REVIEW

Peripheral Artery Disease: Past, Present, and

Future
Umberto Campia, MD,a,b Marie Gerhard-Herman, MD,a,b Gregory Piazza, MD,a,b Samuel Z. Goldhaber, MDa,b
a
Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Mass; bHarvard Medical School, Boston.

ABSTRACT

Peripheral artery disease is a prevalent but underdiagnosed manifestation of atherosclerosis. There is insuf-
ficient awareness of its clinical manifestations, including intermittent claudication and critical limb ische-
mia and of its risk of adverse cardiovascular and limb outcomes. In addition, our inadequate knowledge of
its pathophysiology has also limited the development of effective treatments, particularly in the presence
of critical limb ischemia. This review aims to highlight essential elements of the epidemiology and patho-
physiology of peripheral artery disease, bring attention to the often-atypical manifestations of occlusive
arterial disease of the lower extremity, increase awareness of critical limb ischemia, briefly describe the
diagnostic role of the ankle brachial index, and go over the contemporary management of peripheral artery
disease. An emphasis is placed on evidence-based medical treatments to improve symptoms and quality of
life and to reduce the risk of cardiovascular and limb events in these patients, including supervised exer-
cise training, smoking cessation, antagonism of the renin-angiotensin system, lipid-lowering, antiplatelet,
and antithrombotic therapies.
Ó 2019 Elsevier Inc. All rights reserved.
The American Journal of Medicine (2019) 132:1133−1141

KEYWORDS: Cardiovascular risk; Critical limb ischemia; Intermittent claudication; Peripheral artery disease

INTRODUCTION
Peripheral artery disease is one manifestation of atheroscle-
rotic vascular disease. Despite its high prevalence, peripheral
artery disease often remains unrecognized and underdiag-
nosed. There is insufficient awareness of its clinical manifes-
tations, including impaired walking, classic intermittent
claudication, and critical limb ischemia, and of the associated
adverse cardiovascular events and limb outcomes. Our
incomplete knowledge of peripheral artery disease pathophys-
iology has limited the development of innovative medical
Funding: None.
Conflicts of Interest: UC and MGH, none. GP receives grant and
research support from BMS, Daiichi-Sankyo, BTG, Janssen, Bayer, and
Portola and is on the advisory panel for Pfizer. SZG receives research sup-
port from Boehringer-Ingelheim, BMS, BTG EKOS, Daiichi, Janssen,
NHLBI, and Thrombosis Research Institute and is a consultant for Bayer;
Boehringer-Ingelheim; BMS; Daiichi; Janssen; Portola.
Authorship: All authors had access to the data and a role in writing
this manuscript. UC conceived, drafted, designed figures, and had final
approval of the manuscript. MGH, GP, and SZG revised and had final
approval of the manuscript.
Requests for reprints should be addressed to Umberto Campia, MD, Brig-
ham and Women’s Hospital, 75 Francis St − AB 378, Boston, MA 02115.
E-mail address: ucampia@bwh.harvard.edu
therapy for its symptoms and has contributed to the subopti-
mal outcomes of revascularization, particularly in the pres-
ence of critical limb ischemia. In the present review, we will
highlight essential elements of the epidemiology and patho-
physiology of peripheral artery disease and will describe the
often-atypical manifestations of peripheral artery disease,
including critical limb ischemia, the most advanced form of
occlusive arterial disease. We will describe the diagnostic
role of the ankle brachial index and will outline the contem-
porary management of peripheral artery disease. We have
placed an emphasis on evidence-based medical treatments to
improve symptoms and quality of life and to reduce the risk
of cardiovascular and limb events in patients with peripheral
artery disease, including supervised exercise training, smok-
ing cessation, antagonism of the angiotensin system, and
lipid-lowering, antiplatelet, and antithrombotic therapies.
DEFINITIONS
A number of terms refer to arterial occlusive disease of the
lower and upper extremities (eg, peripheral vascular disease,
peripheral arterial disease, peripheral arterial occlusive dis-
ease, and arteriosclerosis obliterans).1 In this review, periph-
eral artery disease will refer to atherosclerotic disease of the

0002-9343/© 2019 Elsevier Inc. All rights reserved.

