Arteriosclerosis, Thrombosis, and Vascular Biology

ATVB IN FOCUS:
The Science of the ATVB Early Career Committee
Series Editor: Robert A. Hegele

Evidence-Based Medical Management of

Peripheral Artery Disease
Graham H. Bevan, Khendi T. White Solaru

ABSTRACT: Peripheral artery disease is an atherosclerotic disease of the lower extremities associated with high cardiovascular
mortality. Management of this condition may include lifestyle modifications, medical management, endovascular repair, or surgery.
The medical approach to peripheral artery disease is multifaceted and includes cholesterol reduction, antiplatelet therapy,
anticoagulation, peripheral vasodilators, blood pressure management, exercise therapy, and smoking cessation. Adherence to this
regimen can reduce limb-related complications like critical limb ischemia and amputation, as well as systemic complications of
atherosclerosis like stroke and myocardial infarction. Relative to coronary artery disease, peripheral artery disease is an undertreated
condition. In this article, we explore the evidence behind medical therapies for the management of peripheral artery disease.
VISUAL OVERVIEW: An online visual overview is available for this article.

Key Words: atherosclerosis ◼ blood pressure ◼ cardiovascular disease ◼ cholesterol ◼ peripheral artery disease ◼ stroke ◼ vascular medicine

P
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eripheral artery disease (PAD) is a chronic, atheroscle-
rotic disease of the peripheral vasculature resulting
in limb-associated complications such as intermittent
claudication, ischemic rest pain, ischemic ulcer, gangrene,
and functional impairment. Sequelae requiring amputa-
tion carries a mortality of ≤50% at 1 year.1 While limb
complications themselves are destructive, PAD is often
a harbinger of obstructive atherosclerotic disease else-
where, including the cerebral and coronary vasculature.
Indeed, patients with PAD have an increased rate of isch-
emic stroke, myocardial infarction (MI), and cardiovascu-
lar death.2–4 Furthermore, patients with coronary artery
disease (CAD) and PAD have a much higher risk of car-
diovascular mortality than CAD alone.5,6 Importantly, PAD
is a significant burden for patients in terms of quality of
life and financial well-being.7 PAD is a relatively common
condition with 220 million people affected globally and an
increasing prevalence worldwide.8
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for all articles published in this series.
A number of therapies exist for the treatment of PAD,
including those directed toward management of claudi-
cation symptoms, secondary prevention of cardiovascu-
lar complications, and limb salvage therapies. Treatment
strategies can be subdivided into lifestyle modification,
medical management, endovascular therapies, and surgi-
cal interventions. The purpose of this review is to examine
the medical management for the treatment of PAD, which
primarily include cholesterol reduction, antiplatelet therapy,
anticoagulation, peripheral vasodilators, blood pressure
control, smoking cessation, and exercise therapy. Despite
the severity of this condition, patients with PAD are dra-
matically undertreated relative to their CAD counterparts
with comparatively few trials directly assessing the effi-
cacy of medical interventions.9 In particular, blacks who
have a high burden of disease are less likely to receive
evidence-based treatment, potentially resulting in higher
rates of complications.10–12 In addition to a discussion of
the evidence base for current PAD medical management,
this review seeks to increase awareness of this disparity to
improve PAD outcomes in the black community.

 
Correspondence to: Khendi T. White Solaru, MD, Department of Cardiovascular Medicine, Harrington Heart and Vascular Institute, University Hospitals Cleveland
Medical Center, Case Western Reserve University School of Medicine, 11100 Euclid Ave, Cleveland, OH 44106. Email khendi.whitesolaru@uhhospitals.org
For Disclosures, see page 550.
© 2020 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at www.ahajournals.org/journal/atvb

Arterioscler Thromb Vasc Biol. 2020;40:541–553. DOI: 10.1161/ATVBAHA.119.312142 March 2020   541
 Bevan and White Solaru
Nonstandard Abbreviations and Acronyms
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ACC American College of Cardiology
ACE angiotensin-converting enzyme
AHA American Heart Association
ALLHAT Antihypertensive and Lipid-Low-
ering Treatment to Prevent Heart
Attack Trial
ARB angiotensin receptor blocker
BEST-CLI Best Endovascular Versus Best
Surgical Therapy for Patients With
Critical Limb Ischemia
CAD coronary artery disease
CAPRIE Clopidogrel Versus Aspirin in
Patients at Risk for Ischemic Events
CLI critical limb ischemia
CLIPS Critical Leg Ischemia Prevention
Study
COMPASS Cardiovascular Outcomes for
People Using Anticoagulation
Strategies
DAPT dual antiplatelet therapy
HDL high-density lipoprotein
HOPE Heart Outcomes Prevention
Evaluation
INVEST International Verapamil-SR/Tran-
dolapril Study
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LDL low-density lipoprotein
LDL-C low-density lipoprotein cholesterol
MI myocardial infarction
OASIS-II Organization to Assess Strategies
for Ischemic Syndromes
ONTARGET Ongoing Telmisartan Alone and in
Combination With Ramipril Global
End Point Trial
PAD peripheral artery disease
REDUCE-IT Reduction of Cardiovascular Events
With Icosapent Ethyl–Intervention
Trial
VALUE Valsartan Antihypertensive Long-
Term Use Evaluation
WAVE Warfarin Antiplatelet Vascular
Evaluation
CHOLESTEROL REDUCTION
Elevated lipids and lipoproteins including total choles-
terol, non-HDL (high-density lipoprotein) cholesterol,
and LDL (low-density lipoprotein) cholesterol (LDL-C)
are associated with an increased risk of cardiovascu-
lar disease, and PAD is no exception.13–17 Contempo-
rary research on statins, ezetimibe, and more recently
PCSK9 inhibitors indicates that lowering lipids and, in
particular, LDL-C to the lowest possible target greatly
542   March 2020 Arterioscler Thromb Vasc Biol. 2020;40:541–553. DOI: 10.1161/ATVBAHA.119.312142
Medical Management of Peripheral Artery Disease
Highlights
• Peripheral artery disease is a disease of the lower
extremity arteries associated with high cardiovascu-
lar mortality.
