Sulodexide improves pain-free walking
distance in patients with lower extremity
peripheral arterial disease: A systematic
review and meta-analysis
Antonio Vittorino Gaddi
, Fabio Capello
Oana Florentina Gheorghe-Fronea
, Simone Fadda
Roxana Oana Darabont
Peripheral arterial disease is associated with very high cardiovascular risk. The main symptom is intermittent claudica-
tion, which strongly affects the quality of life. Therefore, treatment goals in peripheral arterial disease consist of the
reduction of cardiovascular events and the relief of symptoms. An increase in pain-free walking distance, evaluated based
on the Initial Claudication Distance, was also a strong positive prognostic factor in patients with peripheral arterial
disease. Our objective was to reassess whether sulodexide is effective in improving Initial Claudication Distance. For
this, we searched the literature according to the PRISMA checklist for double blind clinical trials assessing the improve-
ment in the Initial Claudication Distance after 90 days of standard therapeutic regimen with sulodexide in adult patients
with peripheral arterial disease. We found and assessed for bias in 11 studies eligible for review and meta-analysis. Data
extracted from those studies favoured the sulodexide group, showing an overall difference in Initial Claudication
Distance of þ68.9 (CI 95%; 11.9 m) at the end of treatment (p <0.001). According to this review, sulodexide is
effective in improving Initial Claudication Distance and consequently the quality of life in patients with peripheral arterial
disease. Further studies are needed to assess the effects of this drug on disease progression in asymptomatic patients
with peripheral arterial disease.
Peripheral arterial disease, lower extremity arterial disease, drug therapy, intermittent claudication, meta-analysis,
Date received: 23 June 2019; revised: 22 December 2019; accepted: 7 January 2020
Lower extremity peripheral arterial disease (PAD) is a
medical condition mainly secondary to atherosclerosis;
deﬁciency in blood supply might lead to intermittent
claudication, rest pain, cutaneous ulcerations, and
rarely, to gangrene. PAD represents a global health
problem; in Europe, nearly 40 million people are esti-
mated to be affected by this disease.
The prevalence of
PAD, diagnosed by ankle-brachial index test (ABI) – a
quick, non-invasive test, able to detect signiﬁcant ste-
nosis in major leg arteries
– ranges from 8% in the
to approximately 20% in high-risk
In the last decade, the total number of
EuroGenLab, Bologna, Italy
Department of Paediatrics, AUSL della Romagna, Ospedale Morgagni-
Discipline of Cardiology, Clinical Emergency Hospital Bucharest,
University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
Department of Cardiology, ATS Sardegna, Italy
Discipline of Internal Medicine and Cardiology, University Emergency
Hospital Bucharest, University of Medicine and Pharmacy “Carol Davila”,
Oana Florentina Gheorghe-Fronea, Discipline of Cardiology, Clinical
Emergency Hospital Bucharest, University of Medicine and Pharmacy
“Carol Davila”, Calea Floreasca nr. 8, Sector 1, Bucharest, Romania.
JRSM Cardiovascular Disease
Volume 9: 1–14
!The Author(s) 2020
Article reuse guidelines:
Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-
NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and dis-
tribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.
individuals with PAD has increased by 23%, mostly
due to population growth, global aging, diabetes mel-
litus, and smoking habits in low- and middle-income
Most patients with PAD are asymptomatic.
Intermittent claudication (IC) is a lead symptom in
approximately 20% of the people affected.
Claudication is a reproducible discomfort (pain and/
or weakness) of a deﬁned group of muscles of the
lower limbs. The obstruction of one or more vessels
causes IC to reduce the blood ﬂow in the lower extrem-
Exercise, typically walking, elicits IC,
while rest relieves the symptom. In up to 70–80% of
cases of PAD with IC, the evolution is benign, without
progression to limb-threatening lower extremity ische-
Consequently, indications for revascularization
in patients with IC are still under debate and restricted
to speciﬁc categories; thus, conservative treatment
remains the main therapeutic approach.
Patients with PAD are included in the very high
category of cardiovascular risk.
of this disease is characterized by increased rates of
myocardial infarction, stroke or aortic complication;
death occurs in three quarters of cases due to a vascular
event in another territory than the lower extremity
Therefore, ﬁrst-line therapy in PAD, in
symptomatic and asymptomatic patients, must be
addressed to reduce the global cardiovascular risk.
