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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 67, NO.

11, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2015.12.049

THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Peripheral Artery Disease


Evolving Role of Exercise, Medical Therapy, and
Endovascular Options

Jeffrey W. Olin, DO,a Christopher J. White, MD,b Ehrin J. Armstrong, MD, MSC,c Daniella Kadian-Dodov, MD,a
William R. Hiatt, MDd

JACC JOURNAL CME

This article has been selected as the month’s JACC Journal CME activity, peripheral artery disease so as to decrease the likelihood of experiencing
available online at http://www.acc.org/jacc-journals-cme by selecting the a myocardial infarction, stroke, and cardiovascular death; 2) for your
CME tab on the top navigation bar. patients with claudication, counsel on lifestyle modifications to improve
their quality of life; and 3) diagnose patients with critical limb ischemia so
Accreditation and Designation Statement that they may be referred for revascularization to prevent amputation.

The American College of Cardiology Foundation (ACCF) is accredited by


CME Editor Disclosure: JACC CME Editor Ragavendra R. Baliga, MD, has
the Accreditation Council for Continuing Medical Education (ACCME) to
reported that he has no relationships to disclose.
provide continuing medical education for physicians.

The ACCF designates this Journal-based CME activity for a maximum Author Disclosures: Dr. Olin serves on the steering committee and

of 1 AMA PRA Category 1 Credit(s). Physicians should only claim credit scientific advisory board for Merck for the TRAP2 trial; serves on the

commensurate with the extent of their participation in the activity. international steering committee for the EUCLID Trial; and is a site
investigator for AstraZeneca. Dr. White serves on the research advi-
Method of Participation and Receipt of CME Certificate sory board for Lutonix and Surmodics. Dr. Armstrong is a consultant/
advisory board member for Abbott Vascular, Medtronic, Merck, Pfizer,
To obtain credit for JACC CME, you must:
and Spectranetics. Dr. Hiatt has received grant support for clinical
1. Be an ACC member or JACC subscriber.
trial research from AstraZeneca, Bayer, Janssen, GlaxoSmithKline,
2. Carefully read the CME-designated article available online and in this
ReNeuron, and the National Institutes of Health. Dr. Kadian-Dodov
issue of the journal.
has no relationships relevant to the contents of this paper to
3. Answer the post-test questions. At least 2 out of the 3 questions
disclose.
provided must be answered correctly to obtain CME credit.
4. Complete a brief evaluation.
Medium of Participation: Print (article only); online (article and quiz).
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CME Term of Approval

CME Objective for This Article: At the end of this activity the reader Issue Date: March 22, 2016
should be able to: 1) evaluate medical treatment options for patients with Expiration Date: March 21, 2017

From the aZena and Michael A. Wiener Cardiovascular Institute & Marie-Joseé 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-
Listen to this manuscript’s rado, and Veterans Affairs Eastern Colorado Health Care System, Denver, Colorado; and the dDepartment of Medicine, Division of
audio summary by Cardiology, University of Colorado School of Medicine, and CPC Clinical Research, Aurora, Colorado. Dr. Olin serves on the
JACC Editor-in-Chief steering committee and scientific advisory board for Merck for the TRAP2 trial; serves on the international steering committee for
Dr. Valentin Fuster. the EUCLID Trial; and is a site investigator for AstraZeneca. Dr. White serves on the research advisory board for Lutonix and
Surmodics. Dr. Armstrong is a consultant/advisory board member for Abbott Vascular, Medtronic, Merck, Pfizer, 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.
JACC VOL. 67, NO. 11, 2016 Olin et al. 1339
MARCH 22, 2016:1338–57 Management of Patients With Peripheral Artery Disease

Peripheral Artery Disease


Evolving Role of Exercise, Medical Therapy, and
Endovascular Options

ABSTRACT

The prevalence of peripheral artery disease (PAD) continues to increase worldwide. It is important to identify patients
with PAD because of the increased risk of myocardial infarction, stroke, and cardiovascular death and impaired quality of
life because of a profound limitation in exercise performance and the potential to develop critical limb ischemia. Despite
effective therapies to lower the cardiovascular risk and prevent progression to critical limb ischemia, patients with PAD
continue to be under-recognized and undertreated. The management of PAD patients should include an exercise
program, guideline-based medical therapy to lower the cardiovascular risk, and, when revascularization is indicated,
an “endovascular 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 the
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-
last iteration of the guidelines focused on PAD (2–4), idemia (5,9,10,12,13). Smoking and diabetes are
published data have emerged that may alter the stan- particularly virulent and are associated with worse
dard of care for this high-risk patient group. This re- outcomes, independent of other risk factors (14).
view will delve in great detail into the management Identification of patients with PAD is important
of PAD patients, highlighting the roles of exercise, because there is a 3- to 4-fold increased risk of car-
optimal medical management, and endovascular diovascular events, even in the setting of asymp-
therapy. Surgical revascularization will not be dis- tomatic disease (15). At 5 years, approximately 1 of 5
cussed because current expert consensus documents patients with PAD will experience a nonfatal cardio-
recommend an “endovascular first” approach for the vascular event, and 15% to 20% will die (most of
majority of PAD patients requiring revascularization cardiovascular causes) (8,16).
(2,3). Most patients with PAD fall into 1 of 3 groups:
Despite initiatives to improve on the identification classic claudication (10% to 30%), atypical leg pain
and management of PAD (2,5), the number of people (20% to 40%), or asymptomatic (nearly 50%). Formal
affected and disease morbidity continues to rise. As testing to assess functional capacity and endurance
of 2010, more than 200 million people worldwide are shows significant impairment in patients with PAD,
living with PAD, which represents a 28.7% increased even if asymptomatic. Although the majority of pa-
prevalence in low- and middle-income countries and tients report leg symptoms other than classic claudi-
a 13.1% increase in high-income countries over a cation, greater functional decline is associated with
10-year period (6,7). Prevalence studies in the United greater severity of disease, lower baseline ankle-
States estimate that 5.9% of Americans over 40 years brachial index (ABI), and increased numbers of
of age have PAD (8). When specific high-risk pop- cardiovascular events (17–20). In patients with CLI,
ulations are evaluated, estimates of PAD prevalence outcomes are dire: at 1 year, 10% will experience a
are as high as 30% (9). The prevalence and severity of fatal cardiovascular event, and 25% will undergo limb
PAD is increased in African Americans and Hispanics amputation (2).
(10). A recent retrospective cohort study evaluating Patient-reported symptoms underestimate PAD
nearly 12 million insured American adults reported prevalence, and the physical examination is not a
mean annual incidence rates of PAD and critical limb reliable tool for the identification of disease. Diag-
ischemia (CLI) of 2.35% and 0.35%, respectively (11). nosis and prevention of adverse outcomes may
1340 Olin et al. JACC VOL. 67, NO. 11, 2016

