EVIDENCE SUMMARY

Peter F. Lawrence, MD, SECTION EDITOR

Statin use in patients with peripheral arterial disease

Sheena K. Harris, MD, Matt G. Roos, MD, and Gregory J. Landry, MD, Portland, Ore

ABSTRACT
Background: Statins are recommended for use in patients with peripheral arterial disease (PAD) to reduce cardiovascular
events and mortality. However, much of the data regarding benefits of statins stem from the cardiovascular literature.
Here, we review the literature regarding statin use specifically in patients with PAD regarding its effects on cardiovascular
events and mortality, limb-related outcomes, statin use after endovascular interventions, statin dosing, and concerns
about statins.
Methods: We performed a literature review using PubMed for literature after the year 2000. Search terms included “statins,”
“peripheral arterial disease,” “peripheral vascular disease,” “lipid-lowering medication,” and “cardiovascular disease.”
Results: There is good evidence of statins lowering cardiovascular events and cardiovascular-related mortality in patients
with PAD. Though revascularization rates were reduced with statins, amputation rates and amputation-free survival did
not improve. Small randomized controlled trials show that patients taking statins can slightly improve pain-free walking
distance or pain-free walking time, although the extent of the effect on quality of life is unclear. Statin use for patients
undergoing endovascular interventions is recommended because of the reduction of postoperative cardiovascular
events. Not enough data exist to support local effects of systemic statin therapy, such as prevention of restenosis. For
statin dosing, there is little increased benefit to intense therapy compared with the adverse effects, whereas moderate-
dose therapy has significant benefits with very few adverse effects. Adverse effects of moderate-dose statin therapy are
rare and mild and are greatly outweighed by the cardiovascular benefits.
Conclusions: There is strong evidence to support use of statins in patients with PAD to reduce cardiovascular events and
mortality. Use in patients undergoing open and endovascular interventions is also recommended. Statin use may reduce
the need for revascularization, but reductions in amputation have not been shown. Moderate-dose statin therapy is safe,
and the minor risks are greatly outweighed by benefits. (J Vasc Surg 2016;64:1881-8.)

Statins are an integral component of optimal medical
therapy for patients with cardiovascular and peripheral
vascular disease, and use for patients with peripheral
arterial disease (PAD) is currently the standard of care.
The 2013 American College of Cardiology/American
Heart Association (ACC/AHA) guidelines recommend
patients with clinical PAD undergo moderate-dose or
high-dose statin therapy to reduce the risk of cardiovas-
cular events.1 The 2014 ACC/AHA guidelines for manage-
ment of patients undergoing noncardiac vascular
surgery put forth a Class IIa recommendation to start
patients on statins if undergoing vascular surgery, with
or without clinical risk factors, to reduce incidence of
cardiovascular events.2
Reduction of cardiovascular mortality is the driving
force behind recommending statin use. The lipid-
lowering effects of statins contribute to prevention of
cardiovascular events.3 Statins may also contribute to
lowering the frequency of cardiovascular events by
the reduction of systemic inflammation,4 stabilization
of atherosclerotic plaque,5 and by having beneficial
effects on vascular endothelium. Statins have been
shown to inhibit neointimal hyperplasia in ex vivo
human veins through a combination of attenuating
smooth muscle cell proliferation6 and matrix metallo-
proteinase activity.7,8 In addition, statins improve endo-
thelial nitric oxide synthase and the release of nitric
oxide, which acts as a vasodilator and inhibits platelet
aggregation.9
Although statins are currently recommended for use in
patients with PAD, most of the evidence supporting
current guidelines is extrapolated from cardiac literature.
In this evidence-based summary, we review the evidence
for the use of statins in patients with PAD.

