Evidence Based PAD

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
Downloaded from http://ahajournals.org by on April 29, 2021
eripheral artery disease (PAD) is a chronic, atheroscle- A number of therapies exist for the treatment of PAD,
rotic disease of the peripheral vasculature resulting including those directed toward management of claudi-
in limb-associated complications such as intermittent cation symptoms, secondary prevention of cardiovascu-
claudication, ischemic rest pain, ischemic ulcer, gangrene, lar complications, and limb salvage therapies. Treatment
and functional impairment. Sequelae requiring amputa- strategies can be subdivided into lifestyle modification,
tion carries a mortality of ≤50% at 1 year.1 While limb medical management, endovascular therapies, and surgi-
complications themselves are destructive, PAD is often cal interventions. The purpose of this review is to examine
a harbinger of obstructive atherosclerotic disease else- the medical management for the treatment of PAD, which
where, including the cerebral and coronary vasculature. primarily include cholesterol reduction, antiplatelet therapy,
Indeed, patients with PAD have an increased rate of isch- anticoagulation, peripheral vasodilators, blood pressure
emic stroke, myocardial infarction (MI), and cardiovascu- control, smoking cessation, and exercise therapy. Despite
lar death.2–4 Furthermore, patients with coronary artery the severity of this condition, patients with PAD are dra-
disease (CAD) and PAD have a much higher risk of car- matically undertreated relative to their CAD counterparts
diovascular mortality than CAD alone.5,6 Importantly, PAD with comparatively few trials directly assessing the effi-
is a significant burden for patients in terms of quality of cacy of medical interventions.9 In particular, blacks who
life and financial well-being.7 PAD is a relatively common have a high burden of disease are less likely to receive
condition with 220 million people affected globally and an evidence-based treatment, potentially resulting in higher
increasing prevalence worldwide.8 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
Please see www.ahajournals.org/atvb/atvb-focus improve PAD outcomes in the black community.
for all articles published in this series.

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 [email protected]
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 Medical Management of Peripheral Artery Disease
Nonstandard Abbreviations and Acronyms Highlights

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ACC American College of Cardiology • Peripheral artery disease is a disease of the lower
ACE angiotensin-converting enzyme extremity arteries associated with high cardiovascu-
AHA American Heart Association lar mortality.
• Medical management of peripheral artery disease
ALLHAT Antihypertensive and Lipid-Low-
includes cholesterol reduction, antiplatelet therapy,
ering Treatment to Prevent Heart
anticoagulation, peripheral vasodilators, blood pres-
Attack Trial
sure control, exercise therapy, and smoking ces-
ARB angiotensin receptor blocker sation, all of which have the capacity to reduce
BEST-CLI Best Endovascular Versus Best mortality, symptoms, and complications.
Surgical Therapy for Patients With • Peripheral artery disease treatment in blacks
Critical Limb Ischemia remains suboptimal despite a high incidence of
CAD coronary artery disease peripheral artery disease and complications in this
CAPRIE Clopidogrel Versus Aspirin in population.
Patients at Risk for Ischemic Events
CLI critical limb ischemia
CLIPS Critical Leg Ischemia Prevention improves cardiovascular outcomes.18–20 The American
Study College of Cardiology (ACC)/American Heart Associa-
COMPASS Cardiovascular Outcomes for tion (AHA) considers PAD to be equivalent to a history
People Using Anticoagulation of MI or stroke with respect to cholesterol-lowering
Strategies therapies.14,15,17 The ACC/AHA recommends all patients
DAPT dual antiplatelet therapy with symptomatic PAD to be on high-intensity statin. In
HDL high-density lipoprotein addition, individuals with PAD and another major athero-
HOPE Heart Outcomes Prevention sclerotic cardiovascular disease event (or 2 minor risk
Evaluation factors) should be treated to an LDL-C of <70 with a
INVEST International Verapamil-SR/Tran- class I recommendation.14,15 Emerging evidence show-
dolapril Study ing lower risk of ischemic events with the use of icosa-
LDL low-density lipoprotein pent ethyl in REDUCE-IT (Reduction of Cardiovascular