• Medical management of peripheral artery disease
includes cholesterol reduction, antiplatelet therapy,
anticoagulation, peripheral vasodilators, blood pres-
sure control, exercise therapy, and smoking ces-
sation, all of which have the capacity to reduce
mortality, symptoms, and complications.
• Peripheral artery disease treatment in blacks
remains suboptimal despite a high incidence of
peripheral artery disease and complications in this
population.
improves cardiovascular outcomes.18–20 The American
College of Cardiology (ACC)/American Heart Associa-
tion (AHA) considers PAD to be equivalent to a history
of MI or stroke with respect to cholesterol-lowering
therapies.14,15,17 The ACC/AHA recommends all patients
with symptomatic PAD to be on high-intensity statin. In
addition, individuals with PAD and another major athero-
sclerotic cardiovascular disease event (or 2 minor risk
factors) should be treated to an LDL-C of <70 with a
class I recommendation.14,15 Emerging evidence show-
ing lower risk of ischemic events with the use of icosa-
pent ethyl in REDUCE-IT (Reduction of Cardiovascular
Events With Icosapent Ethyl–Intervention Trial) suggests
triglyceride reduction is effective for patients with cardio-
vascular disease, and future work may apply specifically
to PAD.21
Statin Therapy
Statin therapy is by far the most well-recognized choles-
terol-lowering therapy in the management of PAD. While
the Scandinavian Simvastatin Survival Study Group had
previously shown the mortality benefits of simvastatin in
CAD, a secondary post hoc analysis of these data pro-
vided the first randomized trial data that statin therapy
could be used to treat PAD. With a decreased incidence
of carotid bruit and claudication in the simvastatin group
over the median 5.4-year follow-up period, statin ther-
apy appeared to suppress progression of this disease.22
Later studies would detail statin benefits and provide
more definitive evidence for its use in PAD.
The Heart Protection Study Collaborative Group pro-
vided the first randomized controlled trial data on statin
therapy in PAD. Moderate-intensity statin therapy with
simvastatin reduced peripheral vascular events (defined
as noncoronary revascularization, amputation, aneurysm
repair, and death from PAD) by 17% in a prespecified
PAD group.23 However, PAD was not defined by rigorous
contemporary standards. Claudication and amputation
 Bevan and White Solaru
did not require ankle-brachial index measurement or
endovascular studies to confirm the definition of symp-
tomatic PAD. Furthermore, aneurysm repair was included
in the PAD and vascular event definitions as well. Since
the Heart Protection Study, multiple retrospective studies
corroborated the finding that statin therapy reduces the
rate of amputation with relative risk reductions between
18% and 35%.2,24,25 In a 2013 retrospective cohort
study of diabetic patients with and without PAD, Sohn
et al24 compared outcomes for patients taking statins
with those taking nonstatin lipid-lowering agents such as
fibrates, bile acid sequestrants, nicotinic acid, and cho-
lesterol absorption inhibitors (including ezetimibe) and
found that those patients taking nonstatin lipid therapy
did not share a reduction in lower extremity amputation
rates. There was also a dose response with respect to
statin intensity with high-intensity statin therapy result-
ing in a greater reduction of limb loss than moderate-
intensity therapy in a recent observational cohort study
including both symptomatic and asymptomatic patients
with PAD.26
Statin therapy addresses both limb specific and sys-
temic complications from PAD. The Heart Protection
Study showed that irrespective of a prior history of coro-
nary, cerebrovascular disease, or cholesterol levels, statin
therapy reduced the rate of all cardiovascular events in
PAD, with a 30% reduction in coronary revasculariza-
tion, a 21% reduction in major coronary events, and a
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26% reduction in ischemic stroke.23 The Reduction of
Atherothrombosis for Continued Health Registry, which
prospectively followed patients with symptomatic PAD
over 4 years, made similar conclusions with a 17% lower
risk of cardiovascular death, nonfatal MI, or nonfatal
stroke.2 The notion that statin therapy reduces the risk
of vascular events outside the periphery is supported by
meta-analyses.27,28 Despite robust evidence showing a
reduction in vascular events, meta-analysis did not dem-
onstrate an overall reduction in mortality.27,28 While cur-
rent guidelines suggest the use of high-intensity statin
therapy, much of the trial data accumulated on statins in
PAD used moderate-intensity statin dosing.14,15
Ezetimibe
According to the most recent ACC/AHA guidelines for
cholesterol management, statin therapy may not be suf-
ficient in patients at very high risk defined by a history
of multiple atherosclerotic cardiovascular disease events
or a single event and multiple medical comorbidities.14 A
substantial portion of the PAD population falls into this
category. The ACC/AHA cholesterol guidelines recom-
mend the use of ezetimibe in the management of very-
high-risk patients with LDL-C >70 despite maximally
tolerated statin therapy and select non–very-high-risk
patients with similarly resistant cholesterol levels. There
are few studies evaluating the use of this medication
Arterioscler Thromb Vasc Biol. 2020;40:541–553. DOI: 10.1161/ATVBAHA.119.312142
Medical Management of Peripheral Artery Disease
in patients with PAD. The IMPROVE-IT trial (Improved
Reduction of Outcomes: Vytorin Efficacy International
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Trial) randomized patients with recent hospitalization for
acute coronary syndrome (ACS) to receive ezetimibe or
placebo alongside moderate-intensity statin therapy.19
High-risk patients, categorized by the Thrombolysis
in Myocardial Infarction score, appeared to obtain the
greatest reduction in future cardiovascular events from
ezetimibe, and about 18% of these high-risk patients
had PAD.29 This suggests a benefit to the addition of
ezetimibe to statin therapy though a specific analysis
for patients with PAD has not been performed, and the
patient population was limited to those with recent ACS.