From the Oregon Health and Science University.
Author conflict of interest: none.
Correspondence: Gregory J. Landry, MD, Knight Cardiovascular Institute,
Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, OP11,
Portland, OR 97239 (e-mail: landryg@ohsu.edu).
The editors and reviewers of this article have no relevant financial relationships to
disclose per the JVS policy that requires reviewers to decline review of any
manuscript for which they may have a conflict of interest.
0741-5214
Copyright Ó 2016 by the Society for Vascular Surgery. Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.jvs.2016.08.094
METHODS
We performed a literature review using PubMed to
review evidence for use of statins in patients with PAD
and in those who undergo an intervention for PAD.
Search terms included “statins,” “peripheral arterial
disease,” “peripheral vascular disease,” “lipid-lowering
medication,” and “cardiovascular disease.” Studies writ-
ten in English after 2000 were included. The literature
was evaluated by two of the authors of this review, and
grading was mutually agreed upon. End points of

1881
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1882 Harris et al Journal of Vascular Surgery
December 2016

Table. Studies investigating statin use in patients with peripheral arterial disease (PAD)
Year Mean Level of
Author published Study design Patient group follow-up Major findings evidence
Heart Protection 2002 RCT High CV risk 5 years Lower MI, coronary 1b
Study Collaborative death, stroke, or
Group12 revascularization
Heart Protection 2007 RCT PAD 5 years Reduction in major 1b
Study Collaborative vascular events,
Group13 including MI,
stroke, and
revascularization
Mohler et al14 2003 RCT PAD 1 year Improved pain-free 1b
walking distance
Aronow et al21 2003 RCT PAD 1 year Increased time to 1b
onset of
claudication while
walking
Mondillo et al20 2003 RCT PAD 6 months Increased pain-free 1b
walking distance
and improvement
in claudication
symptoms
Antoniou et al15 2014 Meta-analysis of PAD . Lower all-cause 2a
observational mortality
studies, a few
RCTs
De Martino et al16 2016 Retrospective After suprainguinal Perioperative No difference in 2b
review of VQI or infrainguinal period perioperative
bypass mortality or MI
Ramos et al17 2016 Matched-pair asymptomatic PAD, 3.6 years Reduction in MACE 2b
cohort low CV risk and call-cause
mortality
Suckow et al19 2015 Retrospective VSGNE registry, CLI 3.2 years Improved 5-year 2b
review of After infrainguinal survival benefit;
VSGNE bypass 1-year limb-related
database outcomes not
influenced
Kumbhani et al37 2014 Retrospective PAD 4 years Lower risk of primary 2b
review of a adverse limb
prospective outcome at 4 years.
database (REACH) Lower risk of
composite CV
death/MI/stroke
Brunner et al22 2013 RCT PAD 1 years No differences seen 2b
Vidula et al38 2010 Retrospective review PAD 3.7 years Lower all-cause 2b
of a prospective mortality
database (WALCS
and WALCS II)
Schanzer et al18 2008 Retrospective review After infrainguinal . Improved survival at 2b
of a prospective bypass for CLI 1 year
database
(PREVENT III
cohort)
Schillinger et al39 2004 Prospective PAD 21 months Lower level of CRP 2b
observational and improved
study survival and MI-free
survival rates.
Overall survival
benefit seen with
statins only in
patients with
elevated CRP
(Continued on next page)

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Journal of Vascular Surgery Harris et al 1883
Volume 64, Number 6

Table. Continued.
Year Mean Level of
Author published Study design Patient group follow-up Major findings evidence
Westin et al40 2014 Retrospective After diagnostic Median: w1 year Lower MACCE and 2c
review angiography or amputation-free
endovascular survival at 1 year
intervention for CLI
Baril et al41 2013 Retrospective After infrainguinal . Statins found to be 2c
review bypass protective for 1-year
mortality
Tomoi et al42 2013 Retrospective After endovascular 19 months Statins improved 2c
review therapy for isolated overall survival and
below-knee lesions amputation-free
with CLI survival in
ambulatory
patients only
Aiello et al43 2012 Retrospective After endovascular 10 months Improved 2-year 2c
review intervention for CLI primary patency,
secondary patency,
limb salvage.
Ward et al44 2005 Retrospective After infrainguinal 5.5 year Improved composite 2c
review bypass CV and vascular
complications and
long-term survival.
Henke et al45 2004 Retrospective After infrainguinal 17 months Statins 2c
review bypass independently
associated with
increased graft
patency and limb
salvage
Abbruzzese et al46 2004 Retrospective After infrainguinal 18 months Improved primary- 2c
review bypass revised and
secondary graft
patency
CLI, Critical limb ischemia; CRP, C-reactive protein; CV, cardiovascular; MI, myocardial infarction; MACCE, major adverse cardiac and cerebrovascular
event; MACE, major adverse cardiovascular event; PREVENT III, Edifoligide for the Prevention of Infrainguinal Vein Graft Failure; REACH, Reduction of
Atherothrombosis for Continued Health; RCT, randomized controlled trial; VQI, Vascular Quality Initiative; VSGNE, Vascular Study Group of New
England; WALCS, Walking and Leg Circulation Study.

