Professional Documents
Culture Documents
11, 2016
STATE-OF-THE-ART REVIEW
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
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 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).
5. Claim your CME credit and receive your certificate electronically by
following the instructions given at the conclusion of the activity.
CME Term of Approval
CME Objective for This Article: At the end of this activity the reader Issue Date: March 22, 2016
should be able to: 1) evaluate medical treatment options for patients with Expiration Date: March 21, 2017
From the aZena and Michael A. Wiener Cardiovascular Institute & Marie-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
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.
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: 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
ACEIs
30
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
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
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.
T A B L E 3 TASC Classification
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
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%
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
Clinical Trial Name (Ref. #) Device N Lesion length (mm) Restenosis (%) IC/CLI (%) TLR (%) De Novo (%) Occlusions (%) RVD (mm)
*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
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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multicenter comparison of balloon angioplasty and journals-cme to take the CME
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