The benefit from ezetimibe may be dependent on the
presence of statin therapy. A small randomized trial com-
pared femoral artery plaque burden progression between
symptomatic PAD patients assigned statin therapy, statin
therapy plus ezetimibe, and ezetimibe alone. The ezeti-
mibe-alone group showed progression of plaque burden
where the other groups remained stable indicating that
ezetimibe without statin therapy is not sufficient in the
management of PAD.30
PCSK9 Inhibitors
PCSK9 (proprotein convertase subtilisin/kexin type 9)
inhibitors represent a substantial innovation to lipid man-
agement. The FOURIER trial (Further Cardiovascular
Outcomes Research With PCSK9 Inhibition in Subjects
With Elevated Risk) using evolocumab in patients with
atherosclerotic disease and LDL >70 mg/dL contained
patients both with and without PAD. Patients with PAD
had an impressive 59% reduction in LDL-C with evo-
locumab resulting in a 3.5% absolute risk reduction in
the primary end point of cardiovascular events (MI, death,
stroke, hospitalization for unstable angina, and coro-
nary revascularization) compared with a 1.6% absolute
risk reduction in patients without PAD.31,32 Importantly,
patients in a prespecified symptomatic PAD group also
had a reduction of 42% in major adverse limb events:
acute limb ischemia, major amputation, or urgent periph-
eral revascularization for ischemia. This reduction was
seen regardless of the intensity of statin therapy without
excess adverse events.31 There have not yet been any
studies to examine outcomes of other PCSK9 inhibitors
in patients with PAD. A future trial set to complete in
2021 will assess a second PCSK9 inhibitor, alirocumab,
in patients with PAD and evaluate for plaque regres-
sion.33 Future reduction in prices may expand indications
for use as current guidelines recommend using PCSK9
inhibitors sparingly as a result of their high cost.
ANTIPLATELET THERAPY
Platelet activity is instrumental to the development of
complications from cardiovascular disease, and PAD is
March 2020   543
 Bevan and White Solaru
no exception. Not only is platelet adherence an initial
step toward atherosclerotic disease but platelet activ-
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ity is abnormal in PAD. PAD is associated with plate-
let hyperaggregability and increased adhesion with
higher expression of surface protein, P-selectin.34–36
This unique behavior in PAD combined with the central
role platelets play in atherothrombotic complications is
the rationale for its use in PAD, but antiplatelet ther-
apy also has a key role in prevention of complications
in cardiovascular disease as a whole. Despite known
relationships between PAD, platelet activity, and CAD,
large-scale trials investigating the benefits of antiplate-
let therapy in patients with PAD were decades behind
those related to CAD.
Aspirin
The presence or absence of PAD symptoms is a major
defining feature of this condition with drastically dif-
ferent clinical outcomes.37 The use of aspirin has been
evaluated in both asymptomatic and symptomatic PAD.
However, multiple trials failed to show a reduction in
cardiovascular events for aspirin in patients with asymp-
tomatic PAD, including the Aspirin for Asymptomatic
Atherosclerosis Trial, which compared 100 mg aspirin to
placebo in 3350 patients with a follow-up time of >8
years.38,39 These results are in line with emerging data
suggesting that aspirin is not effective in primary preven-
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tion of cardiovascular mortality.40,41
Aspirin has been shown to be effective for symp-
tomatic PAD. The first major data to suggest its utility
in PAD was in 2002 with a meta-analysis of random-
ized trials from the Antithrombotic Trialists’ Collabora-
tion. Analysis was conducted on >9000 patients with
PAD and showed a proportional reduction of 23% in
serious vascular events: nonfatal MI, nonfatal stroke, or
vascular death (P=0.004).42 However, the trial included
all antiplatelet agents including clopidogrel. More direct
evidence came in 2007 with the CLIPS (Critical Leg
Ischemia Prevention Study), which evaluated the use of
low-dose aspirin (81 mg) in 366 patients with symptom-
atic and asymptomatic PAD and found a 64% relative
risk reduction in major vascular events: ischemic stroke,
MI, and vascular death (P=0.022).43 Finally the use of
antiplatelet therapy was directly validated in a PAD popu-
lation, and the risk reduction was at least, in part, driven
by a reduction in fatal and nonfatal MI (hazard ratio, 0.18
[95% CI, 0.04–0.82]; P=0.03). Interestingly, by the time
the CLIPS trial was published comparing aspirin to pla-
cebo, the ACC/AHA had already categorized antiplatelet
therapy as a class I indication for PAD based on previ-
ous meta-analysis.44 The CLIPS trial was followed up by
another meta-analysis including both symptomatic and
asymptomatic patients with PAD. The primary end point
544   March 2020 Arterioscler Thromb Vasc Biol. 2020;40:541–553. DOI: 10.1161/ATVBAHA.119.312142
Medical Management of Peripheral Artery Disease
of cardiovascular events occurred less often in the aspi-
rin group but did not reach statistical significance 8.9%
versus 11.0% (relative risk, 0.88 [95% CI, 0.76–1.04]),
which may be as a result of the inclusion of asymptom-
atic patients in the analysis.45
Clopidogrel
The P2Y12 receptor inhibitor clopidogrel has been com-
pared with aspirin in the CAPRIE trial (Clopidogrel Ver-
sus Aspirin in Patients at Risk for Ischemic Events), which
remains the only trial data with a subgroup analysis com-
paring these 2 antiplatelet agents.46 The results were
impressive: almost a 25% reduction in the primary end
point of vascular death, nonfatal MI, or cerebrovascular
accident in patients with clopidogrel over aspirin. Com-
pared with the other subsets in the trial, the prespecified
symptomatic PAD group benefited the most. The gen-
eral population had only an 8.7% relative risk reduction.46
Single-agent antiplatelet therapy is a 2016 ACC/AHA
class Ia recommendation; however, the guidelines do not
recommend clopidogrel over aspirin despite the results
of this subgroup analysis.15
Ticagrelor
The newer P2Y12 inhibitor, Ticagrelor, debuted in
patients with CAD in the PLATO trial, which randomized