This goal includes risk factor control (smoking cessa-
tion, control of arterial hypertension or diabetes melli-
tus) and pharmacological therapy. A signiﬁcant
amount of data – as per the guidelines currently in
– sustain the use of antiplatelet therapy (aspi-
) or lipid-lowering therapy
) for the reduction of cardiovascular events,
speciﬁcally in patients with PAD.
and rivaroxaban in low doses
seems to reduce major adverse limb
events. However, there is no evidence that these drugs can
improve the walking distance in IC, while an augmented
risk of bleeding was reported for the latter.
Nevertheless, for patients with IC, symptom relief
represents an important therapeutic goal.
A measurable target of treatment is the increment of
the pain-free walking distance (PFWD),
length a patient can walk before pain forces him or her
to stop. Improvement in the Initial Claudication
Distance (ICD) and in the Absolute Claudication
Distance (ACD), particularly in debilitate patients,
considered a positive prognostic factor.
Supervised exercise programmes are known to give
the most convincing beneﬁts.
In fact, lifestyle mod-
iﬁcations, particularly exercise (walking, intensive
walking, and supervised exercise), are effective in
increasing the ICD
: supervised exercise
programmes can increase the ICD by 81.2–143.8 m,
whereas free exercise shows inferior results.
According to the therapeutic algorithms currently in
use, patients with IC start treatment with supervised
exercised programmes; drugs are added in cases of insuf-
ﬁcient improvement after three to six
Recently, new approaches have also been tried: sur-
gical treatment, such as percutaneous transluminal
angioplasty (PTA) and revascularization;
autologous, stem and embryogenic cells for critical
mixed surgical and pharmacological
intervention, such as drug-eluting balloons;
or promising extracorporeal shock-
wave therapy (ESW).
Medical treatments used for cardiovascular risk con-
trol, such as statins, might slightly contribute to ICD
Along with these, data from random-
ized trials and meta-analyses indicate three drug ther-
apies as symptom relievers in patients with IC:
Cilostazol is a phosphodiesterase inhibitor that sup-
presses platelet aggregation and has direct vasodilatory
It has serious side effects and is contraindi-
cated in heart failure of any grade.
Naftidrofuryl is a
5-hydroxytryptamine-2-receptor antagonist whose
mechanism of action is still unclear; it might promote
glucose uptake and increase adenosine triphosphate
Pentoxifylline is a rheologic modiﬁer; it
increases red cell deformability, reduces blood viscosity
and decreases platelet aggregation.
In one meta-analysis, cilostazol appeared slightly
less effective than naftidrofuryl but more effective
In addition, a fourth drug has shown a signiﬁcant
effect on IC. Sulodexide is a highly puriﬁed glycosamino-
glycan. It is a combination of heparin sulfate (80%), with
a molecular weight of 7000 Da and afﬁnity for anti-
thrombin III, and dermatan sulfate (20%) with a molec-
ular weight of 25,000 Da and afﬁnity for the heparin II
Previous studies have demonstrated a note-
worthy improvement of IC parameters in patients treated
with this drug. Sulodexide seems effective in reducing
ﬁbrinogen and circulating lipoprotein levels.
mechanisms, as well as the antithrombotic effect of this
drug, help improve the PFWD in patients with IC.
To better understand the effectiveness of this drug in
treating IC, we thus performed a systematic review to
evaluate the effect of sulodexide on ICD and, conse-
quently, on the improvement in the quality of life of
Materials and methods
The study was performed according to the recommen-
dations of the Preferred Reporting Items for Systematic
2JRSM Cardiovascular Disease
Reviews and Meta-Analyses (PRISMA) statement.
We published the complete protocol in PROSPERO
Eligibility criteria and search strategy
As per our protocol, we searched from December 2017
to September 2018 PubMed, Embase, and Cochrane
Library, Clinicaltrials.gov, WanFang, VIP, and China
National Knowledge Infrastructure databases for clin-
ical trials on the sulodexide effect on vascular diseases
A combination of the following key words (includ-
ing Medical Subject Headings 2017)
was applied for
each selected database: sulodexide (including sulodex-
ide, soludexide, sulodexiden, sulodexid, Sulodeksid)
AND atherosclerosis (arteriosclerosis and MESH
UNIQUE ID D050197 and D001161 (MeSH
C14.907.137.126.307 and C14.307.320).