Management of Patients With Peripheral Artery Disease MARCH 22, 2016:1338–57

ABBREVIATIONS therefore be elusive, unless patients are are $50 years of age with a history of diabetes or
AND ACRONYMS identified with targeted diagnostic testing smoking (2–4,9,25). The goal is to identify and treat
(i.e., ankle-brachial index [ABI]) (21). The patients with increased cardiovascular risk. Despite
BMS = bare-metal stent
treatment of underlying cardiovascular risk these recommendations and the fact that nearly one-
CLI = critical limb ischemia
factors results in reduced morbidity and half of all PAD patients are asymptomatic, there is no
DAPT = dual-antiplatelet
mortality for patients with PAD, although this reimbursement for the performance of an ABI in the
therapy
population continues to be under-recognized absence of clinical symptoms of PAD. Alternative
DCB = drug-coated balloon
and undertreated for their cardiovascular risk diagnostic methods for PAD are beyond the scope of
DES = drug-eluting stent
(2,8). Among 7,458 participants with PAD in this review.
MACE = major adverse
the 1999 to 2004 NHANES (National Health Serum biomarkers have been used for risk predic-
cardiovascular event
and Nutrition Examination Survey) data, only tion and the detection of PAD (26). A combined
PAD = peripheral artery
disease
30.5% of subjects were taking statins, 24.9% biomarker profile that includes fasting glucose, high-
were taking angiotensin-converting enzyme sensitivity C-reactive protein, b2-microglobulin, and
QOL = quality of life
inhibitors (ACEI) or angiotensin receptor cystatin C demonstrated efficacy in the identification
SFA = superficial femoral
artery blockers, and 35.8% were administered of PAD and reclassification of cardiovascular risk
TASC = Trans-Atlantic Inter-
aspirin. Among patients with PAD (and no assessment by Framingham Risk Score in patients who
Society Consensus other clinical cardiovascular disease), use of would have otherwise been misidentified (27). The
multiple preventive therapies was associated BRAVO (Biomarker Risk Assessment in Vulnerable
with a 65% lower all-cause mortality (hazard ratio Outcomes) study evaluated 595 patients with PAD and
[HR]: 0.35; p ¼ 0.02) (8). followed them for 3 years. The primary outcome was
The diagnosis of PAD can be made using the ABI. ischemic heart disease events (myocardial infarction,
Using a handheld continuous-wave Doppler device, unstable angina, or ischemic heart disease death). Of
the ABI can be measured by taking the higher of the the 50 participants who had an event, the D-dimer was
2 systolic pressures in the dorsalis pedis and posterior higher 2 months before the event than the values 10
tibial artery in each leg and dividing by the higher of months, 12 months, 16 months 20 months, 26 months,
the brachial artery systolic blood pressures in each and 32 months before the event. There was no change
arm. An abnormal ABI is diagnostic for PAD (21). in the serum amyloid A or CRP 2 months before an
A normal ABI is between 1.00 and 1.40. An ABI #0.90 event (28). Although there is a clear association
demonstrates 90% sensitivity and 95% specificity for between various biomarkers and PAD, the overall
PAD and is the accepted threshold for diagnosis (2,21). clinical value related to patient outcomes remains
Values between 0.91 and 1.00 are considered border- unclear, and thus, there is no clinical benefit in
line; however, the cardiovascular event rate for an ABI measuring biomarkers at this time.
in this range is increased by 10% to 20% (21). At levels
>1.40, the identification of PAD is not accurate THE ROLE OF EXERCISE
because of the presence of arterial calcification and
noncompressibility of the blood vessels, a finding Patients with PAD have a profound limitation in
frequently encountered in the very elderly and in exercise performance that is related to a complex
those with diabetes and chronic kidney disease. In this pathophysiology (29). Although reduced exercise
setting, the toe-brachial index is used and considered performance is a hallmark of PAD, the symptomatic
abnormal when <0.70 (4,21). There is a strong and manifestations are quite varied, as described previ-
consistent relationship between an abnormal ABI and ously (30). Not surprisingly, patients with claudica-
the presence of coronary or cerebrovascular disease tion slow their walking pace and often avoid walking
(5,16,22). In addition, the ABI is a predictor of cardio- altogether. Thus, patients with PAD present with a
vascular morbidity and mortality independent of complex array of symptoms, health beliefs, and
clinical risk prediction scores such as the Framingham exercise limitations in their daily lives (31,32). These
Risk Score and other surrogate markers of systemic perceptions and attitudes must be addressed if a
atherosclerosis such as the coronary calcium score and treatment plan is to be successful.
carotid artery intimal-medial thickness (23). There is The overall goal in treating the exercise limitation
also a higher cardiovascular event rate in patients with from PAD is to improve exercise performance with a
PAD (even in asymptomatic patients) with known corollary improvement in quality of life (QOL) and
coronary artery disease (CAD) (24). functional status. In this regard, treatments that
Several consensus documents and practice guide- improve treadmill exercise performance, 6-min
lines recommend screening for the presence of PAD walking distance, and patient-related QOL can serve
using the ABI in patients $65 years old or those who as a basis for obtaining regulatory approval of a
JACC VOL. 67, NO. 11, 2016 Olin et al. 1341
MARCH 22, 2016:1338–57 Management of Patients With Peripheral Artery Disease

claudication therapy. In contrast, changes in limb and intensity of the walking exercise to inform the
hemodynamics, such as an improvement in the ABI or research staff and patient as to the patient’s exercise
imaging after a successful revascularization, serve prescription. One randomized trial combined the
only as surrogate measures of clinical benefit. activity monitor with a home-based program that
Exercise training has been a mainstay of treatment used the principles of a hospital-based supervised
for symptomatic PAD, with a well-established benefit program (43). Adherence to the home program was
after a typical 12-week exercise training program >80%, and the results on improvements in treadmill
(33,34). Exercise training directly modifies several exercise performance were comparable between
pathophysiological mechanisms in PAD, including home and supervised programs. A follow-up study
improved skeletal muscle metabolism, endothelial demonstrated similar results (44).
function, and gait biomechanics (35). McDermott et al. (45) have developed a coordinated
exercise program (group-mediated cognitive behav-
SUPERVISED EXERCISE TRAINING IMPROVES MORBIDITY
ioral therapy) that includes weekly group sessions run
AND MORTALITY IN PAD. Individual single-site studies
by a trained facilitator. In a randomized controlled
and a meta-analysis of those studies demonstrate that
trial of 194 patients, subjects in the intervention group
a 12-week intervention of supervised exercise (SE)
improved their 6-min walking distance, peak treadmill
improves exercise performance and QOL in PAD (34).
exercise performance, and several measures of QOL
Supervised exercise is also more effective than a
and accelerometer-measured physical activity (46).
nonstructured community exercise program (36).
In addition, after 6 months, the intervention group
Physical activity in patients with PAD is associated
gained self-efficacy, satisfaction with functioning,
with decreased all-cause and cardiovascular mortality
pain acceptance, and social functioning, and these
(37,38). Standardized supervised training methods
benefits were sustained at the 12-month endpoint (47).
have been published previously (39).
At 12 months, fewer treated patients experienced
On the basis of current evidence, supervised
mobility loss, and treated patients also improved in
walking exercise gets a Class Ia recommendation and
walking velocity and QOL (48).
unsupervised exercise a Class IIb recommendation
It is apparent that many of the exercise methods
(2). Despite clear evidence of benefit, SE programs
discussed are effective in improving walking distance
have not been accepted by payers, providers, or
with less discomfort and improved QOL; however,
patients for a variety of reasons, including questions
they all require resources that are not available in
of long-term adherence and the benefit of exercise as a
many communities, especially those in the lowest
lifestyle intervention, coupled with the desire by most
socioeconomic class. Although a simple recommen-
patients and vascular physicians for a more immedi-
dation between the physician and the patient to exer-
ate approach to relieving claudication with endovas-
cise is usually ineffective, the physician can provide
cular therapy (40). Therefore, SE training programs
a comprehensive exercise prescription (Table 1) on
for claudication are very limited and not reimbursed.
how to structure a home exercise program (50,51).
HOME-BASED EXERCISE DATA AND GENERALIZABILITY This is not a 1-time recommendation but an ongoing
OF THE FINDINGS. The methodology to provide a discussion between the physician and the patient
community (home)-based exercise intervention has in an attempt to change patient behavior. Patients
improved considerably over the past decade, and who are compliant with such a program often experi-
these exercise training methods have provided ence considerable improvement in walking distance
encouraging results. and QOL.
The least resource-intensive home-based program STUDIES ON EXERCISE VERSUS ENDOVASCULAR
can employ education and behavioral interventions THERAPY: ARE WE ASKING THE RIGHT QUESTIONS?
that prepare patients for exercise training (41). Several studies have compared an SE program to
Notably, adherence to a community program may be revascularization in patients with PAD and
poor without proper motivation and engagement. exercise-limiting claudication (52,53). Given the
There are a number of new devices that monitor tremendous expansion and effectiveness of endovas-
the intensity and duration of an exercise session cular treatments for symptomatic PAD, as well as
performed in the home environment. A pilot study patient reluctance to enter an exercise-lifestyle treat-
that used a program of training, monitoring, and ment program (as discussed previously), the most
coaching had encouraging results in a subgroup of prudent approach would be to include both modalities
subjects but was too small to definitively establish the in the treatment plan: exercise and revascularization.
benefits of the interventions (42). Two larger trials In fact, both exercise training and revascularization
used a step activity monitor to record the duration can greatly improve patient exercise performance
1342 Olin et al. JACC VOL. 67, NO. 11, 2016

