicated asprophylactic therapy in an asymptomatic patientwith lower-extremity PAD (Class III, Level ofEvidence: C)

Abbreviations as in Table 4.



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evidence suggesting that the more expensive athe-rectomy devices, cryoplasty, or laser angioplastyshould be preferred over conventional therapy(percutaneous transluminal angioplasty [PTA] andbare-metal stents [BMS]). The ESC guideline distin-guishes bare-metal self-expanding stents fromadjunctive devices, such as atherectomy devices, cit-ing the proven benefit of BMS over PTA inintermediate-length femoral-popliteal lesions.

CLINICAL TRIAL UPDATE. Three randomized controlledtrials of self-expanding BMS compared with PTA haveshown that the advantage for primary stenting isrelated to lesion length. For relatively discrete lesions(mean 45 mm) (110), there was no advantage for pri-mary stent placement; however, 2 other trials(108,109) with longer lesions (>70 mm) showed asignificant patency and functional benefit for primaryfemoral-popliteal BMS (Figure 3, Table 6). The proce-dural success rate of endovascular therapy infemoral-popliteal lesions is very high, but in stablelimb ischemia, durable patency remains a barrier.Cilostazol has been shown to reduce 1-year restenosisby more than one-half (20% vs. 49%, p ¼ 0.0001) in

intermediate-length (128 mm) femoral lesions treatedwith self-expanding BMS (114). These results need tobe confirmed before this can be recommended asstandard therapy.

Recent randomized controlled trials demonstratingbenefit for DES (99,100), DCB (103,105,106), andcovered stents (115–117) in femoral-popliteal arterieswill likely result in a change in the guidelines andindications (Table 6, Figure 3).

There has been some enthusiasm for self-expandingcovered (expanded polytetrafluoroethylene) stentgrafts in complex or lengthy femoral-popliteal seg-ments. Two randomized trials comparing coveredstents to BMS had divergent results. One showed abenefit for 2-year primary patency but no difference intarget-lesion revascularization (TLR) or clinical out-comes (116), whereas the other, in longer (>8 cm) le-sions, found no difference for primary patency (115–117). When covered stents were compared withabove-the-knee femoral bypass with synthetic graftmaterial in a broad range of SFA lesion types (TASC Athru D), no difference was found in the 4-year primarypatency between the 2 options (118).

The Zilver paclitaxel-eluting self-expanding DESwas superior to PTA in a randomized femoral-popliteal trial, with 1-year patency rates of 83.1% forprimary DES and 32.8% for PTA (p < 0.001) (Figure 3,Table 6) (99). There was also a 1-year patencyadvantage for provisional DES after failed PTA(89.9%) compared with provisional BMS (73.0%,p ¼ 0.01). The benefit was sustained at 2 years, withprimary patency for the DES (74.8%) significantlybetter than PTA (26.5%, p < 0.01) (100). To date, therehas been no head-to-head comparison of primary DESto either BMS or DCB in femoral-popliteal arteries,but Zeller et al. (104) published a propensity score–based comparison of DES and DCB in consecutivepatients with TASC C and D long (>10 cm) lesions andfound no significant differences in 1-year patency(Figure 3, Table 6).

DCBs offer the promise of improved patency with areduced need for stents. This is particularly importantin the dynamic environment of the superficial femoraland popliteal arteries, where mechanical fatigue maylead to stent fracture and increased risk of in-stentrestenosis. Each DCB is unique with respect to thepaclitaxel dose (varying from 2 to 3.5 mg/mm2), thecarrier molecule (excipient), the balloon material, andthe coating technology used. Superiority for paclitaxelDCB over PTA was first reported in 2008 (101,102)(Figure 3, Table 6). Subsequently, new DCBs haveemerged, including the IN.PACT (105,106,111,113) andthe Lutonix (103,106) balloons, both of which showedclinical superiority to PTA in femoral-popliteal lesions

FIGURE 3 Relationship Between Target-Lesion Length and Patency in Comparative Femoral Popliteal Trials

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

Rest

enos

is (%

)

0 50 100 150 200Lesion Length (in MM)