patients with ACS to either clopidogrel or ticagrelor and
found that ticagrelor significantly reduced the incidence
of major adverse cardiovascular events at 1 year with-
out significantly increasing the rate of major bleeding.47
A post hoc subgroup analysis of this patient population
included patients with lower extremity PAD and found a
similar 15% relative risk reduction in the composite pri-
mary end point. Furthermore, patients with PAD had a
much higher rate of developing the primary end point,
suggesting that benefit may be larger for this patient
population should a trial be designed for patients with
PAD.48
In 2017, the EUCLID trial (Examining Use of Ticagrelor
in Peripheral Artery Disease) compared clopidogrel and
ticagrelor in almost 14 000 symptomatic PAD patients to
determine whether or not ticagrelor was the better agent
in PAD. Despite high hopes for the newer P2Y12 inhibi-
tor, the primary end point of cardiovascular death, MI, or
ischemic stroke was not significantly different (10.6%
versus 10.8%) between the 2 agents. The only second-
ary end point to reach significance was a 0.5% abso-
lute risk reduction in ischemic stroke for patients taking
ticagrelor. Patients with carotid or coronary revasculariza-
tion and patients with coronary artery stenting appeared
to receive some benefit, although the study was not pow-
ered to distinguish benefit in this specific population and
the results were not significant.49
 Bevan and White Solaru
Dual Antiplatelet Therapy
With platelet activity so critical to the development of ath-
erothrombotic events, dual antiplatelet therapy (DAPT)
was also assessed in PAD. The CHARISMA trial (Clopi-
dogrel for High Atherothrombotic Risk and Ischemic Sta-
bilization, Management, and Avoidance) compared DAPT
to single antiplatelet therapy and included patients with
PAD. The primary outcomes of the trial were stroke,
death, bleeding, and MI, but the authors showed no sig-
nificant difference in outcome between DAPT and single
antiplatelet therapy in the general trial population.50 How-
ever, a post hoc subgroup analysis on PAD patients alone
showed DAPT therapy resulted in a statistically signifi-
cant 15% relative risk reduction in the primary end point
(2.3% versus 3.7%; hazard ratio, 0.63; P=0.028). There
was no difference in severe, fatal, or moderate bleeding
between the 2 groups. The trial included a mixture of
both symptomatic (91.7%) and asymptomatic patients
(8.4%).51 DAPT was evaluated in the 2015 PEGASUS-
TIMI 54 trial (Prevention of Cardiovascular Events in
Patients With Prior Heart Attack Using Ticagrelor Com-
pared to Placebo on a Background of Aspirin–Throm-
bolysis in Myocardial Infarction 54), which examined the
use of ticagrelor and aspirin in patients with MI 1 to 3
years prior. The subgroup analysis of >1000 patients
with symptomatic PAD at the time of enrollment showed
an absolute risk reduction of 4.1% in the primary end
point of cardiovascular death, stroke, or MI for patients
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on DAPT compared with aspirin and placebo. Impor-
tantly, this group also had a significant 35% relative risk
reduction in critical limb ischemia (CLI; P=0.026) at the
cost of increased major and minor bleeding events.52 The
2016 ACC/AHA PAD guidelines provide a lower recom-
mendation (class IIb) for use of DAPT with clopidogrel
suggesting it might be considered for select patients but
that providers should be cautious given the absence of
substantial long-term evidence.15 Since this recommen-
dation, however, a meta-analysis cast doubt on the utility
of DAPT in patients with symptomatic PAD for the pre-
vention of death, MI, or stroke as the reduction in primary
outcome did not reach significance (7.6% versus 8.9%;
odds ratio, 0.84 [CI, 0.65–1.08]; P=0.18) and long-term
DAPT was associated with increased risk of bleeding
(1.47% versus 0.88%; odds ratio, 1.65 [CI, 1.23–2.21];
P=0.001).53
ANTICOAGULATION
Recent research suggests the pathogenesis of CLI, the
most serious limb complication of PAD, is primarily an
atherothromboembolic disease. In a landmark study by
Narula et al, almost 3 quarters of arteries taken from
amputated limbs secondary to CLI show luminal thrombi,
two-thirds of which had no significant atherosclerotic
lesions. These findings suggest a thrombi-dependent
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Medical Management of Peripheral Artery Disease
mechanism in the pathogenesis of many PAD and limb-
related complications since the identified stenosis was
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not secondary to a local atherosclerotic process.54 Trial
data from warfarin, and more recently rivaroxaban, sug-
gest that anticoagulation may in fact prevent limb-related
complications from PAD, as well as all cardiovascular
morbidity and mortality.
Warfarin
Multiple trials have assessed the utility of warfarin anti-
coagulation for the prevention of complications, initially
in patients with a history of ACS. The OASIS (Organi-
zation to Assess Strategies for Ischemic Syndromes)
and WARIS-II (Warfarin, Aspirin, or Both After Myocar-
dial Infarction) trials found the combination of warfarin
and aspirin was better than aspirin alone at preventing
major adverse cardiovascular events in this patient popu-
lation.55,56 These trials paved the way for evaluation of
anticoagulation of patients with known PAD, but initial
results were not as promising. The WAVE trial (Warfarin
Antiplatelet Vascular Evaluation) investigated the use of
warfarin anticoagulation in combination with aspirin for
patients with symptomatic PAD (81.8% of the total trial
population), subclavian disease, and carotid disease. The
trial found no significant difference in the occurrence of
major adverse cardiovascular events between patients
receiving combination aspirin and warfarin therapy
alone.57 Furthermore, they found a significant increase in
the amount of major bleeding events, including intracra-
nial hemorrhage. A subanalysis of this trial did show site
variation and poor compliance with an almost 30% rate
of discontinuation of warfarin at follow-up so the pos-
sibility remained that the lack of efficacy was related to
poor medication adherence.