https://doi.org/10.1016/j.amjmed.2019.04.043
1134 The American Journal of Medicine, Vol 132, No 10, October 2019

lower extremity, including the aortoiliac, femoropopliteal, to maintain calfmuscle perfusion despite a decrease in sys-
and infrapopliteal arterial segments, which comprises its tolic pressure.8 However, in the exercising muscle, this
most prevalent form.2 mechanism fails to sufficiently increase blood flow to match
metabolic demands, with ensuing muscle ischemia. The
occurrence of repetitive cycles of exercise-induced ische-
EPIDEMIOLOGY
mia followed by reperfusion triggers the formation of
Intermittent claudication, the occurrence of leg pain, aching,
reactive oxygen species, leading to abnormal myocyte
cramping, or fatigue triggered by walk-
metabolism and impaired con-
ing and relieved by rest, has long been
tractile performance.9
recognized as a manifestation of a CLINICAL SIGNIFICANCE
reduced arterial perfusion of the lower
Peripheral artery disease is a common CLINICAL
extremities.3 However, when intermittent
manifestation of atherosclerosis and is MANIFESTATIONS OF
clausidcation was used in epidemiologi-
cal studies to define peripheral artery dis-
associated with cardiovascular morbid- PERIPHERAL ARTERY
ease, it led to underestimation of the ity and mortality, and with limb events. DISEASE
prevalence of the disease. This limitation
Peripheral artery disease remains The majority of patients with
was overcome with the introduction of underdiagnosed and undertreated. peripheral artery disease do not
the ankle brachial index, a more objec-
Management aims to improve symp- present with the classic features
tive, noninvasive test that can detect the toms and quality of life and reduce the of intermittent claudication.
presence of arterial occlusive disease in risk of cardiovascular and limb events. The Edinburgh Artery Study
patients who are both symptomatic and
Exercise and novel medical therapy showed that, in participants
asymptomatic. An ankle brachial index reduce risk of cardiovascular and limb with an ankle brachial index
of ≤0.90 is generally considered diag- events in patients with peripheral arte- ≤0.90, only 15% reported clas-
nostic of peripheral artery disease for rial disease. sic intermittent claudication,
both epidemiological and clinical pur- whereas 35% reported no exer-
poses.4 Generally, when this ankle bra- tional leg symptoms. A large
chial index value is used, the prevalence of peripheral artery proportion of patients have possible claudication, defined as
disease in the United States is low in people 50 years and exertional calf pain starting with exertion but not otherwise
younger. However, peripheral artery disease rates increase meeting the standard criteria. Additional presenting symp-
sharply with age, reaching approximately 20% in octogenar- toms include “leg pain/carry on” (leg pain that occurs with
ians. Of note, rates of peripheral artery disease at any given exertion but does not force the patient to stop walking) and
age have been reported to be approximately twice as high in “leg pain on exertion and rest” (consistently triggered by
African Americans compared with other races.3 activity but at times be present at rest; Figure 2, top).

RISK FACTORS FOR PERIPHERAL ARTERY

DISEASE CRITICAL LIMB ISCHEMIA
A small proportion of patients with peripheral artery disease
Lower-extremity peripheral artery disease is associated with
presents with or progresses to the most severe manifesta-
all major atherosclerotic risk factors. Cigarette smoking is
tions of arterial occlusive disease, critical limb ischemia,
associated with a 2- to 4-fold increased risk of peripheral
defined as: “A condition characterized by chronic (≥2
artery disease.5 Similarly, diabetes mellitus is associated with
weeks) ischemic rest pain, nonhealing wound/ulcers, or
an approximately 2- to 4-fold increase in risk. The risk associ-
gangrene in 1 or both legs attributable to objectively proven
ated with hypertension appears to be more modest, with
reported odds ratios from 1.5 to 2.2.3 The association between arterial occlusive disease.”2 Critical limb ischemia is asso-
ciated with a high risk for or actual tissue loss, amputation,
dyslipidemia and peripheral artery disease appears to be multi-
and cardiovascular events. Usually, patients with critical
faceted. Higher total cholesterol is associated with increased
limb ischemia present with an ankle brachial index < 0.4
risk, whereas higher high-density lipoprotein (HDL) choles-
and toe systolic pressure < 30 mm Hg10 (Figure 2, bottom).
terol is associated with decreased risk.3,6