mortality, limb-related outcomes, and patient-related
outcomes were specifically examined. The effect of
statins in graft patency was evaluated, and the safety of
statins was also reviewed. Studies were graded by level
of evidence as defined by the Oxford Centre for
Evidence-Based Medicine, last updated in 2011.10
RESULTS
Mortality and cardiovascular events. Included in the
evidence regarding mortality reduction when patients
with PAD use statins is one Cochrane review of 18 ran-
domized controlled trials (RCTs), one RCT, one meta-
analysis of observational studies and RCTs, and several
observational studies (Table).
In a Cochrane review,11 18 RCTs were examined for
outcomes related to lipid-lowering therapy in patients
with PAD. Of the 18, only three RCTs used statins as a
lipid-lowering agent. Overall, no significant difference
was seen in all-cause mortality between patients who
did and did not take lipid-lowering agents. Two studies
of statin use12,13 investigated cardiovascular outcomes.
The pooled data showed a significantly lower risk of a
cardiovascular event among those taking statins
compared with placebo (odds ratio [OR], 0.74; 95% con-
fidence interval [CI], 0.67-0.82; P < .001).
The Class I recommendation to use statins to reduce
low-density lipoprotein (LDL) to <100 mg/dL in all
patients with PAD materialized largely from the Heart
Protection Study (HPS) in 2002.12 The HPS, a RCT per-
formed in the United Kingdom, assigned 20,536 patients
with coronary disease, vascular disease, or diabetes to
40 mg simvastatin daily or matching placebo for 5 years.
Statin use was associated with a reduction in fatal and
nonfatal cardiovascular events, regardless of baseline
cholesterol levels. The HPS was re-examined in 2007 for
the effects of major vascular events in patients with
PAD. In the 6748 patients in the original trial who had
PAD (w4%), statin therapy significantly reduced by 24%
the rates of a first occurrence of a major vascular event
(myocardial infarction, stroke, or revascularization).