FAST PTALesion length: 44.5Restenosis: 38.6%

FAST BMSLesion length: 45.2Restenosis: 31.7%

FEMPAC PTALesion length: 47Restenosis: 40%

PACIFIER PTALesion length: 66Restenosis: 32.4%

FEMPAC DCBLesion length: 40Restenosis: 17%

ZILVER DESLesion length: 66.4Restenosis: 16.9% PACIFIER DCB

Lesion length: 70Restenosis: 8.6%

THUNDER DCBLesion length: 75Restenosis: 24%

IN.PACT SFA DCBLesion length: 89.4Restenosis: 17.8%

ZILVER PTALesion length: 63.1Restenosis: 67.2%

ASTRON PTALesion length: 71Restenosis: 61.1%

THUNDER PTALesion length: 74Restenosis: 50%

IN.PACT SFA PTALesion length: 88.1Restenosis: 47.6%

ASTRON BMSLesion length: 98Restenosis: 34.4%

ABSOLUTE PTALesion length: 127Restenosis: 63.5%

ABSOLUTE BMSLesion length: 132Restenosis: 31.7%

VIASTAR BMSLesion length: 127Restenosis: 63.0%

VIASTAR CSLesion length: 132Restenosis: 37.0%

ZELLER DCBLesion length: 194Restenosis: 23.9%

ZELLER DESLesion length: 195Restenosis: 30.4%

TABLE 6 Comparative Femoral-Popliteal Trials

Clinical Trial Name (Ref. #) Device N Lesion length (mm) Restenosis (%) IC/CLI (%) TLR (%) De Novo (%) Occlusions (%) RVD (mm)

FAST (110) PTA 121 45 � 28 38.6 96.5/3.5 18.3 59.5 24.8 5.1

BMS 123 45 � 27 31.7 97.5/2.5 14.9 65.9 36.6 5.3

ABSOLUTE (108) PTA 53 92 � 75 63.0 87/13 31 100 32 NR

BMS 51 101 � 75 37.0* 88/12 28 100 37 NR

ASTRON (109) PTA 39 65 � 46* 61.1 97/3 NR 100 39 NR

BMS 34 82 � 67 34.4* 91/9 NR 100 38 NR

ZILVER (100) PTA 238 63 � 41 67.2 90.7/8.5 17.5 24.7 NR NR

DES 241 66 � 39 16.9* 90.2/8.9 9.5* 29.6 NR NR

Zeller (104) DES 97 195 � 65 30.4 91.7/7.2 21.5 55.7 62.9 NR

DCB 131 194 � 86 23.9 81/16.8 19.3 48.1 52.7 NR

THUNDER (111) PTA 54 74 � 67 44.0 NR 48 30 26 4.7

DCB 48 75 � 62 17.0* NR 10 38 27 5.2

FEMPAC (102) PTA 42 47 � 42 47.0 93/7 17 34 19 5.1

DCB 45 40 � 44 19.0* 96/4 7 35 13 5.2

IN.PACT SFA (112) PTA 111 88 � 51 47.6 93.7/6.3 20.6 94.6 19.5 4.68

DCB 220 89 � 48 17.8* 95/5.0 2.4* 95 25.8 5.0

LEVANT-2 (106) PTA 160 63 � 40 47.4 91.9/8.1 37.5 87.5 21.9 4.8

DCB 316 63 � 41 34.8* 92.1/7.9 38 83.9 20.6 4.8

PACIFIER (113) PTA 47 66 � 55 32.4 95.7/4.3 21.4 82.9 38.3 4.9

DCB 41 70 � 53 8.6* 95.5/4.5 7.1 68.2 22.7 4.96

*p < 0.05.