PATHOPHYSIOLOGY OF LOWER-EXTREMITY DIAGNOSIS OF PERIPHERAL ARTERY DISEASE

MANIFESTATIONS
Patients with peripheral artery disease present with a spec-
trum of lower-extremity symptoms and functional
impairment as a result of both blood flow limitation during
exercise and progressive myocyte damage with muscle
remodeling7 (Figure 1). At rest, in the presence of hemody-
namically significant stenosis, vascular resistance decreases
A comprehensive medical history and thorough physical
examination are an essential first step in the diagnosis of
peripheral artery disease (Figure 3). However, various condi-
tions associated with leg symptoms, such as spinal stenosis,
osteoarthritis, chronic venous insufficiency, and neuropathy,
may masquerade as or be present in addition to peripheral
artery disease. Therefore, the diagnosis of peripheral artery
Campia et al Contemporary Management of Peripheral Arterial Disease 1135

Figure 1 Pathophysiology of lower-extremity manifestations in peripheral artery disease. Left panel: In the normal artery, the
healthy endothelium maintains arterial homeostasis through the balanced release of nitric oxide and endothelin-1. The reflected
waves and the elasticity of the vessels lead to an increase of systolic blood pressure in the ankle arteries, with normal ankle brachial
index values. With physical activity, physiologic vasodilatation allows for a large increase in blood flow to match the increased
metabolic demands of the exercising muscles. In the presence of atherosclerosis, endothelial activation and dysfunction lead to
endothelin-mediated baseline vasoconstrictor tone and a prothrombotic milieu. The hemodynamic effects of the stenosis include
the generation of turbulent flow, abnormal shear stress, and loss of potential energy with drop of systolic blood pressure in the ankle
arteries and abnormal ankle brachial index. During exercise, the inability to increase blood flow causes a demand/perfusion mis-
match, leading to muscle ischemia. Right panel: Effects of cycles of recurrent ischemia and reperfusion on the lower-extremity
skeletal muscle in patients with peripheral artery disease. ABI = ankle brachial index; ET-1 = endothelin 1; NO = nitric oxide;
SBP = systolic blood pressure.