Management of Patients With Peripheral Artery Disease MARCH 22, 2016:1338–57

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


T A B L E 1 A Practical Home Exercise Program for Patients
With PAD
follow up, the primary endpoint of peak walking
time on a graded treadmill test was significantly
Frequency
3-5 days per week
improved in both the exercise and stent groups
Modality compared with optimal medical management, but the
Treadmill (this program can be adapted for walking outside) peak walking time was significantly higher in the
Method exercise group than in the stent group (52). The sec-
1. Begin at 2 mph and a grade of 0 (flat) ondary endpoints were changes in responses to QOL
2. Try not to hold onto the treadmill. Use the side panels for balance
questionnaires. Both of these patient-reported out-
only.
3. Stop the treadmill completely when pain is 3–4 on claudication comes were improved with exercise or stenting over
discomfort scale* optimal medical management; however, improve-
4. When the discomfort has ceased, resume exercise at the same ments tended to be greater in the stenting group. The
intensity
same endpoints were measured at 18 months of
5. Repeat rest/exercise cycles
6. Progress to a higher workload when you can walk for 8 min follow-up (55). In 79 of 119 patients who completed
without having to stop for leg symptoms the study, improvements in treadmill peak walking
a) Increase speed by 0.2 mph each time you can walk for 8 min time remained for both the exercise and stenting
b) Once you are able to walk at 3.4 mph, or reach a speed at which
you can no longer keep up, begin increasing the grade by 1%
groups over optimal medical therapy, but the differ-
Duration ences in peak walking time between the exercise and
The total exercise period, including rest periods, should equal stenting groups were no longer statistically signifi-
45 min per day cant. Improved patient-reported outcomes remained
Tips for success
for both the exercise and stent groups.
1. Do not continue walking past 3–4 on claudication pain/discomfort
scale. This way the pain/discomfort should go away in 2–5 min. If CLEVER clearly established the independent, long-
you walk until you are in severe pain, you will build up lactic acid term, and broad-based benefits of both exercise
in your muscles, and it will take much longer for the pain to go
away. training and stent revascularization in symptomatic
2. When at 3–4 on pain/discomfort scale, stop walking completely. PAD. Similar to many such trials, of the nearly 1,000
Do not slow down, but stop and stand on the treadmill until the
patients evaluated, only 11% were randomized, and
discomfort is gone.
This works if you do it! Not only will this improve your walking
fewer were available for 18-month follow-up. Unfor-
performance, decrease your discomfort, and improve your tunately, the arm of CLEVER that would have tested
quality of life, this type of program is also beneficial for your
heart, blood pressure, and lipid (cholesterol and triglyceride)
the combination of exercise plus stenting was drop-
levels. ped because of poor enrollment.
In the recently published ERASE (Endovascular
*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 or Revascularization and Supervised Exercise) trial,
discomfort. Adapted from Weinberg et al. (49). 106 patients were randomized to both endovascular
PAD ¼ peripheral artery disease.
therapy and SE and 106 patients to SE alone (56). After
1 year, the combination group had greater improve-
and QOL, but by very different mechanisms. Revascu- ment in maximum walking distance (MWD) and
larization primarily improves exercise blood flow, health-related QOL scores than the group randomized
whereas exercise training does not (29). In contrast, to SE alone; however, both groups demonstrated
exercise training induces a variety of adaptive re- dramatic improvement in MWD, pain-free walking
sponses, including improved skeletal muscle mito- distance, and QOL. The supervised exercise group
chondrial oxidative metabolism, improved endothelial increased MWD from 285 m to 1,240 m, for an
function, and more efficient biomechanics of walking. improvement of 955 m. The combination group
Thus, the obvious “best” treatment strategy would increased MWD from 264 m to 1,501 m, for an
appear to be the combined program, utilizing endo- improvement of 1,237 m. This study illustrates
vascular revascularization and an optimal home-based 2 important points: 1) the combination of endovascular
and long-term exercise program. This hypothesis therapy and SE is the most effective therapy for many
was initially tested more than 25 years ago, and the patients with claudication; and 2) even the group
combination of bypass surgery and exercise training randomized to SE alone showed marked improvement
was superior to either treatment alone (54). in MWD, pain-free walking distance, and QOL (56).
The CLEVER (Claudication: Exercise Versus Endo- The cost of therapy must also be considered when
luminal Revascularization) study was an important planning a particular strategy to treat symptomatic
and well-designed comparative effectiveness trial PAD. In a single-center Dutch randomized trial,
that compared the outcomes for stenting of aortoiliac endovascular revascularization had similar benefit
disease with SE on a background of optimal medical but higher total mean cumulative costs per patient
JACC VOL. 67, NO. 11, 2016 Olin et al. 1343
MARCH 22, 2016:1338–57 Management of Patients With Peripheral Artery Disease

CENTRAL I LLU ST RAT ION The Peripheral Artery Disease Prescription

Decrease the Risk of MI, Stroke, Improve Symptoms, Quality of Life,


and CV Death and Prevent Amputation

• Discontinue Tobacco Use • Discontinue Tobacco Use

• Walking Program • Walking Program

• Control Blood Pressure to Goal • Cilostazol


-ACE Inhibitor

• High-Dose Statin Therapy • Good Foot Care


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

• Antiplatelet Therapy • Revascularization

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

compared with a hospital-based exercise program compared with patients with CAD (8,59). Adherence
(57). Another study from a Dutch health-care database to these guidelines in real-world practice is associated
of 4,954 patients demonstrated that a stepped with improved outcomes (Figure 1), which empha-
approach of exercise therapy followed by endovas- sizes the benefit of multifactorial risk reduction in
cular revascularization was more cost-effective than this high-risk population (12). Performance measures
revascularization only (58). for PAD will help improve quality of care and may be
Thus, future studies should address not only the incorporated into future quality metrics (60).
clinical benefits but also the effectiveness of the
SMOKING CESSATION
combination of an exercise program and limb revas-
cularization. In this context, effectiveness pertains to
Smoking is a major risk factor for the development and
the ability of a treatment program to be utilized by a
progression of PAD. A multidisciplinary approach to
majority of appropriate patients in a community and
smoking cessation should be used, including group-
to achieve high adherence to the program, as well as
based programs and cognitive behavioral therapy.
that the desired improvements in functional out-
A recent study evaluated the association between
comes are obtained.
successful quitting after endovascular intervention
OPTIMAL MEDICAL THERAPY FOR and long-term outcomes (61). Among 739 patients
PATIENTS WITH PAD undergoing lower-extremity angiography, 28% were
active smokers at the time of endovascular interven-
Medical therapy for PAD should address treatment for tion. In the subsequent year, 30% of active smokers
limb-related outcomes (improve claudication symp- successfully quit. Those who remained off tobacco
toms and prevent CLI and amputation) and treatment had significantly lower 5-year mortality (14% vs. 31%)
to prevent major adverse cardiovascular events and improved amputation-free survival (81% vs.
(MACE; myocardial infarction, stroke, and cardio- 60%). Discontinuation of smoking is the most
vascular death) (Central Illustration). important lifestyle modification in preventing CLI,
Despite the recommendations from societal amputation, and MACE in patients with PAD. This
guidelines on the management of patients with PAD needs to be conveyed to the patient in an empathetic
(2), these patients continue to be undertreated and nonjudgmental way during every office visit. The
1344 Olin et al. JACC VOL. 67, NO. 11, 2016

Management of Patients With Peripheral Artery Disease MARCH 22, 2016:1338–57

which cilostazol improves claudication is not known


F I G U R E 1 Adherence to Guideline-Recommended Medical Therapies and
Outcomes in PAD
(63). A pooled analysis of all of the randomized
trials shows an improvement in absolute claudica-
tion distance of approximately 50% compared with
A
40

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


placebo (64). Although cilostazol appears to be safe
Major Adverse Cardiovascular Events, %

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


discontinuation at 3 years) because of adverse effects
30

including headache, palpitations, and diarrhea (65).


Because of its mechanistic similarity to other type III
20

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
10

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


maximum benefit from this drug (63).
<4 Guideline Therapies 4 Guideline Therapies Pentoxifylline is rarely used today to treat claudi-
0

cation because of a lack of efficacy compared with


0 6 12 18 24 30 36
cilostazol. Naftidrofuryl is a 5-HT2 antagonist that is
Follow-Up (Months)
Number at risk approved in Europe. In a pooled analysis involving
<4 Guideline 502 450 391 355 322 288 256
4 Guideline 237 222 207 180 156 143 123 888 patients randomized to naftidrofuryl, there was a
26% increase in pain-free walking compared with
B placebo (66). It is not available for use in the United
40

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


States.
Major Adverse Limb Events, %

ACEIs
30

ACEIs are associated with a significant reduction in


20

MACE among patients with PAD. These data are


derived primarily from the HOPE (Heart Outcomes
Prevention Evaluation) trial, which randomized 9,297
10

high-risk patients with vascular disease or diabetes


plus 1 other risk factor to ramipril 10 mg daily
<4 Guideline Therapies 4 Guideline Therapies or placebo. Among these, 1,966 patients with PAD
0