Rivaroxaban
The development of factor Xa inhibitors such as rivarox-
aban and apixaban is promising for a number of differ-
ent applications. Its potential benefits include increased
patient compliance and lower likelihood of major bleed-
ing when compared with warfarin.58–60 The COMPASS
trial (Cardiovascular Outcomes for People Using Anti-
coagulation Strategies) published in late 2017 demon-
strated improved mortality with low-dose rivaroxaban in
combination with aspirin for patients with PAD. Low-
dose rivaroxaban, 2.5 mg twice daily, is a regimen previ-
ously used in the ATLAS-TIMI 51 trial (Anti-Xa Therapy
to Lower Cardiovascular Events in Addition to Standard
Therapy in Subjects With Acute Coronary Syndrome–
Thrombolysis in Myocardial Infarction) evaluating the
use of rivaroxaban in patients with recent ACS with the
finding that this dosage decreased mortality of patients
with recent ACS over placebo.61 COMPASS tested this
medication in CAD, PAD, or both. The predetermined
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 Bevan and White Solaru Medical Management of Peripheral Artery Disease

Table.  Evidence Underlying Medical Management of PAD

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Medical ACC/AHA
Therapy Intervention Guideline Study, Year Patient Population Results Interpretation
Cholesterol Statin Class IA for Heart Protection 13 788 high-risk adults, HR, 0.88 (CI, 15–29) Simvastatin reduces major vascular
reduction high-intensity Study, 200724 6748 prespecified events in patients with PAD
statin therapy adults with symptom-
atic PAD
Ezetimibe Class IIA IMPROVE-IT trial, 17 717 patients with HR, 0.81 (CI, 0.73–0.90) High-risk patients, 18% of whom
201621 4393 high-risk patients had PAD, experienced the greatest
benefit from ezetimibe
PCSK9 Class IIA FOURIER trial, 24 081 patients, 3642 HR, 0.79 (CI, 0.66–0.94); PCSK9 inhibitor evolocumab
inhibitors 201833 had symptomatic PAD P=0.0098 decreases the rate of major cardio-
on enrollment vascular events in high-risk PAD
patients
Antiplatelet Aspirin Class IA Antithrombotic Meta-analysis, 9214 23% odds reduction (SE, Antiplatelet therapy, including aspi-
therapy Trialists’ Collabo- PAD 8%) rin, reduces odds of having a seri-
ration, 200245 ous vascular event
CLIPS trial, 366 with symptomatic HR, 0.36; P=0.022 Aspirin decreases the rate of major
200746 and asymptomatic PAD vascular events in symptomatic PAD
Clopidogrel Class IA CAPRIE trial, 19 185 patients, 6452 HR, 0.76; P=0.0028 Clopidogrel reduces major cardio-
199649 with symptomatic PAD vascular events over aspirin
on enrollment
Ticagrelor EUCLID trial, 13 885 with symptom- HR, 1.02 (95% CI, 0.92– Ticagrelor does not reduce major
201752 atic PAD 1.13); P=0.65 cardiovascular events over clopi-
dogrel
Anticoagula- Warfarin Class IIB WAVE trial, 2161 with symptomatic HR, 0.92 (CI, 0.73–1.16); Warfarin did not reduce major car-
tion 200760 PAD P=0.48 diovascular events over placebo
Rivaroxaban COMPASS trial, 27 395 patients, 7470 HR, 0.72 (CI, 0.57–0.90) Low-dose rivaroxaban and aspirin
201765 with symptomatic PAD reduce major cardiovascular events
on enrollment and adverse limb events over aspi-
rin alone
Peripheral Cilostazol Class IA Cochrane Meta- 3718 with symptomatic 31.41 m (CI, 22.38–40.45 Cilostazol increases initial claudica-
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vasodilator Analysis, 201469 PAD m); P<0.00001 tion distance above placebo
Exercise Class IA Cochrane Meta- Meta-analysis, 391 with Mean increase of 82.11 Exercise therapy increases pain-free
therapy Analysis, 201792 PAD and claudication m in pain-free walking walking distance in patients with
distance ([95% CI, 71.73– claudication
92.48] P<0.00001)
Smoking ces- Intensive Class IA Hartmann et 124 with PAD HR, 3.13 at 52 wk; Intensive smoking intervention
sation intervention al, 201088 P=0.023 increases cessation in patients
with PAD

ACC indicates American College of Cardiology; AHA, American Heart Association; CAPRIE, Clopidogrel Versus Aspirin in Patients at Risk for Ischemic Events;
CLIPS, Critical Leg Ischemia Prevention Study; COMPASS, Cardiovascular Outcomes for People using Anticoagulation Strategies; EUCLID, Examining Use of
Ticagrelor in Peripheral Artery Disease; FOURIER, Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk; HR, hazard
ratio; IMPROVE-IT, Improved Reduction of Outcomes: Vytorin Efficacy International Trial; PAD, Peripheral artery disease; PCSK9, proprotein convertase subtilisin/
kexin type 9; and WAVE, Warfarin Antiplatelet Vascular Evaluation.