LDL-C low-density lipoprotein cholesterol Events With Icosapent Ethyl–Intervention Trial) suggests
MI myocardial infarction triglyceride reduction is effective for patients with cardio-
vascular disease, and future work may apply specifically
OASIS-II Organization to Assess Strategies
for Ischemic Syndromes to PAD.21
ONTARGET Ongoing Telmisartan Alone and in
Combination With Ramipril Global Statin Therapy
End Point Trial
Statin therapy is by far the most well-recognized choles-
PAD peripheral artery disease
terol-lowering therapy in the management of PAD. While
REDUCE-IT Reduction of Cardiovascular Events
the Scandinavian Simvastatin Survival Study Group had
With Icosapent Ethyl–Intervention
Trial previously shown the mortality benefits of simvastatin in
CAD, a secondary post hoc analysis of these data pro-
VALUE Valsartan Antihypertensive Long-
Term Use Evaluation vided the first randomized trial data that statin therapy
could be used to treat PAD. With a decreased incidence
WAVE Warfarin Antiplatelet Vascular
Evaluation 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
CHOLESTEROL REDUCTION more definitive evidence for its use in PAD.
Elevated lipids and lipoproteins including total choles- The Heart Protection Study Collaborative Group pro-
terol, non-HDL (high-density lipoprotein) cholesterol, vided the first randomized controlled trial data on statin
and LDL (low-density lipoprotein) cholesterol (LDL-C) therapy in PAD. Moderate-intensity statin therapy with
are associated with an increased risk of cardiovascu- simvastatin reduced peripheral vascular events (defined
lar disease, and PAD is no exception.13–17 Contempo- as noncoronary revascularization, amputation, aneurysm
rary research on statins, ezetimibe, and more recently repair, and death from PAD) by 17% in a prespecified
PCSK9 inhibitors indicates that lowering lipids and, in PAD group.23 However, PAD was not defined by rigorous
particular, LDL-C to the lowest possible target greatly contemporary standards. Claudication and amputation
542 March 2020 Arterioscler Thromb Vasc Biol. 2020;40:541–553. DOI: 10.1161/ATVBAHA.119.312142
did not require ankle-brachial index measurement or in patients with PAD. The IMPROVE-IT trial (Improved
endovascular studies to confirm the definition of symp- Reduction of Outcomes: Vytorin Efficacy International
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tomatic PAD. Furthermore, aneurysm repair was included Trial) randomized patients with recent hospitalization for
in the PAD and vascular event definitions as well. Since acute coronary syndrome (ACS) to receive ezetimibe or
the Heart Protection Study, multiple retrospective studies placebo alongside moderate-intensity statin therapy.19
corroborated the finding that statin therapy reduces the High-risk patients, categorized by the Thrombolysis
rate of amputation with relative risk reductions between in Myocardial Infarction score, appeared to obtain the
18% and 35%.2,24,25 In a 2013 retrospective cohort greatest reduction in future cardiovascular events from
study of diabetic patients with and without PAD, Sohn ezetimibe, and about 18% of these high-risk patients
et al24 compared outcomes for patients taking statins had PAD.29 This suggests a benefit to the addition of
with those taking nonstatin lipid-lowering agents such as ezetimibe to statin therapy though a specific analysis
fibrates, bile acid sequestrants, nicotinic acid, and cho- for patients with PAD has not been performed, and the
lesterol absorption inhibitors (including ezetimibe) and patient population was limited to those with recent ACS.
found that those patients taking nonstatin lipid therapy The benefit from ezetimibe may be dependent on the
did not share a reduction in lower extremity amputation presence of statin therapy. A small randomized trial com-
rates. There was also a dose response with respect to pared femoral artery plaque burden progression between
statin intensity with high-intensity statin therapy result- symptomatic PAD patients assigned statin therapy, statin
ing in a greater reduction of limb loss than moderate- therapy plus ezetimibe, and ezetimibe alone. The ezeti-
intensity therapy in a recent observational cohort study mibe-alone group showed progression of plaque burden
including both symptomatic and asymptomatic patients where the other groups remained stable indicating that
with PAD.26 ezetimibe without statin therapy is not sufficient in the
Statin therapy addresses both limb specific and sys- management of PAD.30
temic complications from PAD. The Heart Protection
Study showed that irrespective of a prior history of coro-
nary, cerebrovascular disease, or cholesterol levels, statin
PCSK9 Inhibitors
therapy reduced the rate of all cardiovascular events in PCSK9 (proprotein convertase subtilisin/kexin type 9)
PAD, with a 30% reduction in coronary revasculariza- inhibitors represent a substantial innovation to lipid man-
tion, a 21% reduction in major coronary events, and a agement. The FOURIER trial (Further Cardiovascular
Outcomes Research With PCSK9 Inhibition in Subjects
26% reduction in ischemic stroke.23 The Reduction of