(42.3%) were randomized to ramipril and 2,085


0 6 12 18 24 30 36
Follow-Up (Months) (44.8%) to placebo. The primary outcome (myocardial
Number at risk
infarction, stroke, cardiovascular death) occurred in
<4 Guideline 502 306 240 201 175 142 125
4 Guideline 237 155 133 102 94 76 64 14.3% of those without PAD versus 22.0% of those
with PAD (67). In the 5,231 patients without PAD, the
Among patients with symptomatic peripheral artery disease (PAD) undergoing primary outcome was observed in 12.6% in the ram-
lower-extremity angiography, adherence to the guideline-recommended therapies of an ipril group and 14.9% in the placebo arm. In those with
antiplatelet agent, statin, angiotensin-converting enzyme inhibitor, and abstention from an ABI <0.6, the primary outcome occurred in 16.4% in
smoking is associated with a significant reduction in (A) major adverse cardiovascular
the ramipril arm versus 22% in the placebo arm. The
events and (B) major adverse limb events. Reproduced with permission from Armstrong
et al. (12). CI ¼ confidence interval; PAD ¼ peripheral artery disease.
cardiovascular benefit 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
VAPOR (Vascular Physician Offer and Report) trial is
possible class effect of ACEI/angiotensin receptor
currently evaluating methods to improve physician-
blockade among patients with PAD (69,70).
patient interactions to encourage patients with PAD
to abstain from smoking (62).
STATINS
PHARMACOTHERAPY TO IMPROVE
CLAUDICATION SYMPTOMS High-intensity statin medications are recommended
for all patients with PAD on the basis of the
Cilostazol is a type III phosphodiesterase inhibitor most recent American College of Cardiology (ACC)/
with a number of properties, but the mechanism by American Heart Association (AHA) guidelines, which
JACC VOL. 67, NO. 11, 2016 Olin et al. 1345
MARCH 22, 2016:1338–57 Management of Patients With Peripheral Artery Disease

emphasize cardiovascular risk over low-density lipo- trial compared low-dose aspirin with placebo in
protein targets (71). The majority of the data in sup- patients with a low ABI. Neither study demonstrated
port of statin use in patients with PAD are derived a reduction in fatal and nonfatal cardiovascular
from subset analysis of larger clinical trials. The events or revascularization with aspirin mono-
Medical Research Council/British Heart Foundation’s therapy, although both notably included low-risk
Heart Protection Study randomized 20,536 high-risk patients with borderline ABI (#0.99 in POPADAD
patients to simvastatin 40 mg daily or placebo (72). and #0.95 in AAA) (77,78).
All-cause mortality occurred in 12.9% of patients Consistent with these results, a meta-analysis
randomized to simvastatin and 14.7% randomized to specifically examined aspirin for PAD in 18 trials
placebo (22% relative risk reduction; p ¼ 0.0003). involving 5,269 patients. In patients taking aspirin
Observational studies have also confirmed the car- monotherapy, there was a nonsignificant reduction
diovascular and overall mortality benefit of statins in cardiovascular events (absolute event rate 8.2%
among patients with more advanced PAD, including vs. 9.6%; relative risk: 0.75; 95% confidence inter-
CLI (73). val [CI]: 0.48 to 1.18); however, there was a sig-
Recent data suggest that statin use is also associ- nificant reduction in nonfatal stroke (HR: 0.64; 95%
ated with a reduction in adverse limb outcomes, CI: 0.42 to 0.99; p ¼ 0.04) (76). In the last iteration
including amputation. In the REACH (Reduction of of the PAD guidelines (2), aspirin was a Class I,
Atherothrombosis for Continued Health) registry, Level of Evidence A recommendation among pa-
statin therapy was associated with a significant tients with symptomatic PAD, a Class IIa recom-
reduction in the combined endpoint of worsening mendation among patients with asymptomatic PAD
claudication, new CLI, new revascularization, or and an ABI <0.90, and a Class IIb indication among
amputation (74). The absolute 4-year event rates were asymptomatic patients with an ABI of 0.90 to 0.99
22.0% versus 26.2%, which emphasizes the high rate of (2). Some of these recommendations may change in
adverse limb events among patients with symptom- the upcoming revision of the ACC/AHA PAD prac-
atic PAD. Importantly, statin therapy was also associ- tice guidelines.
ated with a significant reduction in 4-year rates of
CLOPIDOGREL AND
ischemic amputation (3.8% vs. 5.6%). In an analysis of
DUAL-ANTIPLATELET THERAPY
Medicare claims data of patients undergoing lower-
extremity revascularization, statin use was associ-
Clopidogrel is indicated as an alternative to aspirin
ated with lower rates of amputation at 30 days,
for antiplatelet monotherapy among patients with
90 days, and 1 year (75). Single-center observational
PAD, although recent studies suggest that <20% of
data among patients with CLI suggest that statin
patients with PAD are prescribed clopidogrel in clin-
therapy is also associated with improved 1-year rates
ical practice (79). The data supporting clopidogrel use
of primary patency, secondary patency, and improved
are primarily based on the CAPRIE (Clopidogrel
limb salvage after endovascular intervention (73).
Versus Aspirin in Patients at Risk of Ischaemic
Patients with PAD should be prescribed a high-
Events) study, in which clopidogrel monotherapy was
intensity statin to reduce the risk of cardiovascular
associated with a small benefit compared with aspirin
events. In most studies, the rates of statin prescrip-
325 mg daily in the overall population, but there was a
tion were <75%, which emphasizes the importance of
23.8% relative risk reduction among the subgroup of
maximizing medical therapy among this high-risk
patients with symptomatic PAD (n ¼ 6,452; absolute
group of patients with advanced atherosclerotic
event rate 3.7% vs. 4.9% per year) (80).
disease (59).
Dual-antiplatelet therapy (DAPT) with low-dose
ANTIPLATELET THERAPY aspirin (75 to 162 mg daily) and clopidogrel 75 mg
daily was studied in the CHARISMA (Clopidogrel for
ASPIRIN. Aspirin has been a mainstay of drug ther- High Atherothrombotic Risk and Ischemic Stabiliza-
apy among patients with PAD; however, the data tion, Management, and Avoidance) trial, which
supporting aspirin use in patients with PAD have not included patients at high risk for atherothrombotic
been well substantiated (76,77). events. The overall results of this trial were not sig-
Recent studies investigating the benefit of aspirin nificant, although in subgroup analyses, there was a
among patients with asymptomatic PAD have yielded benefit of DAPT among patients with symptomatic
negative results. Both the POPADAD (Prevention of atherothrombosis (81). In an analysis of the 3,096 pa-
Progression of Arterial Disease and Diabetes) trial and tients in the trial with PAD, DAPT was associated with
the AAA (Aspirin for Asymptomatic Atherosclerosis) a lower rate of myocardial infarction (2.3% vs. 3.7%;
1346 Olin et al. JACC VOL. 67, NO. 11, 2016

Management of Patients With Peripheral Artery Disease MARCH 22, 2016:1338–57

HR: 0.63; 95% CI: 0.42 to 0.96; p ¼ 0.02) and hospital- monophosphate (cAMP) levels subsequently decrease,
ization for ischemic events (16.5% vs. 20.1%; HR: 0.81; which leads to increased platelet aggregation and
95% CI: 0.68 to 0.95; p ¼ 0.011) but not the overall release of further activating factors. Vorapaxar inhibits
composite primary endpoint (82). There was no dif- PAR-1, thereby significantly reducing thrombin-
ference between the groups in moderate, severe, or mediated platelet activation.
fatal bleeding, but there was an increase in minor The TRA 2  P-TIMI 50 trial (Thrombin Receptor
bleeding in the DAPT group. Antagonist for Secondary Prevention–Thrombolysis
In a recent propensity-matched observational in Myocardial Infarction Study Group) studied vor-
study among patients undergoing endovascular apaxar sulfate 2.5 mg daily versus placebo (ASA and/
intervention, there was a significant reduction in or clopidogrel therapy, at the investigators’ discre-
MACE among patients taking DAPT (adjusted HR: tion) among 26,449 patients with a recent myocardial
0.65; 95% CI: 0.44 to 0.96; p ¼ 0.03) compared with infarction, recent ischemic stroke, or symptomatic
those taking aspirin monotherapy (83). The discor- PAD. At 3 years, there was a significant reduction in
dant findings between this study and the CHARISMA the primary endpoint of MACE (absolute event rates:
trial may be explained by inclusion of a cohort 9.3% vs. 10.5%; HR: 0.87; 95% CI: 0.80 to 0.94;
with more advanced atherosclerotic disease under- p < 0.001) (79). After 2 years, the data and safety
going endovascular intervention, including >50% of monitoring board recommended stopping the study
patients with CLI. drug in the patient subgroup entered with prior
The CASPAR (Clopidogrel and Acetylsalicylic Acid ischemic stroke because of an increased risk of
in Bypass Surgery for Peripheral Arterial Disease) trial intracranial hemorrhage. Among the 3,787 patients
studied DAPT versus aspirin 75 to 100 mg daily among with PAD, the majority were treated with aspirin
patients undergoing below-knee surgical bypass for monotherapy plus vorapaxar or placebo. The reduc-
treatment of CLI (84). The primary endpoint of death, tion in MACE was not statistically significant in those
major amputation, index-graft occlusion, or revascu- assigned to vorapaxar (absolute event rates: 11.3% vs.
larization was not different for DAPT versus 11.9%; HR: 0.94; 95% CI: 0.78 to 1.14). Similarly
acetylsalicylic acid (ASA) monotherapy. In a pre- negative results were observed among patients with
specified subgroup analysis, there was a significant PAD who were enrolled in the TRACER (Thrombin
benefit of DAPT in patients treated with prosthetic Receptor Antagonist for Clinical Event Reduction in
grafts (HR: 0.65; 95% CI: 0.45 to 0.95; p ¼ 0.025) but Acute Coronary Syndrome) trial (86). Additionally,
not in those treated with vein grafts. A similar trial, vorapaxar is associated with a significantly increased
the CAMPER study (Clopidogrel and Aspirin in the risk of major bleeding. However, in both of these
Management of peripheral Endovascular Revascular- trials, there were relatively few MACE in the PAD
ization), tested DAPT versus aspirin in patients un- subgroup. The PAD group was underpowered to draw
dergoing infrainguinal endovascular therapy. The any conclusions on efficacy.
study was never completed because of poor enroll- Pre-specified analysis of limb-related outcomes in
ment (doctors would not randomize patients to ASA the TRA 2  P-TIMI 50 trial demonstrated that patients
alone); continued funding could not be justified. assigned to vorapaxar had significantly reduced rates
DAPT is often prescribed after endovascular inter- of acute limb ischemia (2.3% vs. 3.9%; HR: 0.58; 95%
vention, although the data supporting duration of CI: 0.39 to 0.86; p ¼ 0.006), as well as peripheral
DAPT are sparse. In practice, most physicians prescribe artery revascularization (18.4% vs. 22.2%; HR: 0.84;
DAPT for a time period ranging from 1 to 3 months post- 95% CI: 0.73 to 0.97; p ¼ 0.017) during the 3-year
intervention. The ASPIRE-PAD study (Antiplatelet follow-up (Figure 2) (87). These efficacy endpoints
Strategy for Peripheral Arterial Interventions for must be balanced by a significantly increased rate of
Revascularization of Lower Extremities) is currently major bleeding among patients prescribed vorapaxar.
evaluating comparative outcomes of 1 versus 12 Further research into the mechanism by which
months of DAPT after endovascular intervention (85). vorapaxar led to improved limb outcomes is required
to fully understand these effects.
VORAPAXAR
CELL-BASED AND ANGIOGENIC THERAPIES
Thrombin acts through platelets via a unique mecha-
nism: binding of the protease activating receptor-1 Modulation and enhancement of lower-extremity
(PAR-1), a G protein-coupled receptor expressed on blood flow via angiogenesis, arteriogenesis, or vas-
the platelet surface, leads to receptor activation culogenesis could provide a promising breakthrough
and increased intracellular Ca 2þ; cyclic adenosine therapy for patients with PAD (88). Additionally,
JACC VOL. 67, NO. 11, 2016 Olin et al. 1347
MARCH 22, 2016:1338–57 Management of Patients With Peripheral Artery Disease