Data extraction and quality assessment
Two authors independently assessed trials for selection
and independently extracted data. Disagreements were
resolved by discussion. We also considered those
articles originally published in languages different
from English when a translation was available.
Studies that did not speciﬁcally include patients with
IC were excluded. We performed the quality assess-
ment adopting the Cochrane Collaboration Tools;
the JADAD score was evaluated by the Oxford QSS.
Outcome measures and statistical analysis
We set the ICD (sometimes named in the retrieved
articles as PFWD) as the primary outcome because
this index is commonly used to evaluate the IC.
Furthermore, it relates to the quality of life of patients
affected by IC,
and it is strongly linked with its prog-
nosis expressed as the progression of the disease
according to Leriche-Fontaine staging classiﬁcation.
ICD was also considered a primary outcome in
other systematic reviews aimed at evaluating the effec-
tiveness of other drugs used in the treatment of
We set the duration at 90 days of treatment
according to the indications that came from the litera-
ture that we analysed. However, as per our protocol,
we consider the ICD at 60 days of treatment as well.
We did not include the absolute claudication dis-
tance (ACD, or maximum walking distance) because
this measure cannot be standardized and is considered
a less relevant endpoint.
We set as exclusion criteria in our meta-analysis
studies of a lower quality, thus potentially biased,
deﬁned as studies with JADAD score <3.
We performed the meta-analysis with ﬁxed-effects
and random-effects models to evaluate the overall
pooled ICD (yielding equivalent results).
a random effect model when I
was >50%; otherwise,
we used a ﬁxed effect model, as suggested by a recent
Cochrane meta-analysis on ICD in patients with clau-
When useful, we followed the recommenda-
tions of Zwetsloot:
using raw mean differences
instead of standardized difference of means by estimate
of precision funnel plots. Statistics were computed by
Comprehensive Meta Analysis Rel. 2.2.064.
Although not speciﬁcally expressed in our research
protocol, we analysed other comparable measurements
considered of interest in the articles eligible for our
review, as recommended by recent publications on
the clinical evaluation of peripheral vascular disease
(PVD); among those, the ABI
and the number of
patients with a clinical improvement were expressed
according to other indexes.
Methodological and ethical issues
We checked for ethical approval of the papers included
in the study. Some of the oldest publications may not
explicitly state whether the ethical authorization was
granted because of the different laws in use at the
time of the studies. The studies included in the meta-
analysis appear to be deontologically sound.
Study selection for meta-analysis and quality
A total of 723 publications were found from different
literature sources: 444 (61,4%) were letters, editorials,
review and other papers without original data in
humans; 199 (27,5%) articles were excluded as no rel-
evant in terms of patient included, outcomes or treat-
ment used (Figure 1).
Eighty studies (Figure 1) are relevant on the basis of
published study protocol
(humans, sulodexide thera-
py, patients with atherosclerosis). Of those, 23 did not
measure ICD or had been performed on patients with-
out a clear diagnosis of PVD; 32 studies on patients
with PVD outcomes were measured in terms of modi-
ﬁcation of laboratory values with no relevant data on
IC. Twelve studies were excluded because they used an
open protocol without a control group or because of an
Table 1 shows the demographic characteristics of the
included studies: Bodula,
Gaddi et al. 3
All the studies included in the table refer to patients
with type II IC according to Leriche-Fontaine; in two
patients with type III IC were also includ-
ed. All the studies clearly specify PVD patients’ inclu-
sion and exclusion criteria.
In two studies (Table 2), the inclusion criteria are
only summarized. The Borreani study excluded
patients with diabetes or hyperlipoproteinemia;
the Della-Marchina study, patients with diabetes were
whereas the Palmieri study included
patients with hyperlipoproteinemia only (phenotype
IV or IIb according to Fredrickson).
In this same
study, demographic data collected before randomiza-
tion were reported (overall mean age of 42.5 years and
sex distribution, namely male ¼16 and female ¼14).