Atherothrombosis for Continued Health Registry, which With Elevated Risk) using evolocumab in patients with
prospectively followed patients with symptomatic PAD atherosclerotic disease and LDL >70 mg/dL contained
over 4 years, made similar conclusions with a 17% lower patients both with and without PAD. Patients with PAD
risk of cardiovascular death, nonfatal MI, or nonfatal had an impressive 59% reduction in LDL-C with evo-
stroke.2 The notion that statin therapy reduces the risk locumab resulting in a 3.5% absolute risk reduction in
of vascular events outside the periphery is supported by the primary end point of cardiovascular events (MI, death,
meta-analyses.27,28 Despite robust evidence showing a stroke, hospitalization for unstable angina, and coro-
reduction in vascular events, meta-analysis did not dem- nary revascularization) compared with a 1.6% absolute
onstrate an overall reduction in mortality.27,28 While cur- risk reduction in patients without PAD.31,32 Importantly,
rent guidelines suggest the use of high-intensity statin patients in a prespecified symptomatic PAD group also
therapy, much of the trial data accumulated on statins in had a reduction of 42% in major adverse limb events:
PAD used moderate-intensity statin dosing.14,15 acute limb ischemia, major amputation, or urgent periph-
eral revascularization for ischemia. This reduction was
seen regardless of the intensity of statin therapy without
Ezetimibe excess adverse events.31 There have not yet been any
According to the most recent ACC/AHA guidelines for studies to examine outcomes of other PCSK9 inhibitors
cholesterol management, statin therapy may not be suf- in patients with PAD. A future trial set to complete in
ficient in patients at very high risk defined by a history 2021 will assess a second PCSK9 inhibitor, alirocumab,
of multiple atherosclerotic cardiovascular disease events in patients with PAD and evaluate for plaque regres-
or a single event and multiple medical comorbidities.14 A sion.33 Future reduction in prices may expand indications
substantial portion of the PAD population falls into this for use as current guidelines recommend using PCSK9
category. The ACC/AHA cholesterol guidelines recom- inhibitors sparingly as a result of their high cost.
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 ANTIPLATELET THERAPY
patients with similarly resistant cholesterol levels. There Platelet activity is instrumental to the development of
are few studies evaluating the use of this medication complications from cardiovascular disease, and PAD is
no exception. Not only is platelet adherence an initial of cardiovascular events occurred less often in the aspi-
step toward atherosclerotic disease but platelet activ- rin group but did not reach statistical significance 8.9%
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ity is abnormal in PAD. PAD is associated with plate- versus 11.0% (relative risk, 0.88 [95% CI, 0.76–1.04]),
let hyperaggregability and increased adhesion with which may be as a result of the inclusion of asymptom-
higher expression of surface protein, P-selectin.34–36 atic patients in the analysis.45
This unique behavior in PAD combined with the central
role platelets play in atherothrombotic complications is
Clopidogrel
the rationale for its use in PAD, but antiplatelet ther-
apy also has a key role in prevention of complications The P2Y12 receptor inhibitor clopidogrel has been com-
in cardiovascular disease as a whole. Despite known pared with aspirin in the CAPRIE trial (Clopidogrel Ver-
relationships between PAD, platelet activity, and CAD, sus Aspirin in Patients at Risk for Ischemic Events), which
large-scale trials investigating the benefits of antiplate- remains the only trial data with a subgroup analysis com-
let therapy in patients with PAD were decades behind paring these 2 antiplatelet agents.46 The results were
those related to CAD. 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-
Aspirin pared with the other subsets in the trial, the prespecified
The presence or absence of PAD symptoms is a major symptomatic PAD group benefited the most. The gen-
defining feature of this condition with drastically dif- eral population had only an 8.7% relative risk reduction.46
ferent clinical outcomes.37 The use of aspirin has been Single-agent antiplatelet therapy is a 2016 ACC/AHA
evaluated in both asymptomatic and symptomatic PAD. class Ia recommendation; however, the guidelines do not
However, multiple trials failed to show a reduction in recommend clopidogrel over aspirin despite the results
cardiovascular events for aspirin in patients with asymp- of this subgroup analysis.15
tomatic PAD, including the Aspirin for Asymptomatic
Atherosclerosis Trial, which compared 100 mg aspirin to Ticagrelor
placebo in 3350 patients with a follow-up time of >8
The newer P2Y12 inhibitor, Ticagrelor, debuted in
years.38,39 These results are in line with emerging data
patients with CAD in the PLATO trial, which randomized
suggesting that aspirin is not effective in primary preven-
patients with ACS to either clopidogrel or ticagrelor and
tion of cardiovascular mortality.40,41