there has been much interest in the use of stem cell–


F I G U R E 2 Limb-Related Events in Patients Treated With Vorapaxar
derived endothelial cells or modification of resident
stem cells (89). Potential benefits of these therapies
include improved wound healing and limb salvage
A Hospitalization for Acute Limb Ischemia
4.5%
Placebo Vorapaxar
among patients with CLI, as well as improved clau-
4.0%
dication distance. To date, numerous cell-based and
angiogenic therapies have been tested, and despite 3.5%
promising results in early clinical trials, none of these 3.0%

Event Rate (%)


agents have shown benefit in larger trials.
2.5%
ONGOING CLINICAL TRIALS
2.0%

There are currently 2 clinical trials studying novel 1.5%


antiplatelet and anticoagulant agents to reduce MACE 1.0% 2.3% vs. 3.9%
and potentially modify limb-related outcomes. HR 0.58 (0.39 – 0.86)
0.5% P=0.006
EUCLID (Study Comparing Cardiovascular Effects of
Ticagrelor and Clopidogrel in Patients With Periph- 0.0%
0 180 360 540 720 900 1080
eral Artery Disease) is a randomized, blinded, double-
Days Since Randomization
dummy trial comparing ticagrelor 90 mg twice daily
to clopidogrel monotherapy among 13,500 patients B Peripheral Revascularization
with PAD (90). All patients are tested for clopidogrel 25.0%
Placebo Vorapaxar
resistance before randomization. The primary
endpoint is a composite of MACE, and results are
20.0%
expected in late 2016. The COMPASS (Rivaroxaban for
the Prevention of Major Cardiovascular Events in
Event Rate (%)

Coronary or Peripheral Artery Disease) trial is evalu- 15.0%

ating low-dose rivaroxaban alone versus placebo,


aspirin alone, or rivaroxaban and aspirin among 10.0%
21,400 patients with a history of myocardial infarc-
18.4% vs. 22.2%
tion or PAD; the primary endpoint of this trial is a HR 0.84 (0.73 – 0.97)
composite of MACE (91). 5.0% P=0.017

ENDOVASCULAR THERAPY
0.0%
0 180 360 540 720 900 1080
Endovascular revascularization plays a key role in the Days Since Randomization
management of patients with PAD. Patients with sta-
ble claudication have a low risk of limb loss but may be In the TRA 2 P-TIMI 50 trial, patients randomized to vorapaxar had significantly lower
severely limited by their symptoms. In most circum- rates of (A) acute limb ischemia and (B) peripheral revascularization. Reproduced with
stances, patients with claudication should be offered a permission from Bonaca et al. (87). HR ¼ hazard ratio.

trial of cilostazol and an exercise program as initial


therapy. If the patient is not satisfied after a trial of
medical therapy, endovascular revascularization can
be considered. Patients with CLI require more urgent anatomic unit of tissue (consisting of skin, subcu-
revascularization because of an increased risk of tissue taneous tissue, fascia, muscle, and bone) that is fed
loss and amputation, as well as an extremely high risk by a source artery and drained by specific veins.
of cardiovascular events (92). If the patient is a candidate for either endovascular
There are 2 well-established classification schemes or open surgery, the less invasive option (i.e., an
to describe the severity of PAD. The first is a func- endovascular-first strategy) is the current standard of
tional assessment (Fontaine or Rutherford classifica- care. The selection of a complex lesion (TASC D), for
tion [RC]) (Table 2), and the second is an anatomic endovascular therapy will vary with the skill and
lesion classification (Trans-Atlantic Inter-Society experience of the interventionalist. The goal in
Consensus [TASC]) (Table 3) (4,5). In addition, there treating a patient who has functional impairment
has been recent interest in the angiosome concept, in because of claudication is durable relief of symptoms.
helping to influence optimal revascularization stra- In patients with CLI and a threatened limb or tissue
tegies for limb salvage (93). An angiosome is an loss, the goal is rapid reperfusion of the ischemic
1348 Olin et al. JACC VOL. 67, NO. 11, 2016

Management of Patients With Peripheral Artery Disease MARCH 22, 2016:1338–57

diffuse disease (TASC D). This preference for less


T A B L E 2 Classifications of Severity of PAD
invasive therapy is evidence based and driven by
Fontaine Rutherford shorter length of stay (or treatment as an outpatient
Stage Clinical Grade Category Clinical entirely) and lower periprocedural morbidity and
I Asymptomatic 0 0 Asymptomatic mortality rates, while achieving comparable patency
IIa Mild claudication I 1 Mild claudication
rates (4- to 5-year primary patency of 60% to 86%,
IIb Moderate-severe I 2 Moderate claudication
claudication with secondary patency rates of 80% to 98%) (94).
I 3 Severe claudication CURRENT BEST PRACTICES (EVIDENCE-BASED AND
III Ischemic rest pain II 4 Ischemic rest pain GUIDELINES). In 2011, the European Society of Car-
IV Ulceration or III 5 Minor tissue loss
gangrene
diology (ESC) (3) and ACC/AHA PAD guidelines (2)
IV 6 Ulceration or gangrene recommended an endovascular-first approach for
aortoiliac lesions, recommended that borderline
PAD ¼ peripheral artery disease. lesions be assessed with hemodynamic gradients, and
supported primary stent placement in the aortoiliac
arteries (Table 4). The current expert consensus
tissue to relieve the ischemia, prevent amputation, document from the Society for Cardiac Angiography
and restore ambulation. and Interventions (SCAI) on appropriate use criteria
AORTOILIAC OCCLUSIVE DISEASE (AUC) for aortoiliac intervention are similar to the
current guidelines (95).
There has been a practice shift over the past 25 years CLINICAL TRIAL UPDATE. The results of the CLEVER
as the treatment of aortoiliac disease transitioned trial were discussed previously in the section on
from open surgery with aortobiiliac or aortobifemoral exercise. BRAVISSIMO (Belgian-Italian-Dutch Trial
bypass to endovascular treatments for complex and Investigating Abbott Vascular Iliac Stents in the