The Cospite study
also enrolled patients with athero-
masia in district other than the lower limbs (carotids,
coronary) or without IC, and those were excluded from
analysis. Sex distribution was the same in both groups,
while the prevalence of diabetes and hyperlipoproteine-
mia was the same (p >0.1), although it was not analyt-
ically reported in the three subgroups considered
(coronary, cerebral and peripheral vasculopathy). The
Bodula study reports lipid levels in the two groups
without signiﬁcant differences in LDLc or HDLc tri-
the prevalence of hyperlipoproteinemia is
Effect size of ICD differences between and within
Baseline value of ICD (m). Sulodexide group¼183,7
49,6 m.; placebo Groups¼191,0 55,4 m; Hedges’
g for ﬁxed effect 0,07 0,060, p ¼0,308, I
(no heterogeneity, forest plot and funnel plot not
shown). Identical results were obtained, including in
the effect size analysis the two studies against pentox-
yphilline (sulodexide ¼166,3 62,0 m; Controls¼
174,1 65,4, p >0,1, Hedges’g 0,092 0,064,
Mean difference of ICD in the sulodexide group after
three months of therapy. First explorative analysis includ-
ed all available data regardless of the dose administered
or the control group used by the different authors (the
Bodula and the Shustov studies were also included).
The random effect size evaluated on raw data (absolute
differences in meters) showed an overall difference
of þ68,9 m., 11,9, z ¼5,76, p <0,001 with an
¼52,9%. The forest plot is shown in Figure 2.
We performed a random effect on studies with pla-
cebo as a control with a JADAD score >3, a compa-
rable dose and length of therapy: the ICD difference
resulted of þ91.4 m (SEM ¼17.52, z ¼5.21, p <0.001).
Taking into account the heterogeneity of the results in
some of the studies (i.e. higher rise of Delta-ICD in
sulodexide treated patients in the Bonalumi
we analysed intra-group ICD differences with the
leave-one-out meta-analysis method (Figure 3).
The leave-one out analysis demonstrates the absence
of individual studies with a crucial effect on compre-
hensive results. Meta-regression analysis of mean daily
doses on difference in means was not signiﬁcant
(z ¼1.159 p ¼0.246), although two studies with very
low doses (50 mg/day),
and a very short administra-
showed the lowest result in ICD improve-
ment after sulodexide administration (both <55 m).
Effect size analysis of the mean difference in ICD in the control
groups after three months of therapy. The ICD mean dif-
ference (raw data) in placebo-treated patients was
þ5.37 2,77 m (z¼1.935, p ¼0.053, I
with ﬁxed and random effect size analysis. Two studies
with active drugs as a control (pentoxifylline) with
JADAD Score 2 were also included in the forest plot
shown in Figure 4. The delta ICD values (in m) were
þ22.09 8.8 (ﬁxed model) and þ27.09 20.9 (random
Figure 1. Flowchart of the study number identified and
included in the meta-analysis.
ICD: Initial Claudication Distance; PVD: Peripheral Vascular
Disease; RCT: randomized controlled trial.
4JRSM Cardiovascular Disease
Table 1. Eligible trials, characteristics and demographics.
SD/range) Males (%) Diabetes (%)
Author Year Control S C S C S C S C S C S C S C
Bonalumi, F. 1986 Placebo 15 15 15 15 100,0 100,0 60,1 8,6 60,4 9,6 93,3 73,3 40,0 33,3 93,3 86,7
Borreani, B. 1993 Placebo 50 50 50 50 100,0 100,0 67,1 5,1 68,1 4,9 76,0 70,0 no no no no
Coccheri, S. 2002 Placebo 143 143 141 143 98,6 100,0 64,7 7,6 66,2 7,5 83,9 76,9 25,2 23,8 46,9 55,2
Corsi, C. 1985 Placebo 15 15 15 15 100,0 100,0 65,8 11,1 69,8 12,6 80,0 66,7 no no 73,3 80,0