ABSOLUTE ¼ Balloon Angioplasty Versus Stenting With Nitinol Stents in the Superficial Femoral Artery; ASTRON ¼ Balloon angioplasty versus stenting with nitinol stentsin intermediate length superficial femoral artery lesions; BMS ¼ bare-metal stent; CLI ¼ critical limb ischemia; CS ¼ covered stent; DCB ¼ drug-coated balloon; DES ¼ drug-eluting stent; FAST ¼ The Femoral Artery Stenting Trial; FEMPAC ¼ Femoral Paclitaxel Trial; IC ¼ intermittent claudication; IN.PACT SFA ¼ Randomized Trial of IN.PACT(Paclitaxel) Admiral Drug-Coated Balloon (DCB) vs. Standard Percutaneous Transluminal Angioplasty (PTA) for the Treatment of Atherosclerotic Lesions in the SuperficialFemoral Artery (SFA) and/or Proximal Popliteal Artery (PPA); LEVANT-2 ¼ The Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis; NR ¼ notreported; PACIFIER ¼ Paclitaxel-coated Balloons in Femoral Indication to Defeat Restenosis; PTA ¼ percutaneous transluminal (balloon) angioplasty; RVD ¼ reference vesseldiameter; THUNDER ¼ Local Taxan With Short Time Contact for Reduction of Restenosis in Distal Arteries; TLR ¼ target-lesion revascularization; ZELLER ¼ Drug-coatedballoons vs. drug-eluting stents for treatment of long femoropopliteal lesions; ZILVER ¼ PTX Randomized Trial.


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TABLE 7 Tibial-Peroneal (Below-Knee) Guideline-Based Recommendations

for CLI


For individuals with combined inflow andoutflow disease with CLI, inflow lesionsshould be addressed first (Class I, Levelof Evidence: C)

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

For infrapopliteal lesions,angioplasty is the preferredtechnique, and stentimplantation should beconsidered only in the caseof insufficient PTA (Class IIa,Level of Evidence: C)

The effectiveness of uncoated/uncoveredstents, atherectomy, cutting balloons,thermal devices, and lasers for thetreatment of infrapopliteal lesions(except to salvage a suboptimal resultfrom balloon dilation) is not wellestablished. (Class IIb, Level ofEvidence: C)

When revascularization in theinfrapopliteal segment isindicated, the endovascular-first strategy should beconsidered (Class IIa, Levelof 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 (e.g.,ABI <0.4) in the absence of clinicalsymptoms of CLI (Class III, Level ofEvidence: C)

ABI ¼ ankle-brachial index; other abbreviations as in Table 6.



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and excellent safety profiles (Figure 3, Table 6). Thedurability of a paclitaxel-eluting DCB in the SFA hasbeen demonstrated at 2 and 5 years (107,111). At 2 years,patients treated with DCB showed significantly higherprimary patency than those treated with PTA (78.9%vs. 50.1%; p < 0.001), including lower clinically drivenTLR and similar functional status improvement, withfewer repeat interventions. Five-year follow-updemonstrated that TLR remained significantly lower inthe DCB group (21%) than for PTA (56%, p ¼ 0.0005)(117). The TLR benefit in femoral-popliteal arteries wasindependent of lesion length. There have been nosafety concerns raised for DCB regarding aneurysmformation or fibrotic constriction.

TIBIAL-PERONEAL DISEASE

Infrapopliteal or below-the-knee disease begins withthe popliteal artery at the knee joint and continuesto the tibial and peroneal arteries to the ankle.Revascularization is indicated in patients with CLIand, rarely, for those with claudication. The BASIL(Bypass Versus Angioplasty in Severe Ischaemiaof the Leg) trial compared PTA (balloon alone) tosurgery in 452 CLI patients and found no differencefor amputation-free survival but a lower cost withPTA(119).

In general, nonambulatory patients with a short-ened life expectancy and extensive lower-extremitytissue necrosis should undergo amputation. Patientswho have the opportunity to regain ambulatoryfunction should undergo magnetic resonance angi-ography, computed tomography angiography, orcatheter-based angiography to visualize the extent oflower-extremity vascular disease. The goal forrevascularization in patients with CLI is to establishstraight-line flow from the hip to the foot.


GUIDELINES). The ACC/AHA (2006, 2011) and ESC(2011) PAD guidelines agree that an endovascular-firstapproach is reasonable in patients with CLI andinfrapopliteal arterial disease (Table 7) (2,3). In can-didates for endovascular treatment, both guidelinessupport PTA as the initial approach, with the use ofBMS as needed for bailout lesions (Table 7) (2,3). Theguidelines, however, have lagged behind the mostrecent evidence demonstrating that DES and DCBs aresuperior to angioplasty alone and BMS for infrapo-pliteal disease (Table 8).