T A B L E 3 TASC Classification

TASC A TASC B TASC C TASC D

Aortoiliac Unilateral or bilateral Short (#3 cm) stenosis of Bilateral CIA occlusions Infrarenal aortoiliac occlusion
stenoses of CIA infrarenal aorta Bilateral EIA stenoses 3–10 cm Diffuse disease involving the
Unilateral or bilateral single Unilateral CIA occlusion long, not extending into aorta and both iliac arteries
short (#3 cm) stenosis Single or multiple stenoses the CFA Diffuse multiple stenoses
of EIA totaling 3–10 cm involving Unilateral EIA stenosis involving the unilateral CIA,
the EIA, not extending into extending into the CFA EIA, and CFA
the CFA Unilateral EIA occlusion that Unilateral occlusions of both CIA
Unilateral EIA occlusion not involves the origins of and EIA
involving the origins of internal iliac and/or CFA Bilateral occlusions of EIA
internal iliac or CFA Heavily calcified unilateral EIA Iliac stenoses in patients with
occlusion with or without AAA not amenable to
involvement of origins of endograft placement
internal iliac and/or CFA
Femoral-popliteal Single stenosis #10 cm in Multiple lesions (stenoses or Multiple stenoses or Chronic total occlusions of CFA
length occlusions), each #5 cm occlusions totaling or SFA (>20 cm, involving
Single occlusion #5 cm in Single stenosis or >15 cm, with or without the popliteal artery)
length occlusion #15 cm, not heavy calcification Chronic total occlusion of
involving the Recurrent stenoses or popliteal artery and
infrageniculate popliteal occlusions after failing proximal trifurcation vessels
artery treatment
Heavily calcified occlusion
#5 cm in length
Single popliteal stenosis
Infrapopliteal Single focal stenosis, #5 cm in Multiple stenoses, each #5 Multiple stenoses in the Multiple occlusions involving
length, in the target tibial cm in length, or total target tibial artery and/or the target tibial artery with
artery, with occlusion or length #10 cm, or single single occlusion with total total lesion length >10 cm,
stenosis of similar or occlusion #3 cm in length, lesion length >10 cm with or dense lesion calcification
worse severity in the other in the target tibial artery occlusion or stenosis of or nonvisualization of
tibial arteries with occlusion or stenosis similar or worse severity in collaterals; the other tibial
of similar or worse severity the other tibial arteries arteries occluded or with
in the other tibial arteries dense calcification

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 common iliac artery; EIA ¼ external iliac artery; SFA ¼ superficial femoral artery;
TASC ¼ Trans-Atlantic Inter-Society Consensus.
JACC VOL. 67, NO. 11, 2016 Olin et al. 1349
MARCH 22, 2016:1338–57 Management of Patients With Peripheral Artery Disease

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


T A B L E 4 Aortoiliac Guideline-Based Recommendations for
ported 100% technical success in 325 patients with Stable Limb Ischemia (Claudication)
aortoiliac lesions with a 24-month primary patency
ACC/AHA PAD Guidelines (2006, 2011) ESC PAD Guidelines (2011)
rate of 87.9% (96). Neither TASC category nor lesion
Endovascular procedures are indicated for When revascularization is indicated, an
length was predictive of restenosis. These data patients with a vocational or lifestyle- endovascular-first strategy is
further support the endovascular-first strategy, limiting disability due to intermittent recommended in all aortoiliac TASC A–C
claudication when clinical features suggest lesions (Class I, Level of Evidence: C)
regardless of TASC classification, and take into a reasonable likelihood of symptomatic
consideration the evolution of devices (i.e., re-entry improvement with endovascular
intervention and: 1) there has been an
catheters, crossing devices, and stents), which inadequate response to exercise or
improve success rates for the most complex lesions. pharmacological therapy; and/or 2) there is
a very favorable risk-benefit ratio (e.g.,
focal aortoiliac occlusive disease) (Class I,
COMMON FEMORAL DISEASE Level of Evidence: A)
Translesional pressure gradients (with and A primary endovascular approach may be
without vasodilation) should be obtained to considered in aortoiliac TASC D lesions in
Patients with common femoral artery (CFA) disease evaluate the significance of angiographic patients with severe comorbidities, if
are particularly symptomatic because the obstruction iliac arterial stenoses of 50% to 75% done by an experienced team (Class IIb,
diameter before intervention (Class I, Level Level of Evidence: C)
not only occurs proximal to the superficial femoral of Evidence: C)
artery (SFA) but also proximal to the deep femoral Stenting is effective as primary therapy for Primary stent implantation, rather than
artery (profunda femoris), which is the major collat- common iliac artery stenosis and occlusions provisional stenting, may be considered
(Class I, Level of Evidence: B) for aortoiliac lesions (Class IIb, Level of
eral artery supplying blood to the lower limb when Evidence: C)
there is SFA obstruction. Traditionally, common
ACC ¼ American College of Cardiology; AHA ¼ American Heart Association; ESC ¼ European Society of
femoral endarterectomy has been the CFA revascu-
Cardiology; PAD ¼ peripheral artery disease; TASC ¼ Trans-Atlantic Inter-Society Consensus.
larization procedure of choice (2,3), although
advances in endovascular therapy have shown some
promising results (97). A review of the National Sur- femoral-popliteal lesions for patients with CLI or for
gical Quality Improvement Program database for 2005 patients with claudication who have had a suboptimal
to 2010 found a combined mortality and morbidity response to a trial of exercise (Table 5). An
rate of 15% for common femoral endarterectomy, endovascular-first approach is recommended for
which was higher than expected (98). Patients TASC A through C lesions and is a reasonable option
requiring CFA revascularization who are at increased for TASC D lesions, depending on the experience of
surgical risk may be considered for less invasive the operator, the patient’s comorbidities, and proce-
endovascular options. dure safety (Table 5) (2,3,95).
The 2 guidelines are in conflict over the use of
FEMORAL-POPLITEAL DISEASE primary stent placement in the femoral-popliteal ar-
teries, with the ACC/AHA guideline giving it a Class III
This segment begins at the bifurcation of the CFA into recommendation (do not do) and the ESC guideline
the SFA and the deep femoral (profunda femoris) making primary femoral stenting reasonable first-line
artery. The SFA is subject to flexion, elongation, therapy (Class IIa) for intermediate-length lesions
compression, and torsion unlike any other lower- (108,109). The current evidence from several ran-
extremity artery. This complexity leads to many domized controlled trials supports primary stenting
challenges for endovascular technology, but despite in intermediate-length femoral stenoses and occlu-
this, an endovascular-first approach is currently the sions (108–110). The soon-to-be-published updated
standard of therapy for the majority of lesions ACC/AHA guidelines will readdress this issue. In
because of the very high procedural success rate and current practice, the standard is to primarily stent
low risk (3). Some of the most lengthy and complex intermediate to long SFA lesions.
lesions (TASC D) are more approachable because of The ACC/AHA guideline broadly lump stents
the re-entry and crossing devices, more experienced together with atherectomy devices, cryotherapy, laser,
operators, drug-eluting stents (DES) (99,100), and and cutting balloons, stating they may be useful as
drug-coated balloons (DCBs) (101–107) that promise salvage therapy (Class IIa), but also stating that their
improved long-term patency for patients with clau- effectiveness remains to proven (Class IIb). Stents
dication (99,100,103,105). should be removed from this group, because their
CURRENT BEST PRACTICES (EVIDENCE-BASED AND effectiveness has been established in intermediate-
GUIDELINES). The ACC/AHA (2006, 2011) and ESC length femoral lesions. Other than the use of the cut-
(2011) PAD guidelines and the AUC document ting balloon and rotational atherectomy in lesions that
from the SCAI recommend revascularization in are resistant to dilation, there is no comparative
1350 Olin et al. JACC VOL. 67, NO. 11, 2016