Cospite, M. 1985 Placebo 9 8 9 8 100,0 100,0 59,0 40–72 57,0 40–72 na na na na na na
Della Marchina, M. 1992 Placebo 35 35 27 29 77,1 82,9 65,4 59–74 63,8 55–81 54,3 57,1 100,0 100,0 60,0 57,1
Di Stefano, F. 1984 Placebo 15 15 15 15 100,0 100,0 66,9 55–75 68,2 55–75 73,3 66,7 26,7 13,3 60,0 60,0
Liguori, L. 25 b.i.d . 1993 Placebo 62 62 60 61 96,8 98,4 67,7 7,8 66,4 8,6 71,0 74,2 11,3 8,1 21,0 19,4
Liguori, L. 100 q.d . 1993 Placebo 62 62 58 61 93,5 98,4 67,8 8,5 66,4 8,6 69,4 74,2 14,5 8,1 24,2 19,4
Liguori, L. 50 b.i.d . 1993 Placebo 62 62 61 61 98,4 98,4 69,3 8,5 66,4 8,6 59,7 74,2 11,3 8,1 24,2 19,4
Palmieri, G. 84 1984 Placebo 15 15 11 10 73,3 66,7 na 20–60 na 20–60 53,3 53,3 no no 100,0 100,0
Bodula, A . 2010 Pentoxyphylline 23 17 23 17 100,0 100,0 53,6 18,7 53,3 9,1 82,6 65,2 73,9 47,8 na na
Shustov, S.B. 1997 Pentoxyphylline 60 60 56 51 93,3 85,0 71,1 10,8 69,8 17,0 70,0 66,7 31,7 26,7 40,0 41,7
Sum/raw means (placebo, n¼12) 483 482 462 468 94,3 95,0 65,4 8,2 65,3 8,6 71,4 68,7 32,7 27,8 55,9 55,2
Sum/raw means (active control, n¼2) 83 77 79 68 96,7 92,5 62,4 14,8 61,6 13,1 76,3 65,9 52,8 37,2 40,0 41,7
Sum, raw means (all, n¼14) 566 559 541 536 94,7 94,6 64,9 9,6 64,6 9,6 72,2 68,2 37,2 29,9 54,3 53,9
Sum, weighted means (all, n¼14) 95,6 95,9 66,3 66,1 73,1 71,3 29,4 24,4 40,0 40,7
Note: Weighted means were evaluated excluding studies with missing data). The Liguori paper
presented results from three distinct studies in which different clusters of patients and different protocols
were used; findings from these studies were summarized in a single published paper.
Na: not assessed; no: not included.
Gaddi et al. 5
model) with Z ¼2.6, p ¼0.008 and z ¼1.29, p ¼0.195,
respectively. In the Bodula study, the protocols were
not comparable. The analysis considerably favours
sulodexide when compared with placebo; the effect of
pentoxifylline, described in other studies, is not com-
The Borreani study
because it did not report data for effect size evaluation
in the placebo group (mean value without SEM/SD or
paired p value).
ICD differences between the sulodexide and control groups
after three months of therapy
Sulodexide versus placebo. As stated before, we
exclude the Borreani study
in the analysis because
of high heterogeneity among data (overall, placebo
and pentoxifenilline as controls, I
a funnel plot of precision by raw difference in means
also conﬁrms the presence of publication bias
We ﬁrst performed a random effect meta-analysis
with inclusion of all the available data, regardless of
the dose of sulodexide used, including the group
treated with 25 2 mg/day published in the Liguori
study. The random effect size evaluated on raw data
(absolute differences in meters of ICD) in all published
papers resulted of þ80,91 m 5,72, favouring sulodex-
ide (z ¼9,34, p <0,001). We tried to reduce heteroge-
neity excluding individual studies: the random effect
size evaluation after exclusion of the outliers
(Bonalumi and Liguori dose ﬁnding study with low-
), resulted in þ58.2 15.7 m,
favouring sulodexide (z ¼3.709, p ¼0.001; I
The leave-one-out analysis (Figure 6) revealed an
effect on the comprehensive effect size by removing
the Coccheri study (from 58.2 15.6 to 69.5 18.6 m
of the raw ICD difference) and the Di Stefano trial
(decrease from 58.2 to 41.2 12.8 m)
Sulodexide versus pentoxifylline. No differences were
observed in effect size (ﬁxed model, no heterogeneity)
of delta ICD between pentoxifylline and sulodexide
þ2.84 9.00, z ¼0.318, p ¼0.752. However, further
studies are needed for a proper evaluation.