disease requires a high index of suspicion and confirmation
with a more objective and physiology-based approach.
THE ANKLE BRACHIAL INDEX IN THE DIAGNOSIS
OF PERIPHERAL ARTERY DISEASE
In healthy individuals, the systolic blood pressure increases
distally in the arterial circulation4 and is higher in the lower
than in the upper limb. In the presence of hemodynamically
significant stenosis, there is a decline in the systolic pressure
distal to the obstruction that is proportional to its severity.
Based on these principles, the ratio of the systolic pressure
measured at the brachial artery and at the ankle arteries has
been adopted to diagnose peripheral artery disease.4 Of note,
ankle brachial index values >1.40 result from reduced arte-
rial compressibility and cannot be used to diagnose periph-
eral artery disease. In that case, the ratio of the pressure
measured at the first toe and at the brachial artery (toe bra-
chial index) should be used (Figure 3). A toe brachial index
≤ 0.7 is diagnostic of arterial occlusive disease. Currently,
the resting ankle brachial index is the initial diagnostic test
recommended by the 2016 American Heart Association/
American College of Cardiology (AHA/ACC) guideline on
the management of patients with peripheral artery disease.2
CARDIOVASCULAR AND LIMB EVENTS RISK IN
PERIPHERAL ARTERY DISEASE
Peripheral artery disease is associated with high risk of coro-
nary artery disease or cerebrovascular disease.11 The rates of
myocardial infarction, ischemic stroke, and vascular death in
patients with peripheral artery disease without critical limb
ischemia has been estimated at 5%-7% per year. The most
common causes of death in patients with peripheral artery
disease are coronary and cerebrovascular disease, which
account for 40%-60% and for 10%-20% of occurrences,
respectively. Of note, in patients with critical limb ischemia,
the risk of death at 1 year is as high as 25%.3 Major amputa-
tions in patients with intermittent claudication have been
reported in 1% to 3% of patients over a 5-year period. How-
ever, in the presence of critical limb ischemia, the risk of
major amputation at 1 year is approximately 50%.10
MEDICAL MANAGEMENT OF PERIPHERAL ARTERY
DISEASE
The goals of medical therapy for peripheral artery disease
include improvement of limb symptoms, exercise perfor-
mance, and quality of life, as well as reduction of the risk
of adverse cardiovascular events and limb events (Figure 4).
1136
Figure 2 Clinical manifestations of peripheral artery disease. ABI = ankle brachial index; IC = intermittent clau-
dication.
The availability of evidence-based treatments has led to the
publication of focused guidelines to help manage patients
with peripheral artery disease.2,12 Unfortunately, despite
evidence that adherence to guideline-recommended man-
agement is associated with better outcomes,13 patients with
peripheral artery disease are undertreated in comparison
with those with coronary artery disease.14
IMPROVEMENT OF LIMB SYMPTOMS, EXERCISE
PERFORMANCE, AND QUALITY OF LIFE
The most effective approaches include supervised exercise
training and endovascular revascularization. Supervised tread-
mill exercise is associated with an increase in maximal tread-
mill walking distance.15 Endovascular revascularization of the
lower extremity often results in rapid improvement of walking
distance and quality of life.16 In the Endovascular Revasculari-
zation and Supervised Exercise (ERASE) trial, patients with
peripheral artery disease were randomized to either supervised
exercise alone or supervised exercise and endovascular revas-
cularization.17 In the exercise-alone group, significant
increases from baseline were observed at 1 year in mean walk-
ing distance (285 m vs 1240 m, P = 0.001), pain-free walking
distance (135 m vs 712 m, P <0.001), and quality of life
measures, including the VascuQOL score and SF36 scores.
Both primary and secondary outcomes improved more in the
combination group compared with the exercise-alone group.
The results of this trial confirm the efficacy of supervised exer-
cise and support a combination strategy when revasculariza-
tion is feasible. Based on the high-quality evidence, the
2016 AHA/ACC guideline has given a class 1A recommenda-
tion for structured-exercise therapy.2 Supervised treadmill
exercise is now covered by the Center for Medicare and Med-
icaid Services, which should lead to more widespread use.18
The American Journal of Medicine, Vol 132, No 10, October 2019
Currently, evidence supporting the use of medical therapy
is limited to cilostazol, a phosphodiesterase type 3 inhibitor
with unclear mechanism of action. Cilostazol increases walk-
ing distance from baseline by approximately 50%, or 42
meters, over placebo.19 Based on the available evidence, the
2016 AHA/ACC guideline gives a class Ia recommendation
for cilostazol.2
REDUCTION OF RISK OF CARDIOVASCULAR AND
LIMB EVENTS
Intensive treatment of risk factors should be the first step to
reduce the risk of cardiovascular and limb events in patients
with peripheral artery disease.
SMOKING CESSATION
Cigarette smoking is one of the strongest risk factors for
peripheral artery disease. More than one-third of patients with
peripheral artery disease are current smokers.20 Smoking ces-
sation is the most important modifiable risk factor and is con-
sidered a performance measure in the management of patients
with peripheral artery disease.21 Smoking cessation is associ-
ated with improved cardiovascular and limb outcomes.22
However, despite the availability of counseling and pharma-
cologic strategies (eg, nicotine replacement, bupropion, and
varenicline), abstinence rates are as low as 21% at 6 months
despite intensive intervention.23 The recently published Expert
Consensus Decision Pathway provides a useful approach to
help clinicians in the evaluation and treatment of patients with
tobacco dependence.24 A simplified algorithm based on the
document’s recommendations is reported in Figure 5.
STATINS AND OTHER LIPID-LOWERING THERAPIES
A wealth of data indicate that statins lowers cardiovascular
risk in patients with atherosclerotic risk factors or stable
Campia et al Contemporary Management of Peripheral Arterial Disease 1137