Management of Patients With Peripheral Artery Disease MARCH 22, 2016:1338–57

intermediate-length (128 mm) femoral lesions treated


T A B L E 5 Femoral-Popliteal Guideline Based Recommendations for
Stable Limb Ischemia (Claudication)
with self-expanding BMS (114). These results need to
be confirmed before this can be recommended as
ACC/AHA PAD Guidelines (2006, 2011) ESC PAD Guidelines (2011)
standard therapy.
Endovascular procedures are indicated for patients When revascularization is indicated, an
with a vocational or lifestyle-limiting disability endovascular-first strategy is Recent randomized controlled trials demonstrating
due to intermittent claudication when clinical recommended in all femoropopliteal benefit for DES (99,100), DCB (103,105,106), and
features suggest a reasonable likelihood of TASC A–C lesions (Class I, Level of
symptomatic improvement with endovascular Evidence: C) covered stents (115–117) in femoral-popliteal arteries
intervention and: 1) there has been an will likely result in a change in the guidelines and
inadequate response to exercise or
pharmacological therapy, and/or 2) there is a indications (Table 6, Figure 3).
very favorable risk-benefit ratio (e.g., focal There has been some enthusiasm for self-expanding
stenosis) (Class I, Level of Evidence: A)
covered (expanded polytetrafluoroethylene) stent
Stents (and other adjunctive techniques such as Primary stent implantation should be
lasers, cutting balloons, atherectomy devices, considered in femoropopliteal TASC grafts in complex or lengthy femoral-popliteal seg-
and thermal devices) can be useful in the B lesions (Class IIa, Level of ments. Two randomized trials comparing covered
femoral, popliteal, and tibial arteries as salvage Evidence: A)
therapy for a suboptimal or failed result from stents to BMS had divergent results. One showed a
balloon dilation (e.g., persistent translesional benefit for 2-year primary patency but no difference in
gradient, residual diameter stenosis >50%, or
flow-limiting dissection) (Class IIa, Level of target-lesion revascularization (TLR) or clinical out-
Evidence: C) comes (116), whereas the other, in longer (>8 cm) le-
The effectiveness of stents, atherectomy, cutting A primary endovascular approach may
sions, found no difference for primary patency (115–
balloons, thermal devices, and lasers for the also be considered in TASC D lesions
treatment of femoral-popliteal arterial lesions is in patients with severe comorbidities 117). When covered stents were compared with
not well established (except to salvage a if an experienced interventionist is
above-the-knee femoral bypass with synthetic graft
suboptimal result from balloon dilation) (Class available (Class IIb, Level of
IIb, Level of Evidence: A) Evidence: C) material in a broad range of SFA lesion types (TASC A
Primary stent placement is not recommended in the thru D), no difference was found in the 4-year primary
femoral, popliteal, or tibial arteries (Class III,
Level of Evidence: C) patency between the 2 options (118).
Endovascular intervention is not indicated as The Zilver paclitaxel-eluting self-expanding DES
prophylactic therapy in an asymptomatic patient was superior to PTA in a randomized femoral-
with lower-extremity PAD (Class III, Level of
Evidence: C) popliteal trial, with 1-year patency rates of 83.1% for
primary DES and 32.8% for PTA (p < 0.001) (Figure 3,
Abbreviations as in Table 4.
Table 6) (99). There was also a 1-year patency
advantage for provisional DES after failed PTA
(89.9%) compared with provisional BMS (73.0%,
evidence suggesting that the more expensive athe- p ¼ 0.01). The benefit was sustained at 2 years, with
rectomy devices, cryoplasty, or laser angioplasty primary patency for the DES (74.8%) significantly
should be preferred over conventional therapy better than PTA (26.5%, p < 0.01) (100). To date, there
(percutaneous transluminal angioplasty [PTA] and has been no head-to-head comparison of primary DES
bare-metal stents [BMS]). The ESC guideline distin- to either BMS or DCB in femoral-popliteal arteries,
guishes bare-metal self-expanding stents from but Zeller et al. (104) published a propensity score–
adjunctive devices, such as atherectomy devices, cit- based comparison of DES and DCB in consecutive
ing the proven benefit of BMS over PTA in patients with TASC C and D long (>10 cm) lesions and
intermediate-length femoral-popliteal lesions. found no significant differences in 1-year patency
(Figure 3, Table 6).
CLINICAL TRIAL UPDATE. Three randomized controlled DCBs offer the promise of improved patency with a
trials of self-expanding BMS compared with PTA have reduced need for stents. This is particularly important
shown that the advantage for primary stenting is in the dynamic environment of the superficial femoral
related to lesion length. For relatively discrete lesions and popliteal arteries, where mechanical fatigue may
(mean 45 mm) (110), there was no advantage for pri- lead to stent fracture and increased risk of in-stent
mary stent placement; however, 2 other trials restenosis. Each DCB is unique with respect to the
(108,109) with longer lesions (>70 mm) showed a paclitaxel dose (varying from 2 to 3.5 m g/mm2 ), the
significant patency and functional benefit for primary carrier molecule (excipient), the balloon material, and
femoral-popliteal BMS (Figure 3, Table 6). The proce- the coating technology used. Superiority for paclitaxel
dural success rate of endovascular therapy in DCB over PTA was first reported in 2008 (101,102)
femoral-popliteal lesions is very high, but in stable (Figure 3, Table 6). Subsequently, new DCBs have
limb ischemia, durable patency remains a barrier. emerged, including the IN.PACT (105,106,111,113) and
Cilostazol has been shown to reduce 1-year restenosis the Lutonix (103,106) balloons, both of which showed
by more than one-half (20% vs. 49%, p ¼ 0.0001) in clinical superiority to PTA in femoral-popliteal lesions
JACC VOL. 67, NO. 11, 2016 Olin et al. 1351
MARCH 22, 2016:1338–57 Management of Patients With Peripheral Artery Disease

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

100%

90%

80%
ZILVER PTA
Lesion length: 63.1
Restenosis: 67.2% ABSOLUTE PTA
70% ASTRON PTA Lesion length: 127
Restenosis: 63.5%
Lesion length: 71
Restenosis: 61.1%

60%
Restenosis (%)

THUNDER PTA
Lesion length: 74
Restenosis: 50%
50% FEMPAC PTA
IN.PACT SFA PTA
Lesion length: 47
Restenosis: 40% Lesion length: 88.1
Restenosis: 47.6%
FAST PTA
40% Lesion length: 44.5 ZELLER DES
Restenosis: 38.6% ASTRON BMS Lesion length: 195
Lesion length: 98 Restenosis: 30.4%
PACIFIER PTA
FAST BMS Restenosis: 34.4% VIASTAR BMS
Lesion length: 66
Lesion length: 127
30% Lesion length: 45.2
Restenosis: 31.7%
Restenosis: 32.4%
Restenosis: 63.0%
ABSOLUTE BMS
Lesion length: 132
Restenosis: 31.7%
20% THUNDER DCB ZELLER DCB
Lesion length: 75 IN.PACT SFA DCB Lesion length: 194
Restenosis: 24% Lesion length: 89.4 Restenosis: 23.9%
Restenosis: 17.8%
FEMPAC DCB ZILVER DES
10% Lesion length: 40 Lesion length: 66.4
PACIFIER DCB VIASTAR CS
Restenosis: 17% Restenosis: 16.9%
Lesion length: 70 Lesion length: 132
Restenosis: 8.6% Restenosis: 37.0%

0 50 100 150 200


Lesion Length (in MM)

T A B L E 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 stents
in 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 Superficial
Femoral Artery (SFA) and/or Proximal Popliteal Artery (PPA); LEVANT-2 ¼ The Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis; NR ¼ not
reported; PACIFIER ¼ Paclitaxel-coated Balloons in Femoral Indication to Defeat Restenosis; PTA ¼ percutaneous transluminal (balloon) angioplasty; RVD ¼ reference vessel
diameter; THUNDER ¼ Local Taxan With Short Time Contact for Reduction of Restenosis in Distal Arteries; TLR ¼ target-lesion revascularization; ZELLER ¼ Drug-coated
balloons vs. drug-eluting stents for treatment of long femoropopliteal lesions; ZILVER ¼ PTX Randomized Trial.
1352 Olin et al. JACC VOL. 67, NO. 11, 2016