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1884 Harris et al
The vascular event rate was compared between patients
with and without PAD, and the absolute reduction of
major vascular events was greater, at 63 (standard error,
11) per 1000 patients with PAD vs 50 (standard error, 7)
per 1000 patients without PAD.13
The HPS investigated long-term results of patients with
PAD taking statins. A 2014 meta-analysis of 12 observa-
tional studies and two RCTs assessed statin use and its
effect in the perioperative period (<30 days or within
the hospital stay). Open and endovascular interventions
were included. Reductions of mortality were similar to
the HPS: statins were associated with decreased long-
term all-cause mortality, cardiovascular mortality, and
myocardial infarction, but within the perioperative
period.15 All-cause mortality was reduced to 17% in the
patient group taking statins compared with 25% in the
patient group not taking statins (OR, 0.6; 95% CI, 0.46-
0.78; P < .001). Stroke rates were reported in five studies
with low heterogeneity and were significantly reduced
from 7% in patients not taking statins to 5% in those
who were (OR, 0.77; 95% CI, 0.67-0.89; P < .001). Although
this meta-analysis was thorough, there was significant
heterogeneity among studies, particularly on timing
and duration of statin use.
In contrast, a recent retrospective review performed
from the Vascular Quality Initiative database suggests
that statins may not be associated with improved periop-
erative outcomes when other risk factors are consid-
ered.16 Patients undergoing elective suprainguinal or
infrainguinal bypass who took statins did not have reduc-
tions in in-hospital cardiovascular events (specifically
myocardial infarction) or death in the perioperative
period after major open vascular operations. Instead,
cardiovascular risk and intraoperative blood loss were
more closely associated with perioperative events. This
raises the concern that other studies involving statin
use and perioperative mortality may need to more care-
fully adjust for variables before examining the relation-
ship between statin and perioperative mortality.
Although patients with cardiovascular risk and clinically
apparent PAD are recommended to take statins, guide-
lines are unclear for low-risk patients. A matched-
cohort pair study of 5480 patients investigated use of
statins in asymptomatic patients with a low ankle-
brachial index and no history of cardiovascular disease.17
In those who took statins, the incidence of major adverse
cardiac events was w20 events per 1000 person-years in
those who started taking statins compared with w25
events per 1000 person-years in those who did not take
statins. All-cause mortality was w25 per 1000 person-
years for statin users and 30 per 1000 person-years for
nonusers.
Observational studies also show mortality benefit for
patients with PAD with statins use, with reductions of
mortality of w30% for patients with critical limb ischemia
at 1 year18 and 5 years19 after infrainguinal bypass. On the
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Journal of Vascular Surgery
December 2016
basis of one large RCT, a meta-analysis, and several
observational studies, statin use in patients with PAD is
beneficial in reducing major vascular events, particularly
long-term survival, compared with patients of similar
risk who do not take statins (Level 1b). Further research
on perioperative event reduction as well as use in pa-
tients with low risk and asymptomatic PAD is warranted.
Limb-related outcomes. Limb-related outcomes
remain a mixed picture. The HPS finding published in
the Journal of Vascular Surgery in 2007 reported a signif-
icant 16% reduction in noncoronary revascularization
among patients with PAD13; however, other evi-
dence15,18,19 shows that statin use is not associated with
reductions in amputation at 1 year or with reduced graft
occlusion.19 The reduction in peripheral revascularization
may be an errant finding in the HPS study or may reflect
advanced unsalvageable disease in the group of patients
who progress to amputation. This presents a field that
warrants further study.
Symptom-related outcomes. Several RCTs have exam-
ined the effect of statin use on intermittent claudication.
In a moderately-sized RCT, 354 patients with intermittent
claudication attributable to PAD were randomized in a
double-blind fashion to placebo or atorvastatin (10 mg or
80 mg daily) for 1 year.14 The 80-mg atorvastatin group
improved pain-free walking distance by 63% compared
with an improvement of 38% in the placebo group. There
was no difference between the 10-mg atorvastatin group
and placebo. Maximal walking distance was not signifi-
cantly different among the groups. Questionnaires
regarding quality of life did not show a significant dif-
ference among the groups.
Two smaller RCTs showed similar results: in one, 86
patients with PAD and high cholesterol were random-
ized to 40 mg simvastatin or placebo and showed a sig-
nificant increase of 90 meters in pain-free walking
distance compared with placebo.20 Another small RCT
of 69 patients showed an increase in pain-free walking
distance in patients taking simvastatin vs placebo of
54 seconds (24% increase; P < .001) at 6 months and
95 seconds (42% increase at 1 year; P < .001), a statistically
significant but realistically minimal improvement.21
Although statins have been shown to statistically
improve pain-free walking distance in several small