Surrogate outcome analysis
Number of patients with relevant improvement of
ICD. The absolute number of patients markedly
improved (see Materials and methods) after adminis-
tration of sulodexide or placebo is reported only in six
surveys. The data are heterogeneous (I
ever, the absolute rates are very different: 177 out of
328 (53.9%) patients markedly improved in the
sulodexide-treated group, 24 out of 319 (7.2%) in
placebo-treated controls. The random effect size eval-
uated on the log of odds ratio (OR) favoured
Table 2. Assessment for bias in each study included in the review and the quality of those same studies.
score Study design
Bonalumi, F. 3 DB ITT Yes Sufficient Low Low Low Low Low Low
Borreani, B. 3 DB ITT Yes Sufficient Low Low Low Low Low High
Coccheri, S. 5 DB MC ITT PP Yes Good Low Low Low Low Low Low
Corsi, C. 5 DB ITT Yes Good Low Low Low Low Low Low
Cospite, M. 5 DB ITT NA Sufficient Low Low Low Low Low Unclear
Della Marchina, M. 3 DB PP Yes Good Low Low Low Low Low Low
Di Stefano, F. 4 DB ITT Yes Good Low Low Low Low Low Low
Liguori, L. 25 b.i.d. 4 DB MC DD ITT PP Yes Good Low Low Low Low Low Low
Liguori, L. 100 q.d. 4 DB MC DD ITT PP Yes Good Low Low Low Low Low Low
Liguori, L. 50 b.i.d. 4 DB MC DD ITT PP Yes Good Low Low Low Low Low Low
Palmieri, G. 84 3 DB ITT NA Good Low NA Low NA Low Low
Bodula, A. 2 CO NA Yes Good NA NA High NA Low Low
Shustov, S.B. 2 CO PP Yes Good Low NA High NA Low Low
Note: Assessment was also done for every study according to the JADAD scale. JADAD is scored according to the Oxford Quality Scoring System (http://www.pmidcalc.org/?sid=8721797&newtest=Y).
DB: double blind; MC: multicenter research trial; DD: double dummy; CO: cross Over; ITT: intention to treat; PP: per-protocol; NA: not available.
6JRSM Cardiovascular Disease
sulodexide: OR log ¼3.345 0.837, z ¼3.997,
p<0.0001) (Figure 7)
Ankle-brachial (Winsor) index. The ankle-brachial
(Winsor) index was evaluated in seven surveys with
placebo as a control (plus one with pentoxifylline,
which we do not considered in our analysis). Several
authors reported only the p values at end (paired p
within group and/or independent sample t and p
values at the end of the study). The data resulted in
homogenous and ﬁxed effect meta-analysis demon-
strating an improvement of the Winsor index in
sulodexide-treated patients (Hedge’s 0.346 0.078,
z¼4.0531, p <0.0001).
Long-term period variations of ICD. Four studies reported
data on ICD differences after six months of sulodexide
therapy (three versus placebo and one versus pentoxi-
fylline). Funnel plot analysis revealed the presence of
publication bias; however, the mean effect size evaluat-
ed with or without predicted values is still the same.
The overall analysis of effect size (ﬁxed effect, I
on raw ICD within group differences in sulodexide
group resulted in 89.0 13.71 m, z¼6.491, p <0.001.
Figure 2. ICD mean difference (raw data) with ICD calculated in m in sulodexide-treated patients. The forest plot shows the mean
difference between 0 and þ3 months of treatment. The results favour treatment with sulodexide.
Figure 3. Leave-one-out analysis of ICD improvement measured in m in the sulodexide group. The plot shows the results on
computed random effect size (raw difference in means and 95% interval of confidence) calculated removing one study at a time. The
analysis indicates that the influence and the weight of each individual study are very light.
Gaddi et al. 7
Adverse events/side effect. No serious or clinically
relevant side effects were described in the surveys
included in this review. The Shustov study reports
lower side effects, referred ad minor complaints, in
the pentoxifylline group (p <0.05).
Our meta-analysis aimed to evaluate the effect size
of sulodexide on ICD improvement in patients with
well-established peripheral vascular disease (particu-
larly in stage IIa and IIB according to Leriche classiﬁ-
cation). After three months of therapy, the effect size
was 70–90 m; this is an increase of the PFWD of
approximately 45%, which is signiﬁcantly higher than
the placebo controls (þ3%). There are no sufﬁcient
data available to compare sulodexide with other
drugs; we found only two studies where sulodexide
was compared with pentoxifylline. These two studies
formally show similar results in the raw ICD difference
The one-study inﬂuence and cumulative analyses
reﬂect the stability of the effect-size results reported
As stated before, we also found a slight rise of ICD in
placebo-treated controls; several studies reported in
show a slight increment in patients
Figure 4. ICD mean difference (raw data) in pentoxifylline (top diamond) and placebo (bottom diamond)-treated patients. The
graphs show the forest plot of the mean difference between 0 and þ3 months of treatment.