PAD subgroup included patients with symptomatic
lower extremity disease (55.2% of subgroup), as well
as carotid artery disease. The primary end point of car-
diovascular death, stroke, or MI occurred in 4.1% in the
aspirin and low-dose rivaroxaban group compared with
4.9% in the rivaroxaban-alone group and 5.4% in the
aspirin-alone group for all patients including those with
CAD. In those patients enrolled with PAD, the primary
end point occurred in the aspirin and low-dose rivaroxa-
ban group 5.1% of the time versus 6.9% of the time
for the aspirin-alone group. A comparison of the riva-
roxaban-alone group and the aspirin-alone group was
not different.62 Importantly, major adverse limb events
occurred less often in patients with PAD taking rivaroxa-
ban and aspirin than aspirin alone, though these events
were uncommon (1% versus 2%).63 As expected, both
the rivaroxaban-plus-aspirin group and the rivaroxaban-
alone group had higher major bleeding events than the
aspirin-alone group (3.1%, 2.8%, and 1.9%), though the
impact of this adverse event was somewhat mitigated
by no statistically significant increase in fatal bleeding
or symptomatic intracranial bleeding between the rivar-
oxaban-plus-aspirin group and the aspirin-alone group
(P=0.40). Patients ≥75 years of age with and without
PAD did not have a significant reduction in the primary
end point with low-dose rivaroxaban and aspirin, so
providers should consider the use of anticoagulation
in this geriatric population with caution.62,63 Low-dose
rivaroxaban and aspirin combination therapy compares
favorably to other effective PAD medications such as
statins. The Heart Protection Study found a 22% rela-
tive risk reduction in the first major vascular event with

546   March 2020 Arterioscler Thromb Vasc Biol. 2020;40:541–553. DOI: 10.1161/ATVBAHA.119.312142
 Bevan and White Solaru
moderate-intensity statin therapy while the COMPASS
trial showed a 28% relative risk reduction in the pri-
mary outcome with thw use of low-dose rivaroxaban
and aspirin.23,62,63 Importantly, the primary end point of
cardiovascular death, stroke, or MI occurred more often
in the PAD group, once again highlighting the impor-
tance of maximizing effective therapies in this patient
population.
PERIPHERAL VASODILATORS
Intermittent claudication represents peripheral isch-
emia distal to a stenosis in the setting of exertion. This
supply-demand mismatch is often a result of the steno-
sis, thus insufficient vasodilatory response may result in
symptoms that are relieved by rest. As such, peripheral
vasodilators are potentially beneficial for claudication.
Claudication itself is associated with functional decline,
and thus improvement of this symptom should be a focus
of providers.64 The ACC/AHA guidelines include a class
IA recommendation cilostazol in the treatment of symp-
tomatic claudication.15
Cilostazol
Multiple trials have evaluated the utility of this medica-
tion for the treatment of symptomatic PAD. A systematic
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Cochrane Review of 15 trials concluded that cilostazol
increases exercise tolerance compared with placebo.
Eight of the trials reviewed could be compared on the
basis of walking distance before the onset of claudica-
tion symptoms with 100 mg twice daily improving the
weighted mean walking distance by 31.41 m ([95% CI,
22.38–40.45 m] P<0.00001). No difference in absolute
mortality was appreciated though there were a small
number of events in the trials.65,66 For comparison, a
Cochrane Review found supervised exercise programs
resulted in ≈150 m increase in walking distance or ≈30%
to 35% increase, which was sustained at 6 months.67 The
improvement seen with cilostazol is subtle in comparison
to supervised exercise programs. Incidence of headache,
palpitations, and diarrhea are relatively common adverse
effects.68 More importantly, cilostazol is contraindicated
in patients with heart failure as medications in this
class may be associated with excess mortality.69 Medi-
cal comorbidities like diabetes mellitus, hyperlipidemia,
and hypertension are common in patients with PAD, so
patients are frequently taking a number of medications.
The side effect profile, heart failure contraindication, pill
burden, and subtle benefit are all reasons cilostazol is
infrequently used and should only be considered in oth-
erwise medically optimized patients with refractory clau-
dication who are able to tolerate the medication.
Arterioscler Thromb Vasc Biol. 2020;40:541–553. DOI: 10.1161/ATVBAHA.119.312142
Medical Management of Peripheral Artery Disease
BLOOD PRESSURE MANAGEMENT
ATVB IN FOCUS - VB
The 2016 ACC/AHA guidelines for lower extremity
peripheral artery disease gives antihypertensive therapy
a class IA recommendation for patients with peripheral
artery disease and suggests that blood pressure man-
agement should be in accordance with current hyperten-
sion guidelines given significant cardiovascular mortality
in this population.15 According to current 2017 ACC/
AHA guidelines on hypertension, antihypertensive medi-
cation is recommended for patients with cardiovascular
disease and systolic pressure >130 or diastolic blood
pressure >80.70 However, a post hoc analysis of INVEST
(International Verapamil-SR/Trandolapril Study), which
included 2699 patients with both PAD and CAD, showed
a j-shaped curve of mortality and blood pressure. For
patients with PAD, mortality benefits were seen with a
treated systolic blood pressure of 135 to 145 mm Hg
and treated diastolic pressure of 60 to 90 mm Hg with
higher mortality observed in low systolic and high sys-
tolic blood pressure ranges, supporting the paradigm
that blood pressure management in PAD is a balance
between limb perfusion and risk factor modification.71
As a result, the European Society of Cardiology recom-
mends lowering blood pressure in patients with PAD to
<140/90 with a class IA recommendation.72 Perhaps
future trials will elucidate the ideal blood pressure range
for patients with PAD.
Angiotensin-Converting Enzyme Inhibitors and
Angiotensin Receptor Blockers
The use of ACE (angiotensin-converting enzyme) inhib-
itors as an antihypertensive class has been evaluated
for patients with PAD with some evidence to suggest
benefit of this medication over other antihypertensives.
In 2000, the HOPE trial (Heart Outcomes Prevention
Evaluation) compared the use of ramipril to placebo in
patients with cardiovascular disease without heart fail-
ure with reduced ejection fraction. The study included
3099 patients with PAD defined as low ankle-brachial
index. A post hoc analysis found that patients with
PAD benefited from a significant reduction in the pri-
mary outcome of cardiovascular death, MI, or stroke as
did those patients without peripheral vascular disease.