randomized trials (Level 2b), realistically, this is not
impactful unless quality of life is assessed. The largest
of the RCTs did not show improvement in quality of life
based on two separate questionnaires answered by
patients. Future trials involving symptom-based end
points should focus on other patient-centered outcomes
such as quality of life and level of independence.
Local effects of statin use after endovascular
interventions. In the United States, endovascular inter-
ventions rapidly have begun to outpace the number of
Journal of Vascular Surgery
Volume 64, Number 6
open procedures performed for treatment of PAD. As
reviewed previously, statin therapy is recommended in
patients with PAD to reduce the risk of death long-
term2 and in the perioperative period.15 The literature
investigating local effects of statins on patients under-
going endovascular intervention is limited to small
observational studies, several of which are reviewed here.
The Effect of Lipid Modification on Peripheral Artery
Disease after Endovascular Intervention Trial (ELIMIT)
examined effect of dose-dependent statin therapy after
endovascular intervention in 102 people. Lipid levels
and magnetic resonance imaging-derived superficial
femoral artery wall and lumen characteristics were
examined. Triple-therapy with simvastatin, niacin, and
ezetimibe significantly decreased lipid levels vs simva-
statin monotherapy, but there was no difference in
superficial femoral artery vessel characteristics.22
Of significant concern is the potential for restenosis
after endovascular intervention. Although systemic
statins have not been shown to reduce restenosis after
angioplasty in studies involving coronary arteries23 or in
arteriovenous fistulas,24 there is some evidence that
statins may aid in reducing restenosis after stenting.
Experimental studies on porcine coronary arteries have
shown that oral statins inhibit neointimal hyperplasia.8
A retrospective review of 525 patients showed that statin
therapy reduced repeat target vessel revascularization
and increased minimal lumen diameter 6 months after
percutaneous coronary stenting.25 There has been inter-
est in development of statin-eluting stents, which would
theoretically reduce neointimal hyperplasia while allow-
ing for endothelialization. Current immunosuppressive
drug-eluting stents currently inhibit endothelialization,
which may increase risk of in-stent thrombosis.26
In both the human simvastatin-eluting stent
(SIMVASTENT)27 trial and in porcine trials,7 statin-
eluting stents were safe for use but did not significantly
reduce in-stent stenosis. In lower extremity interventions
for PAD, no trials have yet investigated the specific effects
of statins on angioplasty or stenting. In a retrospective
review of 113 bypass grafts and 105 endovascular interven-
tions, postoperative statin use was predictive of patency
and freedom from restenosis; however, the association
did not reach statistical significance when the endovas-
cular group was examined in isolation.28
Although there is tantalizing theorization that suggests
statins may be useful in preventing in-stent restenosis
and thrombosis, definitive evidence has not yet been
established in peripheral stents. More research is
required in endovascular patients to elucidate specific
benefits attributable to statins in limb-related outcomes.
Regardless of the paucity of evidence regarding local
effects, statin therapy is recommended in patients un-
dergoing endovascular treatment because of the bene-
fits in cardiovascular risk reduction.
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Harris et al 1885
Statin dosing. Evidence for optimal dosing of statins
comes from three meta-analyses of RCTs and one
randomized open-label trial.
When statin use of any dose was examined in a meta-
analysis of 18 RCTs in the past 11 years, statin therapy
increased the odds of adverse events compared with pla-
cebo by 39% (P ¼ .008) but also reduced the risk of car-
diovascular events by 26% (P < .001).29 A meta-analysis of
four RCTs conducted in 2007 by the same authors exam-
ined intensive-dose therapy vs moderate-dose therapy
and found that intensive-dose therapy was associated
with a significant reduction in cardiovascular death.30
This echoed results from a similar meta-analysis
performed a year prior that showed a 16% reduction of
composite coronary death or any cardiovascular event.31
However, Silva et al30 specifically analyzed adverse events
and found those receiving intensive-dose therapy were
at significantly increased risk. The risk may not be worth
the benefit. For 1000 patients taking intensive-dose ther-
apy, four cardiovascular deaths are prevented; however,
for every cardiovascular event prevented, eight have an
adverse event.30 In the European Incremental Decrease
in End Points Through Aggressive Lipid Lowering (IDEAL)
trial, 8888 patients with coronary artery disease (defined
as a previous myocardial infarction) were randomized to
high-dose (80 mg atorvastatin) or usual-dose (20-40 mg
simvastatin daily) therapy. Patients with PAD were less
likely to have a hospitalization or intervention related to
PAD in the high-dose statin group than in the usual-
dose statin group. The frequency of new PAD in patients
was also lower in the high-dose statin group.32
Although several meta-analyses show cardiovascular
benefit from intensive-dose therapy, the risk of adverse
events seen in a meta-analysis of RCTs (Level 1a) is