Figure 3 Diagnosis of peripheral artery disease. DM = diabetes mellitus; PAD = peripheral artery disease.
*Diabetes mellitus, smoking, hyperlipidemia, hypertension, and family history of peripheral artery disease.
#Coronary, carotid, subclavian, renal, or mesenteric stenosis, or abdominal aortic aneurysm
yNon-joint related and not fitting the pattern of classic claudication. Consider alternative diagnoses: spinal stenosis;
nerve root compression; hip, knee, or ankle arthritis; venous claudication; chronic compartment syndrome; popli-
teal entrapment; and symptomatic Baker’s cyst.

coronary artery disease. In the Heart Protection Study,
which included a large group of patients with peripheral
artery disease, the use of simvastatin was associated with a
reduction of all-cause mortality, cardiovascular events,25 and
peripheral vascular events.26 Data from an international regis-
try suggest that statin therapy also leads to reduction in pro-
gression of claudication, incident critical limb ischemia, need
for revascularization, or amputation.27 Based on the overall
beneficial effects of statin, the ACC/AHA guideline give a
class I indication for statin treatment in all patients with
peripheral artery disease.2 More recent evidence of the impact
of lipid-lowering therapy in patients with peripheral artery
disease is provided by the results of the Further Cardiovascu-
lar Outcomes Research With PCSK9 Inhibition in Subjects
1138 The American Journal of Medicine, Vol 132, No 10, October 2019

Figure 4 Management of peripheral artery disease. ACE = angiotensin converting enzyme; ARB
= angiotensin receptor blocker; PAR = protease activated receptor; PCSK9 = proprotein convertase
subtilisin/kexin type 9; QOL = quality of life.

With Elevated Risk (FOURIER) trial. This study randomized
27,564 patients with atherosclerotic disease on statin therapy
to the PCSK9 inhibitor evolocumab or to placebo. Among
them, 3642 patients had symptomatic peripheral artery dis-
ease, defined as having intermittent claudication and an ankle
brachial index <0.85 or a history of prior peripheral vascular
procedure. Almost all of the patients (99.8%) were on
moderate- or high-intensity statin therapy, and the median
low-density lipoprotein (LDL)-cholesterol at baseline was
94 mg/dL. Evolocumab significantly reduced the primary
composite end point (eg, hospital admission for unstable
angina, myocardial infarction, coronary revascularization,
stroke, or cardiovascular death) as well as the risk of major
adverse limb events (eg, acute limb ischemia, urgent

Figure 5 Smoking cessation algorithm.