Patients entering the trial had a similar blood pressure
of 139/79 mm Hg in both groups. The mean blood
pressure was 133/76 mm Hg in the ramipril group and
137/78 mm Hg in the placebo group at 1 month and
maintained a similarly small reduction throughout the
duration of the study.73 The relatively small reduction in
blood pressure in the treatment arm implies there may
be an additional benefit to the use of ACE inhibitors
over other antihypertensives.74 The ONTARGET trial
(Ongoing Telmisartan Alone and in Combination With
Ramipril Global End Point Trial) compared angiotensin
March 2020   547
 Bevan and White Solaru
receptor blocker (ARB) telmisartan to ramipril or com-
bination ARB and ACE inhibitor therapy and found no
ATVB IN FOCUS - VB
significant difference in the primary end point of cardio-
vascular mortality, MI, stroke, or hospitalization for heart
failure between all 3 groups but a higher rate of adverse
events in the combination group. The trial included
3468 patients with PAD.75 Several prospective and ret-
rospective studies have shown a reduction in mortality
with ACE inhibitor and ARB over other antihypertensive
agents.76,77 As a result of these data, both the European
Society of Cardiology and ACC/AHA guidelines give a
class II recommendation for ACE inhibitor or ARB for
PAD.15,72
Nevertheless, a post hoc subanalysis of the ALL-
HAT (Antihypertensive and Lipid-Lowering Treatment
to Prevent Heart Attack Trial) and a prespecified sub-
group analysis of VALUE (Valsartan Antihypertensive
Long-Term Use Evaluation) did not show a significant
reduction in primary end points of fatal or nonfatal MI
and major adverse cardiovascular events, respectively,
with ACE inhibitor or ARB over other antihypertensive
classes in subgroup analysis of patients with symptom-
atic PAD.78–80 Certainly, control of hypertension is an
important facet to medical therapy in PAD, but it remains
to be seen whether ACE inhibitor or ARB offer benefits
beyond blood pressure control in PAD.
SMOKING CESSATION
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Smoking is the single greatest modifiable risk factor
for the development and progression of PAD. Tobacco
smoke increases endothelial cell permeability by forma-
tion of reactive oxygen species, which enables athero-
sclerosis to settle within vessel walls.81 The magnitude of
this effect is clinically evident with the prevalence of PAD
increased 2.3-fold in current smokers, by one system-
atic review.82 The risk of incident PAD persists for ≤30
years even with cessation.83 Patients with PAD experi-
ence smoking-related complications and increased
mortality. In one registry of 739 patients with PAD who
underwent angiography, those who continued smoking
had increased mortality at follow-up to 5 years (31%
versus 14%; P<0.05). In the same registry, amputation
rate was also higher in survivors who continued to smoke
(40% versus 19%; P<0.05).84 Smoking fosters PAD and
augments complication rates, and thus providers should
focus on cessation.
Multidisciplinary efforts to intervene on smoking can
be effective. In one randomized trial of 124 patients,
an intensive intervention group, which included cogni-
tive behavioral counseling, motivational interviewing,
and pharmacological therapy, resulted in a significantly
higher rate of cessation than verbal advice alone (21.3%
versus 6.8%; P=0.023).85 Even physician verbal advice
alone has been associated with improved smoking ces-
sation.86 Pharmacological therapy for smoking cessation
548   March 2020 Arterioscler Thromb Vasc Biol. 2020;40:541–553. DOI: 10.1161/ATVBAHA.119.312142
Medical Management of Peripheral Artery Disease
is recommended in patients with PAD to reduce cravings.
Varenicline was assessed in 714 patients with stable
cardiovascular disease including 179 patients with PAD.
While there was not a subanalysis of this PAD group,
patients taking varenicline did have higher rates of smok-
ing cessation for the duration of the trial at 52 weeks
(19.2% versus 7.2%; P<0.0001). There was no change
in cardiovascular mortality or all-cause mortality between
patients taking varenicline and placebo (cardiovascu-
lar mortality, 0.3% versus 0.6% [CI, 1.3–0.7]; all-cause
mortality, 0.6% versus 1.4% [CI, 2.3–0.6]).87 Accord-
ing to guidelines, bupropion is equivalent in efficacy to
varenicline for smoking cessation purposes.86 Nicotine
replacement therapy is also recommended as a therapy
to aid smoking cessation. A recent Cochrane Review on
the safety and efficacy of 136 nicotine replacement ther-
apy trials found that all varieties of nicotine replacement
therapy (gum, patch, lozenge, spray) effectively increase
the rate of cessation. Combined nicotine replacement
therapy, for example, using a nicotine patch and gum, is
also felt to be more effective than use of a single agent
alone. Furthermore, while side effects of tachycardia and
arrhythmia were more common with the use of nicotine
replacement therapy than placebo, serious cardiovascu-
lar side effects such as stroke, MI, and cardiovascular
death were not more common in nicotine replacement
therapy groups.86,88 Though evidence is lacking for a
direct reduction in PAD-related mortality with use of
counseling or pharmacological therapy such as nico-
tine replacement therapy, bupropion, and varenicline, the
impact these interventions can have on smoking cessa-
tion efforts was sufficient to codify these interventions as
class IA recommendations for PAD patients.15
EXERCISE THERAPY
Plaque burden and endothelial dysfunction narrow and
stiffen the arteries supplying lower extremity skeletal
muscles in patients with PAD. The debilitating pain of
claudication results from increased skeletal muscle
demand for oxygen during exercise not met with ade-
quate supply as a result of complex alterations in arterial
physiology including changes in flow-mediated dilation—
a measure of endothelial function.89–91 Exercise therapy
is designed to address lifestyle limitations imposed by
claudication symptoms of PAD.