concerning and warrants further investigation.
Concerns about statins. The benefits of statins on
patients with PAD and infrainguinal bypass are sup-
ported with a growing body of literature, but questions
remain regarding the safety of long-term statin use.
The most common adverse effect includes myopathy-
related symptoms, which are reported by 7% to 29% of
patients when reviewing patient registries; however, in
RCTs, the proportion of myalgia reported from patients
taking statins or placebo is similar.33 In addition, in most
patients who report muscle symptoms, creatine kinase
levels are usually normal or mild to moderately
elevated.34 The European Atherosclerosis Society
consensus panel recommends that, upon reports of
muscle pain or weakness, management should hinge on
the level of creatine kinase elevation and the magnitude
of cardiovascular disease risk. Physicians should stop
statins upon development of significant myalgia or
elevated creatine kinase, and with resolution of symp-
toms or laboratory values, attempt to restart statins at a
1886 Harris et al
lower dose to continue to benefit from the reduction in
cardiovascular disease risk. The American Academy of
Family Physicians notes that myopathy is dose-
dependent, may occur with all statins, and offers a
Class C recommendation that only patients at high risk
of muscle toxicity (because of comorbid conditions or
other medications) should undergo baseline creatine
kinase testing.35
Statins have been associated with the development of
diabetes. A large, well-designed meta-analysis of large
RCTs in 2010 found a 9% increased risk in incident
diabetes (95% CI, 1.02-1.17), although trials were not
heterogeneous. Overall, treatment of 255 (95% CI, 150-
182) patients with statins over 4 years may result in one
patient developing diabetes. However, the risk is
ultimately outweighed by the benefit of cardiovascular
risk reduction, and the authors recommended current
clinical practice should not change.
Early clinical trials of statins raised concern of possible
liver injury in patients. However, liver injury is rare, with
an incidence rate of hospitalization due to acute liver
injury of two to three per 100,000 person-days in statin
users.36 The previous Class C recommendation to period-
ically check liver function tests was refuted by the United
States Food and Drug Administration (FDA) in 2014 on
the basis of there being no evidence of prevention of liver
injury. The National Lipid Association, an expert panel of
hepatologists, states that chronic liver disease is not a
contraindication to statin use. The most recent recom-
mendation from the FDA is to check baseline liver func-
tion tests and to repeat only if the patient shows clinical
signs of liver injury.
In 2012, the FDA issued a warning that statins may
cause memory loss or confusion. This was on the heels
of several case reports linking memory loss and statin
use with subsequent attenuation of symptoms with
cessation of the statin regimen. However, a definitive
link has yet to be substantiated. Several systematic
reviews and meta-analyses, mostly of observational trials,
failed to show a statistically significant difference in
cognition between those who did and did not take a
statin. Among these studies, however, the type of cogni-
tive assessment varied greatly, and so the heterogeneity
is substantial. As of 2014, the FDA recommends patients
inform their physician of cognitive symptoms but
cautions against stopping the medication because the
consequences of stopping statins are likely more
significant.
Moderate-dose statin therapy has been associated with
the adverse effects of myopathy, liver disease, increased
incidence of diabetes development, and cognitive
impairment. These events are rare and usually not
serious. For most patients, the risk-to-benefit calculation
involving these adverse effects does not overtake the
significant benefit of reduction in cardiovascular events
and mortality. Currently, the AHA/ACC guidelines have
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Journal of Vascular Surgery
December 2016
put forth Class 1 recommendations for routine use of
statins.2
CONCLUSIONS
For patients with PAD, there is strong evidence support-
ing use of statins to reduce cardiovascular events and
mortality. For patients undergoing open and endovascu-
lar procedures, statin use reduces cardiovascular events
and mortality in the perioperative period and also in
long-term follow-up. There are data supporting reduced
incidence of revascularization as a result of statin use, but
not reductions in amputation, which may reflect PAD
patients presenting with advanced disease. Data are
incomplete regarding the local effect of statins after
endovascular treatment. Although intensive-dose statin
therapy may further reduce cardiovascular events, the
risk of adverse events warrants further investigation.
Moderate-dose statin therapy is safe, and the minor risks
posed by statins are greatly outweighed by benefits.
AUTHOR CONTRIBUTIONS
Conception and design: GL
Analysis and interpretation: SH, MR, GL
Data collection: SH, MR, GL
Writing the article: SH, MR, GL
Critical revision of the article: SH, MR, GL
Final approval of the article: SH, MR, GL
Statistical analysis: Not applicable
Obtained funding: Not applicable
Overall responsibility: GL
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Journal of Vascular Surgery
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Submitted Apr 28, 2016; accepted Aug 23, 2016.