found that ticagrelor significantly reduced the incidence
Aspirin has been shown to be effective for symp-
of major adverse cardiovascular events at 1 year with-
tomatic PAD. The first major data to suggest its utility out significantly increasing the rate of major bleeding.47
in PAD was in 2002 with a meta-analysis of random- A post hoc subgroup analysis of this patient population
ized trials from the Antithrombotic Trialists’ Collabora- included patients with lower extremity PAD and found a
tion. Analysis was conducted on >9000 patients with similar 15% relative risk reduction in the composite pri-
PAD and showed a proportional reduction of 23% in mary end point. Furthermore, patients with PAD had a
serious vascular events: nonfatal MI, nonfatal stroke, or much higher rate of developing the primary end point,
vascular death (P=0.004).42 However, the trial included suggesting that benefit may be larger for this patient
all antiplatelet agents including clopidogrel. More direct population should a trial be designed for patients with
evidence came in 2007 with the CLIPS (Critical Leg PAD.48
Ischemia Prevention Study), which evaluated the use of In 2017, the EUCLID trial (Examining Use of Ticagrelor
low-dose aspirin (81 mg) in 366 patients with symptom- in Peripheral Artery Disease) compared clopidogrel and
atic and asymptomatic PAD and found a 64% relative ticagrelor in almost 14 000 symptomatic PAD patients to
risk reduction in major vascular events: ischemic stroke, determine whether or not ticagrelor was the better agent
MI, and vascular death (P=0.022).43 Finally the use of in PAD. Despite high hopes for the newer P2Y12 inhibi-
antiplatelet therapy was directly validated in a PAD popu- tor, the primary end point of cardiovascular death, MI, or
lation, and the risk reduction was at least, in part, driven ischemic stroke was not significantly different (10.6%
by a reduction in fatal and nonfatal MI (hazard ratio, 0.18 versus 10.8%) between the 2 agents. The only second-
[95% CI, 0.04–0.82]; P=0.03). Interestingly, by the time ary end point to reach significance was a 0.5% abso-
the CLIPS trial was published comparing aspirin to pla- lute risk reduction in ischemic stroke for patients taking
cebo, the ACC/AHA had already categorized antiplatelet ticagrelor. Patients with carotid or coronary revasculariza-
therapy as a class I indication for PAD based on previ- tion and patients with coronary artery stenting appeared
ous meta-analysis.44 The CLIPS trial was followed up by to receive some benefit, although the study was not pow-
another meta-analysis including both symptomatic and ered to distinguish benefit in this specific population and
asymptomatic patients with PAD. The primary end point the results were not significant.49
Dual Antiplatelet Therapy mechanism in the pathogenesis of many PAD and limb-
With platelet activity so critical to the development of ath- related complications since the identified stenosis was
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erothrombotic events, dual antiplatelet therapy (DAPT) not secondary to a local atherosclerotic process.54 Trial
was also assessed in PAD. The CHARISMA trial (Clopi- data from warfarin, and more recently rivaroxaban, sug-
dogrel for High Atherothrombotic Risk and Ischemic Sta- gest that anticoagulation may in fact prevent limb-related
bilization, Management, and Avoidance) compared DAPT complications from PAD, as well as all cardiovascular
to single antiplatelet therapy and included patients with morbidity and mortality.
PAD. The primary outcomes of the trial were stroke,
death, bleeding, and MI, but the authors showed no sig-
Warfarin
nificant difference in outcome between DAPT and single
antiplatelet therapy in the general trial population.50 How- Multiple trials have assessed the utility of warfarin anti-
ever, a post hoc subgroup analysis on PAD patients alone coagulation for the prevention of complications, initially
showed DAPT therapy resulted in a statistically signifi- in patients with a history of ACS. The OASIS (Organi-
cant 15% relative risk reduction in the primary end point zation to Assess Strategies for Ischemic Syndromes)
(2.3% versus 3.7%; hazard ratio, 0.63; P=0.028). There and WARIS-II (Warfarin, Aspirin, or Both After Myocar-
was no difference in severe, fatal, or moderate bleeding dial Infarction) trials found the combination of warfarin
between the 2 groups. The trial included a mixture of and aspirin was better than aspirin alone at preventing
both symptomatic (91.7%) and asymptomatic patients major adverse cardiovascular events in this patient popu-
(8.4%).51 DAPT was evaluated in the 2015 PEGASUS- lation.55,56 These trials paved the way for evaluation of
TIMI 54 trial (Prevention of Cardiovascular Events in anticoagulation of patients with known PAD, but initial
Patients With Prior Heart Attack Using Ticagrelor Com- results were not as promising. The WAVE trial (Warfarin
pared to Placebo on a Background of Aspirin–Throm- Antiplatelet Vascular Evaluation) investigated the use of
bolysis in Myocardial Infarction 54), which examined the warfarin anticoagulation in combination with aspirin for
use of ticagrelor and aspirin in patients with MI 1 to 3 patients with symptomatic PAD (81.8% of the total trial
years prior. The subgroup analysis of >1000 patients population), subclavian disease, and carotid disease. The
with symptomatic PAD at the time of enrollment showed trial found no significant difference in the occurrence of
major adverse cardiovascular events between patients
an absolute risk reduction of 4.1% in the primary end
receiving combination aspirin and warfarin therapy
point of cardiovascular death, stroke, or MI for patients
alone.57 Furthermore, they found a significant increase in
on DAPT compared with aspirin and placebo. Impor-