A number of randomized trials have demonstrated
improvement in functional capacity following exercise
therapy, and as such, the ACC/AHA provides a class 1A
recommendation for supervised therapy for patients with
claudication.15 A recent meta-analysis of exercise ther-
apy trials found a mean difference of 82.11 m ([95% CI,
71.73–92.48] P<0.00001) in pain-free walking distance,
in addition to improvements in quality-of-life metrics.92
Meta-analysis also showed that supervised exercise
 Bevan and White Solaru
therapy programs appear to be even more effective than
home-based therapy with similar adherence rates.93 The
duration of benefit from exercise therapy is prolonged
well beyond the completion of the program, ≤7 years fol-
lowing a 28-week supervised program.94 Several studies
have shown improvements in flow-mediated dilation fol-
lowing exercise therapy, but not all trials demonstrated
success.95–97 Exercise therapy does not have a clear
effect on mortality or amputation rates.92,93
HEALTH DISPARITIES
Special emphasis on the optimization of medical man-
agement for PAD should be placed on at-risk popula-
tions. In particular, blacks face elevated rates of PAD
leading to high morbidity and mortality.10,11 The incidence
of PAD among blacks remains strikingly high, ≈2 to 3×
the rate of non-Hispanic whites at all age groups. This
elevated incidence occurs in spite of a lower smok-
ing rate in this population.98,99 Black race is one of the
strongest risk factors for the development of PAD and
remains so even when controlling for traditional cardio-
vascular risk factors (smoking, diabetes mellitus, and
hypertension) and nontraditional inflammatory markers
associated with cardiovascular disease (CRP [C-reac-
tive protein], IL-6 [interleukin 6], D-dimer, fibrinogen,
and homocysteine).10,11,100,101 Age-adjusted mortality for
black men is higher than non-Hispanic whites and His-
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panic men (24.8 versus 19.9 versus 15.4 per 100 000),
and rates are similarly elevated for blacks above non-
Hispanic whites and Hispanic women (16.5 versus 13.8
versus 10.7).102,103 Importantly, mobility loss secondary to
PAD is also worse for blacks.104 In addition, blacks are 2
to 4× more likely to undergo amputation when compared
with non-Hispanic whites.12,105,106 Furthermore, graft fail-
ure and amputation following bypass is more common in
blacks, in particular, black women.107
Management of PAD in blacks has been shown to be
suboptimal. Although smoking is a significant risk fac-
tor for the development of PAD and its complications,
smoking is the least successful factor modification in
blacks.108 Furthermore, blacks are more likely to attempt
to quit than whites though less likely to succeed.109
Though CLI is more common in the black population,
blacks are less likely to be offered and to receive salvage
revascularization attempts.110–112 This could be due to a
number of factors including unconscious bias and more
advanced disease at time presentation.113 Improvement
of medical optimization in this population may mitigate
the disparity in limb salvage rate. As of yet, medical man-
agement appears to be underutilized in blacks. Choles-
terol-lowering therapies are less frequently prescribed in
blacks even when indicated by the guidelines.114,115 Black
women, in particular, appear to have even lower rates of
Arterioscler Thromb Vasc Biol. 2020;40:541–553. DOI: 10.1161/ATVBAHA.119.312142
Medical Management of Peripheral Artery Disease
guideline-based statin use.116 On review of >23 000
PAD interventions, one study found that blacks were less
ATVB IN FOCUS - VB
likely to be on a statin before abdominal aortic aneu-
rysm repair or PAD intervention. Furthermore, blacks
were less likely to be discharged on combination statin
and antiplatelet regimen after either abdominal aortic
aneurysm repair or PAD intervention.117 In addition to
improving application of guideline-based therapy, nontra-
ditional healthcare settings may improve delivery of care.
A recent pharmacist-led intervention in predominantly
black barbershops identified hypertensive adults and
prescribed antihypertensives with excellent control in
blood pressure and improved medication adherence.118
Utilization of barbershops for identification and medical
optimization of PAD in the black population is an emerg-
ing area of interest and may result in similarly improved
control of blood pressure, as well as reduction in choles-
terol, platelet activity, and coagulation.119
CONCLUSIONS
PAD is a devastating disease with high morbidity and high
mortality. Though trials assessing effectiveness of medi-
cal interventions for PAD remain few in number, provid-
ers and patients alike should remain optimistic given the
expanding number of available management strategies.
Beyond medical therapy, ongoing trials such as BEST-
CLI (Best Endovascular Versus Best Surgical Therapy for
Patients With Critical Limb Ischemia) will provide insight
into optimal interventional practices for patients with
PAD.120 A number of medical therapies exist to reduce
cardiovascular mortality, as well as prevent progression,
limb loss, and the need for invasive interventions. Cho-
lesterol management includes not only high-intensity
statin therapy but ezetimibe and PCSK9 inhibitors, all of
which have the potential to reduce limb loss and improve
cardiovascular outcomes. Antiplatelet therapy remains
a cornerstone of PAD management with clopidogrel
decreasing limb events, stroke, and MI even above aspi-
rin. New to the repertoire of the treating provider, rivar-
oxaban adds to a growing list of effective medications
possibly by addressing atherothromboembolism—a com-
mon source of complications in PAD. Cilostazol and ACE
inhibitor continue to have a role in the management of
select patients though evidence supporting their use
for PAD is less robust. Patients with claudication symp-
toms can find symptomatic improvement with supervised
exercise therapy. Finally, interventions to aid in smok-
ing cessation such as counseling, nicotine replacement
therapy, bupropion, and varenicline are effective and safe
tools for risk factor modification. Despite the multitude
of medical treatment options available, PAD is chroni-
cally undertreated relative to CAD. Future advancements
in management strategies and improved application of
March 2020   549
 Bevan and White Solaru
available medical therapies will prevent complications
and improve the quality of life for patients with PAD.
ATVB IN FOCUS - VB
ARTICLE INFORMATION
Received October 7, 2019; accepted January 17, 2020.
Affiliations
From the Department of Medicine (G.H.B., K.T.W.S.) and Harrington Heart and
Vascular Institute (K.T.W.S.), University Hospitals Cleveland Medical Center, OH;
and Case Western Reserve University School of Medicine, Cleveland, OH (G.H.B.,
K.T.W.S.).
Disclosures
None.
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