The expert consensus infrapopliteal AUC documentfrom the SCAI supports endovascular interventionfor patients with severe claudication and focal targetlesions, as well as for anatomically suitable lesionsin patients with CLI (RC 4 to 6) (126). Endovasculartherapy may be appropriate in patients with moderateto severe claudication with occlusions or diffuse dis-ease of 2 or 3 infrapopliteal vessels and for ischemicrest pain or minor tissue loss with 1- or 2-vesselinfrapopliteal disease. It would rarely be appropriateto perform infrapopliteal intervention for mild clau-dication (RC 1) or for moderate to severe claudicationwith major tissue loss for single-vessel infrapoplitealobstruction (i.e., 2 vessels are patent to the foot).

CLINICAL TRIAL UPDATES. There have been 4 ran-domized trials (Table 8) (120–122,125,127) demon-strating superiority for infrapopliteal DES versuseither PTA, BMS, or DCB. These data provideconvincing evidence favoring infrapopliteal DES overPTA, BMS, or DCB for: 1) patency; 2) reduced rein-terventions; 3) reduced amputation; and 4) improvedevent-free survival. These results are not limited topatients with CLI, because most trials have includedpatients with severe claudication. It would beappropriate to revise the guideline statements infavor 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 forBelow the Knee Angioplasty Evaluation) trial ran-domized 158 infrapopliteal lesions in diabetic

TABLE 8 Comparative Tibial-Peroneal Trials

Clinical Trial Name (Ref. #) Device N Lesion length (mm) Restenosis (%) IC/CLI (%) TLR (%) De Novo (%) Occlusions (%) RVD (mm)

ACHILLES (120) PTA 101 27 � 21 42.9 NR 16.5 98.2 75.4 2.6

DES 99 27 � 21 22.4* NR 10.0 94.7 81.3 2.6

DESTINY (121) BMS 66 19 � 10 36.0 0/100 35.0 100 17.0 2.9

DES 74 16 � 10 17.0 0/100 8.0* 100 15.0 3.0

YUKON-BTX (122) BMS 79 31 � 9 44.4 58.2/41.8 17.5 100 21.5 3.0

DES 82 30 � 8 19.4* 48.8/51.2 9.7 100 23.2 3.0

DEBATE-BTK (123) PTA 67 131 � 79 74.0 0/100 43.0 NR 82.1 2.9

DCB 65 129 � 83 27.0* 0/100 18.0 NR 77.5 2.9

IN.PACT DEEP CLI (124) PTA 119 129 � 95 35.5 0.8/99.2 13.1 88.2 45.9 12.9

DCB 239 102 � 91 41.0 0/100 9.2 77.2 38.6 10.2

IDEAS (125) DCB 25 148 � 57 57.9 NR 13.6 NR 12.0 NR

DES 27 127 � 47 28.0* NR 7.7 NR 23.0 NR

*p < 0.05.

ACHILLES ¼ Comparing Angioplasty and DES in the Treatment of Subjects With Ischemic Infrapopliteal Arterial Disease; DEBATE-BTK ¼ Drug-Eluting Balloon in PeripheralIntervention for Below the Knee Angioplasty Evaluation trial; DESTINY ¼ Drug Eluting Stents in the Critically Ischemic Lower Leg; IDEAS ¼ Infrapopliteal Drug Eluting An-gioplasty Versus Stenting for the Treatment of Long-segment Arterial Disease: The IDEAS-I Randomized Controlled Trial; IN.PACT DEEP CLI ¼ Randomized Study of IN.PACTAmphirion� Drug Eluting Balloon vs. Standard PTA (Percutaneous Transluminal Angioplasty) for the Treatment of Below the Knee Critical Limb Ischemia; YUKON-BTX ¼YUKON-drug-eluting Stent Below The Knee - Prospective Randomized Double-blind Multicenter Study; other abbreviations as in Table 6.