the amount of major bleeding events, including intracra-
tantly, this group also had a significant 35% relative risk
nial hemorrhage. A subanalysis of this trial did show site
reduction in critical limb ischemia (CLI; P=0.026) at the
variation and poor compliance with an almost 30% rate
cost of increased major and minor bleeding events.52 The
of discontinuation of warfarin at follow-up so the pos-
2016 ACC/AHA PAD guidelines provide a lower recom-
sibility remained that the lack of efficacy was related to
mendation (class IIb) for use of DAPT with clopidogrel
poor medication adherence.
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- Rivaroxaban
dation, however, a meta-analysis cast doubt on the utility The development of factor Xa inhibitors such as rivarox-
of DAPT in patients with symptomatic PAD for the pre- aban and apixaban is promising for a number of differ-
vention of death, MI, or stroke as the reduction in primary ent applications. Its potential benefits include increased
outcome did not reach significance (7.6% versus 8.9%; patient compliance and lower likelihood of major bleed-
odds ratio, 0.84 [CI, 0.65–1.08]; P=0.18) and long-term ing when compared with warfarin.58–60 The COMPASS
DAPT was associated with increased risk of bleeding trial (Cardiovascular Outcomes for People Using Anti-
(1.47% versus 0.88%; odds ratio, 1.65 [CI, 1.23–2.21]; coagulation Strategies) published in late 2017 demon-
P=0.001).53 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-
ANTICOAGULATION ously used in the ATLAS-TIMI 51 trial (Anti-Xa Therapy
Recent research suggests the pathogenesis of CLI, the to Lower Cardiovascular Events in Addition to Standard
most serious limb complication of PAD, is primarily an Therapy in Subjects With Acute Coronary Syndrome–
atherothromboembolic disease. In a landmark study by Thrombolysis in Myocardial Infarction) evaluating the
Narula et al, almost 3 quarters of arteries taken from use of rivaroxaban in patients with recent ACS with the
amputated limbs secondary to CLI show luminal thrombi, finding that this dosage decreased mortality of patients
two-thirds of which had no significant atherosclerotic with recent ACS over placebo.61 COMPASS tested this
lesions. These findings suggest a thrombi-dependent medication in CAD, PAD, or both. The predetermined
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-
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 the rivaroxaban-plus-aspirin group and the rivaroxaban-
lower extremity disease (55.2% of subgroup), as well alone group had higher major bleeding events than the
as carotid artery disease. The primary end point of car- aspirin-alone group (3.1%, 2.8%, and 1.9%), though the
diovascular death, stroke, or MI occurred in 4.1% in the impact of this adverse event was somewhat mitigated
aspirin and low-dose rivaroxaban group compared with by no statistically significant increase in fatal bleeding
4.9% in the rivaroxaban-alone group and 5.4% in the or symptomatic intracranial bleeding between the rivar-
aspirin-alone group for all patients including those with oxaban-plus-aspirin group and the aspirin-alone group
CAD. In those patients enrolled with PAD, the primary (P=0.40). Patients ≥75 years of age with and without
end point occurred in the aspirin and low-dose rivaroxa- PAD did not have a significant reduction in the primary
ban group 5.1% of the time versus 6.9% of the time end point with low-dose rivaroxaban and aspirin, so
for the aspirin-alone group. A comparison of the riva- providers should consider the use of anticoagulation
roxaban-alone group and the aspirin-alone group was in this geriatric population with caution.62,63 Low-dose
not different.62 Importantly, major adverse limb events rivaroxaban and aspirin combination therapy compares
occurred less often in patients with PAD taking rivaroxa- favorably to other effective PAD medications such as
ban and aspirin than aspirin alone, though these events statins. The Heart Protection Study found a 22% rela-
were uncommon (1% versus 2%).63 As expected, both tive risk reduction in the first major vascular event with
moderate-intensity statin therapy while the COMPASS BLOOD PRESSURE MANAGEMENT

trial showed a 28% relative risk reduction in the pri-
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The 2016 ACC/AHA guidelines for lower extremity
mary outcome with thw use of low-dose rivaroxaban
peripheral artery disease gives antihypertensive therapy
and aspirin.23,62,63 Importantly, the primary end point of a class IA recommendation for patients with peripheral
cardiovascular death, stroke, or MI occurred more often artery disease and suggests that blood pressure man-
in the PAD group, once again highlighting the impor- agement should be in accordance with current hyperten-
tance of maximizing effective therapies in this patient sion guidelines given significant cardiovascular mortality
population. in this population.15 According to current 2017 ACC/
AHA guidelines on hypertension, antihypertensive medi-
cation is recommended for patients with cardiovascular
PERIPHERAL VASODILATORS disease and systolic pressure >130 or diastolic blood
Intermittent claudication represents peripheral isch- pressure >80.70 However, a post hoc analysis of INVEST
emia distal to a stenosis in the setting of exertion. This (International Verapamil-SR/Trandolapril Study), which
supply-demand mismatch is often a result of the steno- included 2699 patients with both PAD and CAD, showed
sis, thus insufficient vasodilatory response may result in a j-shaped curve of mortality and blood pressure. For
symptoms that are relieved by rest. As such, peripheral patients with PAD, mortality benefits were seen with a
vasodilators are potentially beneficial for claudication. treated systolic blood pressure of 135 to 145 mm Hg
Claudication itself is associated with functional decline, and treated diastolic pressure of 60 to 90 mm Hg with
and thus improvement of this symptom should be a focus higher mortality observed in low systolic and high sys-
tolic blood pressure ranges, supporting the paradigm
of providers.64 The ACC/AHA guidelines include a class
that blood pressure management in PAD is a balance
IA recommendation cilostazol in the treatment of symp-
between limb perfusion and risk factor modification.71
tomatic claudication.15
As a result, the European Society of Cardiology recom-
mends lowering blood pressure in patients with PAD to
Cilostazol <140/90 with a class IA recommendation.72 Perhaps
future trials will elucidate the ideal blood pressure range
Multiple trials have evaluated the utility of this medica-
for patients with PAD.
tion for the treatment of symptomatic PAD. A systematic
Cochrane Review of 15 trials concluded that cilostazol