Campia et al Contemporary Management of Peripheral Arterial Disease
peripheral revascularization for ischemia, or major amputa-
tion). Of note, in the FOURIER trial, the lower the level
of LDL cholesterol achieved, the lower the risk of limb
events.28
LOWERING BLOOD PRESSURE
In the patients with peripheral artery disease enrolled in the
Heart Outcomes Prevention Evaluation (HOPE) trial, treat-
ment with the angiotensin-converting enzyme inhibitor
(ACE-I) ramipril was associated with a significant reduc-
tion in the primary outcome (ie, myocardial infarction,
stroke, or cardiovascular death)29 independent of symptoms
and ankle brachial index values.30 In addition, a retrospec-
tive analysis of data from the Peripheral Artery Disease-
University of California−Davis Registry showed that using
ACE-I or angiotensin receptor blockers is associated with
significantly lower risk of cardiovascular and cerebrovascu-
lar events and mortality in patients with critical limb
ischemia.31
ANTIPLATELET THERAPY
The benefit of antiplatelet drugs in peripheral artery disease
is not universal. Aspirin as a single agent in patients with
asymptomatic peripheral artery disease was not better than
placebo in the Prevention of Progression of Arterial Disease
and Diabetes (POPADAD) trial32 and in the Aspirin for
Asymptomatic Atherosclerosis (AAA) trial.33 However, in
patients with symptomatic peripheral artery disease, aspirin
monotherapy can reduce the risk of systemic atherothrom-
botic events.34 Clopidogrel was evaluated in the Clopidog-
rel versus Aspirin in Patients at Risk of Ischaemic Events
(CAPRIE) trial. Among patients with peripheral artery dis-
ease enrolled in the study, clopidogrel was associated with
an almost 24% relative risk reduction of the combined risk
of myocardial infarction, ischemic stroke, or vascular death
compared with 325 mg of aspirin. In a subgroup analysis of
the Clopidogrel for High Atherothrombotic Risk and Ische-
mic Stabilization, Management, and Avoidance (CHA-
RISMA) trial, patients with documented prior myocardial
infarction, ischemic stroke, or symptomatic peripheral
artery disease had a significantly lower rate of cardiovascu-
lar death, myocardial infarction, or stroke with dual-anti-
platelet therapy with low-dose aspirin and clopidogrel
compared with aspirin alone.35
COMBINED ANTIPLATELET AND
ANTITHROMBOTIC THERAPY
Atherothrombosis is considered a fundamental mechanism
in the pathogenesis of peripheral artery disease and its com-
plications.36 Although intensifying antiplatelet therapy
appears to exert some benefits in the reduction of risk of
cardiovascular events35 and, in the case of vorapaxar, of
limb events,37 the results of the pivotal COMPASS trial
indicate that the combination of antiplatelet and a low-dose
anticoagulant represent one of the most promising advances
1139
in the treatment of atherosclerotic cardiovascular disease.38
The study randomized 27,395 patients with stable coronary
artery disease, peripheral artery disease, or both to receive
aspirin (100 mg once daily), rivaroxaban (5 mg twice
daily), or rivaroxaban (2.5 mg twice daily) plus aspirin
(100 mg once daily) The primary outcome was a composite
of cardiovascular death, stroke, or myocardial infarction.
Of note, COMPASS was stopped early, after a mean follow
up of 23 months, for superiority of the rivaroxaban-plus-
aspirin group compared with the aspirin alone in reducing
the primary efficacy outcome (4.1% vs 5.4%, respectively;
hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.66
to 0.86; P < 0.001). A total of 7470 participants had periph-
eral artery disease, defined as history of revascularization,
amputation for arterial disease, intermittent claudication
with documented occlusive disease, carotid disease, or cor-
onary artery disease and an ankle brachial index of < 0.90.
Besides the primary cardiovascular efficacy endpoint, the
primary peripheral artery disease outcome was major
adverse limb events including acute limb ischemia, chronic
limb ischemia, and major amputation.39 When treatment
with rivaroxaban 2.5 mg twice daily plus aspirin was com-
pared with aspirin alone, it reduced the primary efficacy
outcome (5% vs 7%, respectively, HR 0.72, 95% CI 0.57
−0.90, P = 0.0047) as well as major adverse limb events
(1% vs 2%; HR 0.54 95% CI 0.35−0.82, P = 0.0037). The
combination of rivaroxaban plus aspirin was associated
with higher risk of major bleeding compared to aspirin
alone (3% vs 2%, respectively; HR 1.61, 95% CI 1.12
−2.31, P = 0.0089). However, no excess in fatal or critical
organ bleeding was observed with the combination therapy.
The benefit−risk analysis showed a net benefit for the com-
bination therapy compared with aspirin alone (7% vs 9%,
respectively; HR 0.72, 95% CI 0.59−0.87, P = 0.0008).
SUMMARY AND CONCLUSIONS
Peripheral artery disease is a common but often unrecog-
nized and underdiagnosed manifestation of atherosclerotic
vascular disease. Intermittent claudication, the classic man-
ifestation of peripheral artery disease, is associated with
reduced quality of life and mobility limitation. However,
even when patients with peripheral artery disease report no
or atypical symptoms, they present with functional
impairment and are at risk of adverse limb events, including
acute and chronic limb ischemia requiring revascularization
or amputation. Furthermore, peripheral artery disease is
associated with high risk of systemic atherothrombotic
events, including myocardial infarction, stroke, and cardio-
vascular death. Analyses of large clinical trials have
demonstrated that using statins and ACE-Is reduce cardio-
vascular risk in patients with peripheral artery disease, with
less clear effects for antiplatelet therapies. Additionally,
both low-dose antithrombotic therapy in association with
aspirin and lipid lowering with a PCSK9 inhibitor are asso-
ciated with reduction of both cardiovascular and limb
adverse events. Implementation of these therapies remains
1140
challenging because of cost and the burden of polyphar-
macy. Further study is necessary to identify the patients
with peripheral artery disease who will benefit the most
from these advances.
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