Figure 5. Funnel plot of precision by ICD difference in means. The graph shows a remarkable deviation from the funnel distribution,
highlighting the possible presence of publication bias in the Borreani study.
8JRSM Cardiovascular Disease
treated with placebo, which refers to improvement in the
lifestyle or in the physical activities of the patients when
assessed for confounders;
this was particularly evi-
dent when the placebo group went through supervised
and personalized physical activity programmes
the optimization of concomitant treatments.
In the studies that we included in our ﬁnal review,
concomitant treatments were homogeneous in the sulo-
dexide group and in the control group, with no speciﬁc
activity programmes in place, as suggested by guide-
in one study, a progressive walking pro-
gramme was strongly recommended.
The number of patients who improved their medical
condition after treatment with sulodexide suggests that
this drug can be useful in the management of IC.
The Momsen systematic review
on drugs for
improvement of walking distance in claudication, accord-
ing to European guidelines, states that an improvement
of 30% or more of the ICD is clinically meaningful to
help maintain essential daily living activities. In addition,
a walking distance of 70 m without leg pain enables
patients to work in non-physical jobs. The Momsen
review shows results close to the upper limit of these
cut-offs when statins, cilostazol, indobrufen and nafti-
drofuryl were used.
Momsen cited only one article on
sulodexide stating that “of the individual drugs, the effect
estimate pointed to sulodexide as the most effective with
an increase in MWD of 86 meters (95%IC 83–89)”.
Similar results are described for pentoxifylline,
although some studies show a negative or non-
Figure 6. Forest plot of raw ICD difference between sulodexide and placebo, with the leave-one-out method (details in the text).
Figure 7. The forest plot shows the random effect size evaluated on the log of OR of number of patients with marked ICD
improvement in sulodexide- or placebo-treated groups. The results favour the sulodexide group.
Gaddi et al. 9
signiﬁcant effect: Girolami, in a recent meta-analysis,
conﬁrms signiﬁcant inhomogeneities in the results
when pentoxifylline is considered, with a mild improve-
ment of the ICD (þ44, IC95% 14–74 m when com-
pared with the placebo group).
Our meta-analysis, with only two studies in which
pentoxifylline was used in the control groups (both
with a JADAD score of 2), does not add any informa-
tion. We can speculate that the inclusion of these
studies – namely, the raw ICD difference in
pentoxifylline-treated patients of þ7m(p>0.05) and
þ49 m (p <0.01) in Bodula
and in Shustov
respectively – in the Girolami meta-analysis would not
have modiﬁed its conclusions.
In addition, recent guidelines include cilostazol
among the drugs suggested for the treatment of IC.
Nonetheless, there are no recommendations related to
the use of pentoxifylline, although a recent review pub-
lished in the Cochrane database showed signiﬁcant
differences among cilostazol and pentoxifylline, as
also stated by FDA;
a further analysis concluded
that cilostazol is not cost-effective, suggesting that naf-
tidrofuryl oxalate is the only vasoactive drug for PAD,
which is likely to be cost-effective.
According to the
ESC guidelines, however, there is no evidence that
cilostazol, naftidrofuryl, pentoxifylline, buﬂomedil,
carnitine and propionyl-L-carnitine can improve the
walking distance in IC.
In terms of increment of ICD, the naftidrofuryl
(nafronyl) had a better ranking,
with a percentage
increase of ICD similar to that of sulodexide as per our
In this meta-analysis, there is a good concordance
among other indexes used to measure the effectiveness
of sulodexide on claudication, which is also indirectly
expressed in terms of improvement of the ABI.
Nevertheless, some discrepancies remain evident in
the protocols of individual studies, so that both the
number of patients that showed some improvements
and the data on ABI are not properly reported; how-
ever, it is easy to measure and to standardize. Thus, an
in-depth analysis is not possible. Data on the Winsor
index are not relevant. Recent literature suggests that
future high quality studies are required to objectively
deﬁne the best training programme to facilitate ABI
teaching and learning,
considering also that ABI
can make diagnosis of PAD even when symptoms are
not present yet and can give valuable information in
relation to its prognosis and to the prediction of
the overall cardiovascular complications of the
The lack of homogenous data collection is an inter-
pretative limitation of this meta-analysis, as also seen
in a similar review of patients with PAD.