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patients with CLI to either DCB (In.Pact Amphirion,Medtronic, Minneapolis, Minnesota) or PTA (123). Themean lesion length was 129 � 83 mm, significantly(w100 mm) longer than those in the infrapoplitealDES randomized trials. The primary endpoint, reste-nosis at 1 year, occurred in 27% of patients in the DCBgroup and 74.3% of those in the PTA group(p < 0.001). Twelve-month major adverse eventsoccurred less frequently in the DEB (31%) than in thePTA (51%) group (p ¼ 0.02), driven mainly by areduction 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 In.Pact Deep CLI trialresulted in the DCB (In.Pact 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 2:1 to DCB andPTA, respectively. The restenosis rate and TLR werenot different between the 2 groups. There was anonsignificant trend toward higher amputation ratesin the DEB (8.8%) compared with the PTA group(3.6%, p ¼ 0.08). It seems clear that more data andmore experience are needed to understand the rela-tive benefits of DEB for infrapopliteal lesions (124).

In practical terms, an endovascular-first approachis the current standard of care for symptomaticinfrainguinal atherosclerotic disease. Adverse peri-procedural events with endovascular therapy forthe treatment of infrapopliteal disease appear to below, with mortality rates in observational series <1%.The recent technological advances of DES and DEBswill strengthen this consensus recommendation. The

BEST-CLI (Best Endovascular Versus Best SurgicalTherapy in Patients With CLI) trial has just beenlaunched and will answer the question of whethersurgery in selected patients with CLI and withgood-quality saphenous veins is a better choice thanendovascular therapy (128).

THE FUTURE OF ENDOVASCULAR THERAPY

The emphasis on value-based care that offers theright procedure for the right patient at the right timerequires justification of expensive devices in thecontext of cost-conscious medical care. Unfortu-nately, we often lack head-to-head comparative datato determine which device or strategy is preferred forspecific clinical situations. It is reasonable to chooselower-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 byreducing (but not eliminating) variation in clinicalpractice. Essentially, AUC offer care pathways thatare meant to offer guidance. It is recognized thatdeviation from the care pathway will be the rightthing to do in specific cases. Responsible cliniciansshould be able to articulate their reasons for deviatingfrom the “appropriate” care pathway, thereby navi-gating the Scylla and Charybdis of cost-effectivenessand clinical necessity.

Independent accreditation of hospital facilities,such as noninvasive and invasive laboratories, is avaluable tool for benchmarking quality of care and



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reducing variation. Accreditation for CardiovascularExcellence (ACE) offers on-site reviews for cardiac,peripheral, carotid, electrophysiology, and congenitalheart disease. Importantly, accreditation must beindependent of professional societies, regulators,and payers to avoid bias. The value of accreditationis in establishing ongoing procedures to ensurequality and safety. When done properly, independentaccreditation functions more like a coach than apoliceman to promote a culture of continuousimprovement. Payers and regulators should requireor reward independent accreditation to supportvalue-based health care.

CONCLUSIONS

Despite the increased prevalence over the past 20years, PAD continues to be underdiagnosed andundertreated compared with CAD. Because mostdeaths in patients with PAD are attributable to car-diovascular disease, patients with PAD (even thosewho are asymptomatic) who are not diagnosed ortreated will needlessly experience MACE. There areeffective therapies to prevent cardiovascular events,

yet they are still not offered to a large percentage ofpatients with PAD. Additionally, there have beenmany advances in minimally invasive techniques toimprove the circulation to the lower extremities, andin the past decade, more physicians have becomecompetent to provide high-level care to patients withclaudication and CLI. The endovascular arena haschanged so dramatically over the past 5 years that it isdifficult for the guidelines to keep up with thesechanges. The goal for the future should be earlyidentification of the PAD patient so that progression toCLI and amputation can be prevented and appropriatetherapy to prevent MACE can be implemented. Theoptimal treatment of an individual patient involves acombination of exercise, pharmacological therapy,and revascularization (endovascular or open surgery).

REPRINT REQUESTS AND CORRESPONDENCE: Dr. JeffreyW. Olin, Vascular Medicine and Vascular DiagnosticLaboratory, Zena and Michael A. Wiener CardiovascularInstitute and Marie-Joseé and Henry R. Kravis Center forCardiovascular Health, Icahn School of Medicine atMount Sinai, One Gustave L. Levy Place, New York, NewYork 10029. E-mail: [email protected].

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KEY WORDS ankle-brachial index,claudication, drug-eluting stents,endovascular therapy, exercise therapy,vascular diseases

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