increases exercise tolerance compared with placebo. Angiotensin-Converting Enzyme Inhibitors and
Eight of the trials reviewed could be compared on the Angiotensin Receptor Blockers
basis of walking distance before the onset of claudica- The use of ACE (angiotensin-converting enzyme) inhib-
tion symptoms with 100 mg twice daily improving the itors as an antihypertensive class has been evaluated
weighted mean walking distance by 31.41 m ([95% CI, for patients with PAD with some evidence to suggest
22.38–40.45 m] P<0.00001). No difference in absolute benefit of this medication over other antihypertensives.
mortality was appreciated though there were a small In 2000, the HOPE trial (Heart Outcomes Prevention
number of events in the trials.65,66 For comparison, a Evaluation) compared the use of ramipril to placebo in
Cochrane Review found supervised exercise programs patients with cardiovascular disease without heart fail-
resulted in ≈150 m increase in walking distance or ≈30% ure with reduced ejection fraction. The study included
to 35% increase, which was sustained at 6 months.67 The 3099 patients with PAD defined as low ankle-brachial
improvement seen with cilostazol is subtle in comparison index. A post hoc analysis found that patients with
to supervised exercise programs. Incidence of headache, PAD benefited from a significant reduction in the pri-
palpitations, and diarrhea are relatively common adverse mary outcome of cardiovascular death, MI, or stroke as
did those patients without peripheral vascular disease.
effects.68 More importantly, cilostazol is contraindicated
Patients entering the trial had a similar blood pressure
in patients with heart failure as medications in this
of 139/79 mm Hg in both groups. The mean blood
class may be associated with excess mortality.69 Medi-
pressure was 133/76 mm Hg in the ramipril group and
cal comorbidities like diabetes mellitus, hyperlipidemia, 137/78 mm Hg in the placebo group at 1 month and
and hypertension are common in patients with PAD, so maintained a similarly small reduction throughout the
patients are frequently taking a number of medications. duration of the study.73 The relatively small reduction in
The side effect profile, heart failure contraindication, pill blood pressure in the treatment arm implies there may
burden, and subtle benefit are all reasons cilostazol is be an additional benefit to the use of ACE inhibitors
infrequently used and should only be considered in oth- over other antihypertensives.74 The ONTARGET trial
erwise medically optimized patients with refractory clau- (Ongoing Telmisartan Alone and in Combination With
dication who are able to tolerate the medication. Ramipril Global End Point Trial) compared angiotensin
receptor blocker (ARB) telmisartan to ramipril or com- is recommended in patients with PAD to reduce cravings.
bination ARB and ACE inhibitor therapy and found no Varenicline was assessed in 714 patients with stable
ATVB IN FOCUS - VB
significant difference in the primary end point of cardio- cardiovascular disease including 179 patients with PAD.
vascular mortality, MI, stroke, or hospitalization for heart While there was not a subanalysis of this PAD group,
failure between all 3 groups but a higher rate of adverse patients taking varenicline did have higher rates of smok-
events in the combination group. The trial included ing cessation for the duration of the trial at 52 weeks
3468 patients with PAD.75 Several prospective and ret- (19.2% versus 7.2%; P<0.0001). There was no change
rospective studies have shown a reduction in mortality in cardiovascular mortality or all-cause mortality between
with ACE inhibitor and ARB over other antihypertensive patients taking varenicline and placebo (cardiovascu-
agents.76,77 As a result of these data, both the European lar mortality, 0.3% versus 0.6% [CI, 1.3–0.7]; all-cause
Society of Cardiology and ACC/AHA guidelines give a mortality, 0.6% versus 1.4% [CI, 2.3–0.6]).87 Accord-
class II recommendation for ACE inhibitor or ARB for ing to guidelines, bupropion is equivalent in efficacy to
PAD.15,72 varenicline for smoking cessation purposes.86 Nicotine
Nevertheless, a post hoc subanalysis of the ALL- replacement therapy is also recommended as a therapy
HAT (Antihypertensive and Lipid-Lowering Treatment to aid smoking cessation. A recent Cochrane Review on
to Prevent Heart Attack Trial) and a prespecified sub- the safety and efficacy of 136 nicotine replacement ther-
group analysis of VALUE (Valsartan Antihypertensive apy trials found that all varieties of nicotine replacement
Long-Term Use Evaluation) did not show a significant therapy (gum, patch, lozenge, spray) effectively increase
reduction in primary end points of fatal or nonfatal MI the rate of cessation. Combined nicotine replacement
and major adverse cardiovascular events, respectively, therapy, for example, using a nicotine patch and gum, is
with ACE inhibitor or ARB over other antihypertensive also felt to be more effective than use of a single agent
classes in subgroup analysis of patients with symptom- alone. Furthermore, while side effects of tachycardia and
atic PAD.78–80 Certainly, control of hypertension is an arrhythmia were more common with the use of nicotine
important facet to medical therapy in PAD, but it remains replacement therapy than placebo, serious cardiovascu-
to be seen whether ACE inhibitor or ARB offer benefits lar side effects such as stroke, MI, and cardiovascular
beyond blood pressure control in PAD. death were not more common in nicotine replacement
therapy groups.86,88 Though evidence is lacking for a
SMOKING CESSATION direct reduction in PAD-related mortality with use of
counseling or pharmacological therapy such as nico-