Management of Patients With Peripheral Artery Disease MARCH 22, 2016:1338–57

In general, nonambulatory patients with a short-


T A B L E 7 Tibial-Peroneal (Below-Knee) Guideline-Based Recommendations
for CLI
ened life expectancy and extensive lower-extremity
tissue necrosis should undergo amputation. Patients
ACC/AHA PAD Guidelines (2006, 2011) ESC PAD Guidelines (2011)
who have the opportunity to regain ambulatory
For individuals with combined inflow and
outflow disease with CLI, inflow lesions function should undergo magnetic resonance angi-
should be addressed first (Class I, Level ography, computed tomography angiography, or
of Evidence: C)
catheter-based angiography to visualize the extent of
For patients with limb-threatening lower- For infrapopliteal lesions,
extremity ischemia and an estimated life angioplasty is the preferred lower-extremity vascular disease. The goal for
expectancy #2 years in whom an technique, and stent revascularization in patients with CLI is to establish
autogenous vein conduit is not available, implantation should be
balloon angioplasty is reasonable to considered only in the case straight-line flow from the hip to the foot.
perform when possible as the initial of insufficient PTA (Class IIa,
procedure to improve distal blood flow Level of Evidence: C)
CURRENT BEST PRACTICES (EVIDENCE-BASED AND
(Class IIa, Level of Evidence: B)
The effectiveness of uncoated/uncovered When revascularization in the
GUIDELINES). The ACC/AHA (2006, 2011) and ESC
stents, atherectomy, cutting balloons, infrapopliteal segment is (2011) PAD guidelines agree that an endovascular-first
thermal devices, and lasers for the indicated, the endovascular-
treatment of infrapopliteal lesions first strategy should be approach is reasonable in patients with CLI and
(except to salvage a suboptimal result considered (Class IIa, Level infrapopliteal arterial disease (Table 7) (2,3). In can-
from balloon dilation) is not well of Evidence: C)
established. (Class IIb, Level of
didates for endovascular treatment, both guidelines
Evidence: C) support PTA as the initial approach, with the use of
Primary stent placement is not recommended BMS as needed for bailout lesions (Table 7) (2,3). The
in the femoral, popliteal, or tibial arteries
(Class III, Level of Evidence: C) guidelines, however, have lagged behind the most
Surgical and endovascular intervention is not recent evidence demonstrating that DES and DCBs are
indicated in patients with severe
superior to angioplasty alone and BMS for infrapo-
decrements in limb perfusion (e.g.,
ABI <0.4) in the absence of clinical pliteal disease (Table 8).
symptoms of CLI (Class III, Level of
The expert consensus infrapopliteal AUC document
Evidence: C)
from the SCAI supports endovascular intervention
ABI ¼ ankle-brachial index; other abbreviations as in Table 6. 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
and excellent safety profiles (Figure 3, Table 6). The therapy may be appropriate in patients with moderate
durability of a paclitaxel-eluting DCB in the SFA has to severe claudication with occlusions or diffuse dis-
been demonstrated at 2 and 5 years (107,111). At 2 years, ease of 2 or 3 infrapopliteal vessels and for ischemic
patients treated with DCB showed significantly higher rest pain or minor tissue loss with 1- or 2-vessel
primary patency than those treated with PTA (78.9% infrapopliteal disease. It would rarely be appropriate
vs. 50.1%; p < 0.001), including lower clinically driven to perform infrapopliteal intervention for mild clau-
TLR and similar functional status improvement, with dication (RC 1) or for moderate to severe claudication
fewer repeat interventions. Five-year follow-up with major tissue loss for single-vessel infrapopliteal
demonstrated that TLR remained significantly lower in obstruction (i.e., 2 vessels are patent to the foot).
the DCB group (21%) than for PTA (56%, p ¼ 0.0005)
CLINICAL TRIAL UPDATES. There have been 4 ran-
(117). The TLR benefit in femoral-popliteal arteries was
domized trials (Table 8) (120–122,125,127) demon-
independent of lesion length. There have been no
strating superiority for infrapopliteal DES versus
safety concerns raised for DCB regarding aneurysm
either PTA, BMS, or DCB. These data provide
formation or fibrotic constriction.
convincing evidence favoring infrapopliteal DES over
TIBIAL-PERONEAL DISEASE PTA, BMS, or DCB for: 1) patency; 2) reduced rein-
terventions; 3) reduced amputation; and 4) improved
Infrapopliteal or below-the-knee disease begins with event-free survival. These results are not limited to
the popliteal artery at the knee joint and continues patients with CLI, because most trials have included
to the tibial and peroneal arteries to the ankle. patients with severe claudication. It would be
Revascularization is indicated in patients with CLI appropriate to revise the guideline statements in
and, rarely, for those with claudication. The BASIL favor of DES for infrapopliteal lesions at this time.
(Bypass Versus Angioplasty in Severe Ischaemia The evidence supporting the use of DCB for infra-
of the Leg) trial compared PTA (balloon alone) to popliteal lesions is less certain. The DEBATE-BTK
surgery in 452 CLI patients and found no difference (Drug-Eluting Balloon in Peripheral Intervention for
for amputation-free survival but a lower cost with Below the Knee Angioplasty Evaluation) trial ran-
PTA (119). domized 158 infrapopliteal lesions in diabetic
JACC VOL. 67, NO. 11, 2016 Olin et al. 1353
MARCH 22, 2016:1338–57 Management of Patients With Peripheral Artery Disease

T A B L E 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 Peripheral
Intervention 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.PACT
Amphirion Drug Eluting Balloon vs. Standard PTA (Percutaneous Transluminal Angioplasty) for the Treatment of Below the Knee Critical Limb Ischemia; YUKON-BTX ¼
YUKON-drug-eluting Stent Below The Knee - Prospective Randomized Double-blind Multicenter Study; other abbreviations as in Table 6.

patients with CLI to either DCB (In.Pact Amphirion, BEST-CLI (Best Endovascular Versus Best Surgical
Medtronic, Minneapolis, Minnesota) or PTA (123). The Therapy in Patients With CLI) trial has just been
mean lesion length was 129  83 mm, significantly launched and will answer the question of whether
(w100 mm) longer than those in the infrapopliteal surgery in selected patients with CLI and with
DES randomized trials. The primary endpoint, reste- good-quality saphenous veins is a better choice than
nosis at 1 year, occurred in 27% of patients in the DCB endovascular therapy (128).
group and 74.3% of those in the PTA group
(p < 0.001). Twelve-month major adverse events THE FUTURE OF ENDOVASCULAR THERAPY
occurred less frequently in the DEB (31%) than in the
PTA (51%) group (p ¼ 0.02), driven mainly by a The emphasis on value-based care that offers the
reduction in TLR and better ulcer healing. However, right procedure for the right patient at the right time
there was no difference in the rate of amputation, requires justification of expensive devices in the
limb salvage, or mortality between the groups. context of cost-conscious medical care. Unfortu-
In contrast, the results of the In.Pact Deep CLI trial nately, we often lack head-to-head comparative data
resulted in the DCB (In.Pact Amphirion) being with- to determine which device or strategy is preferred for
drawn from the market worldwide by the sponsor specific clinical situations. It is reasonable to choose
(124). The trial enrolled 358 CLI patients with infra- lower-cost strategies, unless there is evidence justi-
popliteal lesions and randomized them 2:1 to DCB and fying a more expensive choice.
PTA, respectively. The restenosis rate and TLR were AUC have been introduced in a variety of cardio-
not different between the 2 groups. There was a vascular subspecialties. AUC are intended to aid
nonsignificant trend toward higher amputation rates clinicians in improving patient quality and safety by
in the DEB (8.8%) compared with the PTA group reducing (but not eliminating) variation in clinical
(3.6%, p ¼ 0.08). It seems clear that more data and practice. Essentially, AUC offer care pathways that
more experience are needed to understand the rela- are meant to offer guidance. It is recognized that
tive benefits of DEB for infrapopliteal lesions (124). deviation from the care pathway will be the right
In practical terms, an endovascular-first approach thing to do in specific cases. Responsible clinicians
is the current standard of care for symptomatic should be able to articulate their reasons for deviating
infrainguinal atherosclerotic disease. Adverse peri- from the “appropriate” care pathway, thereby navi-
procedural events with endovascular therapy for gating the Scylla and Charybdis of cost-effectiveness
the treatment of infrapopliteal disease appear to be and clinical necessity.
low, with mortality rates in observational series <1%. Independent accreditation of hospital facilities,
The recent technological advances of DES and DEBs such as noninvasive and invasive laboratories, is a
will strengthen this consensus recommendation. The valuable tool for benchmarking quality of care and
1354 Olin et al. JACC VOL. 67, NO. 11, 2016

Management of Patients With Peripheral Artery Disease MARCH 22, 2016:1338–57

reducing variation. Accreditation for Cardiovascular yet they are still not offered to a large percentage of
Excellence (ACE) offers on-site reviews for cardiac, patients with PAD. Additionally, there have been
peripheral, carotid, electrophysiology, and congenital many advances in minimally invasive techniques to
heart disease. Importantly, accreditation must be improve the circulation to the lower extremities, and
independent of professional societies, regulators, in the past decade, more physicians have become
and payers to avoid bias. The value of accreditation competent to provide high-level care to patients with
is in establishing ongoing procedures to ensure claudication and CLI. The endovascular arena has
quality and safety. When done properly, independent changed so dramatically over the past 5 years that it is
accreditation functions more like a coach than a difficult for the guidelines to keep up with these
policeman to promote a culture of continuous changes. The goal for the future should be early
improvement. Payers and regulators should require identification of the PAD patient so that progression to
or reward independent accreditation to support CLI and amputation can be prevented and appropriate
value-based health care. therapy to prevent MACE can be implemented. The
optimal treatment of an individual patient involves a
CONCLUSIONS combination of exercise, pharmacological therapy,
and revascularization (endovascular or open surgery).
Despite the increased prevalence over the past 20
years, PAD continues to be underdiagnosed and REPRINT REQUESTS AND CORRESPONDENCE: Dr. Jeffrey
undertreated compared with CAD. Because most W. Olin, Vascular Medicine and Vascular Diagnostic
deaths in patients with PAD are attributable to car- Laboratory, Zena and Michael A. Wiener Cardiovascular
diovascular disease, patients with PAD (even those Institute and Marie-Joseé and Henry R. Kravis Center for
who are asymptomatic) who are not diagnosed or Cardiovascular Health, Icahn School of Medicine at
treated will needlessly experience MACE. There are Mount Sinai, One Gustave L. Levy Place, New York, New
effective therapies to prevent cardiovascular events, York 10029. E-mail: jeffrey.olin@mountsinai.org.

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112. Tepe G, Laird J, Schneider P, et al., for the IN. infrapopliteal stenting with the sirolimus-eluting quiz for this article.
PACT SFA Trial Investigators. Drug-coated balloon stent in patients with ischemic peripheral arterial

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