Smoking is the single greatest modifiable risk factor tine replacement therapy, bupropion, and varenicline, the
for the development and progression of PAD. Tobacco impact these interventions can have on smoking cessa-
smoke increases endothelial cell permeability by forma- tion efforts was sufficient to codify these interventions as
tion of reactive oxygen species, which enables athero- class IA recommendations for PAD patients.15
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-
EXERCISE THERAPY
atic review.82 The risk of incident PAD persists for ≤30
years even with cessation.83 Patients with PAD experi- Plaque burden and endothelial dysfunction narrow and
ence smoking-related complications and increased stiffen the arteries supplying lower extremity skeletal
mortality. In one registry of 739 patients with PAD who muscles in patients with PAD. The debilitating pain of
underwent angiography, those who continued smoking claudication results from increased skeletal muscle
had increased mortality at follow-up to 5 years (31% demand for oxygen during exercise not met with ade-
versus 14%; P<0.05). In the same registry, amputation quate supply as a result of complex alterations in arterial
rate was also higher in survivors who continued to smoke physiology including changes in flow-mediated dilation—
(40% versus 19%; P<0.05).84 Smoking fosters PAD and a measure of endothelial function.89–91 Exercise therapy
augments complication rates, and thus providers should is designed to address lifestyle limitations imposed by
focus on cessation. claudication symptoms of PAD.
Multidisciplinary efforts to intervene on smoking can A number of randomized trials have demonstrated
be effective. In one randomized trial of 124 patients, improvement in functional capacity following exercise
an intensive intervention group, which included cogni- therapy, and as such, the ACC/AHA provides a class 1A
tive behavioral counseling, motivational interviewing, recommendation for supervised therapy for patients with
and pharmacological therapy, resulted in a significantly claudication.15 A recent meta-analysis of exercise ther-
higher rate of cessation than verbal advice alone (21.3% apy trials found a mean difference of 82.11 m ([95% CI,
versus 6.8%; P=0.023).85 Even physician verbal advice 71.73–92.48] P<0.00001) in pain-free walking distance,
alone has been associated with improved smoking ces- in addition to improvements in quality-of-life metrics.92
sation.86 Pharmacological therapy for smoking cessation Meta-analysis also showed that supervised exercise
therapy programs appear to be even more effective than guideline-based statin use.116 On review of >23 000
home-based therapy with similar adherence rates.93 The PAD interventions, one study found that blacks were less
ATVB IN FOCUS - VB
duration of benefit from exercise therapy is prolonged likely to be on a statin before abdominal aortic aneu-
well beyond the completion of the program, ≤7 years fol- rysm repair or PAD intervention. Furthermore, blacks
lowing a 28-week supervised program.94 Several studies were less likely to be discharged on combination statin
have shown improvements in flow-mediated dilation fol- and antiplatelet regimen after either abdominal aortic
lowing exercise therapy, but not all trials demonstrated aneurysm repair or PAD intervention.117 In addition to
success.95–97 Exercise therapy does not have a clear improving application of guideline-based therapy, nontra-
effect on mortality or amputation rates.92,93 ditional healthcare settings may improve delivery of care.
A recent pharmacist-led intervention in predominantly
black barbershops identified hypertensive adults and
HEALTH DISPARITIES prescribed antihypertensives with excellent control in
Special emphasis on the optimization of medical man- blood pressure and improved medication adherence.118
agement for PAD should be placed on at-risk popula- Utilization of barbershops for identification and medical
tions. In particular, blacks face elevated rates of PAD optimization of PAD in the black population is an emerg-
leading to high morbidity and mortality.10,11 The incidence ing area of interest and may result in similarly improved
of PAD among blacks remains strikingly high, ≈2 to 3× control of blood pressure, as well as reduction in choles-
the rate of non-Hispanic whites at all age groups. This terol, platelet activity, and coagulation.119
elevated incidence occurs in spite of a lower smok-
ing rate in this population.98,99 Black race is one of the
CONCLUSIONS
strongest risk factors for the development of PAD and
remains so even when controlling for traditional cardio- PAD is a devastating disease with high morbidity and high
vascular risk factors (smoking, diabetes mellitus, and mortality. Though trials assessing effectiveness of medi-
hypertension) and nontraditional inflammatory markers cal interventions for PAD remain few in number, provid-
associated with cardiovascular disease (CRP [C-reac- ers and patients alike should remain optimistic given the
tive protein], IL-6 [interleukin 6], D-dimer, fibrinogen, expanding number of available management strategies.
and homocysteine).10,11,100,101 Age-adjusted mortality for Beyond medical therapy, ongoing trials such as BEST-
black men is higher than non-Hispanic whites and His- CLI (Best Endovascular Versus Best Surgical Therapy for
panic men (24.8 versus 19.9 versus 15.4 per 100 000), Patients With Critical Limb Ischemia) will provide insight
and rates are similarly elevated for blacks above non- into optimal interventional practices for patients with
Hispanic whites and Hispanic women (16.5 versus 13.8 PAD.120 A number of medical therapies exist to reduce
versus 10.7).102,103 Importantly, mobility loss secondary to cardiovascular mortality, as well as prevent progression,
PAD is also worse for blacks.104 In addition, blacks are 2 limb loss, and the need for invasive interventions. Cho-
to 4× more likely to undergo amputation when compared lesterol management includes not only high-intensity
with non-Hispanic whites.12,105,106 Furthermore, graft fail- statin therapy but ezetimibe and PCSK9 inhibitors, all of
ure and amputation following bypass is more common in which have the potential to reduce limb loss and improve
blacks, in particular, black women.107 cardiovascular outcomes. Antiplatelet therapy remains
Management of PAD in blacks has been shown to be a cornerstone of PAD management with clopidogrel
suboptimal. Although smoking is a significant risk fac- decreasing limb events, stroke, and MI even above aspi-
tor for the development of PAD and its complications, rin. New to the repertoire of the treating provider, rivar-
smoking is the least successful factor modification in oxaban adds to a growing list of effective medications
blacks.108 Furthermore, blacks are more likely to attempt possibly by addressing atherothromboembolism—a com-
to quit than whites though less likely to succeed.109 mon source of complications in PAD. Cilostazol and ACE
Though CLI is more common in the black population, inhibitor continue to have a role in the management of
blacks are less likely to be offered and to receive salvage select patients though evidence supporting their use
revascularization attempts.110–112 This could be due to a for PAD is less robust. Patients with claudication symp-
number of factors including unconscious bias and more toms can find symptomatic improvement with supervised
advanced disease at time presentation.113 Improvement exercise therapy. Finally, interventions to aid in smok-
of medical optimization in this population may mitigate ing cessation such as counseling, nicotine replacement
the disparity in limb salvage rate. As of yet, medical man- therapy, bupropion, and varenicline are effective and safe
agement appears to be underutilized in blacks. Choles- tools for risk factor modification. Despite the multitude
terol-lowering therapies are less frequently prescribed in of medical treatment options available, PAD is chroni-
blacks even when indicated by the guidelines.114,115 Black cally undertreated relative to CAD. Future advancements
women, in particular, appear to have even lower rates of in management strategies and improved application of
available medical therapies will prevent complications heart disease prediction from lipoprotein cholesterol levels, triglycerides,
lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions:
and improve the quality of life for patients with PAD.
ATVB IN FOCUS - VB
The Atherosclerosis Risk in Communities (ARIC) Study. Circulation.

2001;104:1108–1113. doi: 10.1161/hc3501.095214
14. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS,
ARTICLE INFORMATION Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, et al. 2018
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/
Received October 7, 2019; accepted January 17, 2020.
NLA/PCNA guideline on the management of blood cholesterol: a report
Affiliations of the American College of Cardiology/American Heart Association
task force on clinical practice guidelines. J Am Coll Cardiol. 2019;73:e285–
From the Department of Medicine (G.H.B., K.T.W.S.) and Harrington Heart and
e350. doi: 10.1016/j.jacc.2018.11.003
Vascular Institute (K.T.W.S.), University Hospitals Cleveland Medical Center, OH;
15. Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA,
and Case Western Reserve University School of Medicine, Cleveland, OH (G.H.B.,
Drachman DE, Fleisher LA, Fowkes FG, Hamburg NM, Kinlay S, et al. 2016
K.T.W.S.).
AHA/ACC guideline on the management of patients with lower extrem-
Disclosures ity peripheral artery disease: executive summary: a report of the Ameri-
can College of Cardiology/American Heart Association task force on
None.
clinical practice guidelines. Circulation. 2017;135:e686–e725. doi:
10.1161/CIR.0000000000000470
16. Pischon T, Girman CJ, Sacks FM, Rifai N, Stampfer MJ, Rimm EB. Non-
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Evidence Based PAD

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Arteriosclerosis, Thrombosis, and Vascular Biology

Evidence-Based Medical Management of

Nonstandard Abbreviations and Acronyms Highlights

LDL low-density lipoprotein pent ethyl in REDUCE-IT (Reduction of Cardiovascular

26% reduction in ischemic stroke.23 The Reduction of

tion of cardiovascular mortality.40,41

on DAPT compared with aspirin and placebo. Impor-

Table. Evidence Underlying Medical Management of PAD

moderate-intensity statin therapy while the COMPASS BLOOD PRESSURE MANAGEMENT

Cochrane Review of 15 trials concluded that cilostazol

counseling or pharmacological therapy such as nico-

The Atherosclerosis Risk in Communities (ARIC) Study. Circulation.

of atherothrombotic events. N Engl J Med. 2006;354:1706–1717. doi:

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