However, the comparison of the different drugs
available to treat or improve IC is not the aim of this
Considering the social implications and the impact
of PAD on the quality of life, and the lack of effective
programmes for the screening and early diagnosis of
this disease – as also highlighted by a recent review
by the Cochrane Collaboration
– further clinical
trials including patients with poor or no symptoms,
are highly recommended.
The improvement of ICD in symptomatic patients in
stage II and higher according to the Leriche staging
scale remains a major target to improve the quality of
life of these patients.
According to our review, a three-month treatment
with sulodexide resulted in an effective improvement in
ICD with an effect size higher than those reported for
other medications currently in use or suggested in the
international guidelines for the treatment of PAD. For
these reasons, we suggest that sulodexide should be con-
sidered as the primary choice in the treatment of IC.
This review indicates that treatment with sulodexide 60
to 100 mg/day for three months can signiﬁcantly
increase ICD in patients with stage IIa/IIb PAD,
according to the Leriche classiﬁcation. The magnitude
of the ICD increase was 70–90 m in the intragroup
analysis and 60–80 m when compared with the placebo.
These results are consistent with other data reported in
Few studies have followed the effects of a six-month
treatment with sulodexide and have found even a
higher increment of ICD (90 m on the average).
Our results show that improvement of ICD with
sulodexide can reach equal or higher values than
other symptomatic treatments in PAD, e.g., cilostazol.
This meta-analysis is not able to provide data on the
comparison between sulodexide and pentoxifylline
effects in PAD.
Further research is needed to clarify whether a
longer duration of treatment with sulodexide – 6 to
12 months – can bring a higher beneﬁt for ICD
improvement and to assess the effect of this drug in
asymptomatic patients with PAD.
AVG designed the research protocol, assessed the studies,
extracted data, wrote the statistical analysis plan, analysed
the data and drafted and revised the paper. FC designed
the research protocol, assessed the studies, extracted data,
drafted and revised the paper. ROD analysed the data and
drafted and revised the paper. SF reviewed data analysis,
10 JRSM Cardiovascular Disease
drafted and revised the paper. OFG-F monitored data anal-
ysis and analysed the data, and drafted and revised the paper.
Declaration of conflicting interests
The author(s) declared no potential conﬂicts of interest with
respect to the research, authorship, and/or publication of this
The author(s) received no ﬁnancial support for the research,
authorship, and/or publication of this article.
Prof. AV Gaddi.
Fabio Capello https://orcid.org/0000-0002-1074-6979
a. Lower ankle/brachial index, as calculated by averaging the
dorsalis pedis and posterior tibial arterial pressures,
and association with leg functioning in peripheral arterial
e. comparable data: studies versus placebo, with measure-
ment of ICD in meters in patients with PVD in stage II:
Naftidrofuryl raw difference of ICD þ49% (95%IC¼23–
81), cilostazol 13% (95%IC¼2–26), pentoxifylline 9%
(95%IC¼–2–22), sulodexide 49% (95%IC¼26–72).
1. Fowkes FG, Rudan D, Rudan I, et al. Comparison of
global estimates of prevalence and risk factors for periph-
eral artery disease in 2000 and 2010: a systematic review
and analysis. Lancet 2013; 382: 1329–1340.
2. Alzamora MT, Fores R, Baena-Diez JM, et al. The
peripheral arterial disease study (PERART/ARTPER):
prevalence and risk factors in the general population.
BMC Public Health 2010; 10: 38.
3. Aboyans V, Ricco J-B, Bartelink M-L, et al. 2017 ESC
guidelines on the diagnosis and treatment of peripheral
arterial diseases, in collaboration with the European
Society for Vascular Surgery (ESVS) Document covering
atherosclerotic disease of extracranial carotid and verte-
bral, mesenteric, renal, upper and lower extremity arteries
Endorsed by: the European Stroke Organization (ESO)
The Task Force for the Diagnosis and Treatment of
Peripheral Arterial Diseases of the European Society of
Cardiology (ESC) and of the European Society for
Vascular Surgery (ESVS). Eur Heart J 2017; 39: 763–816.
4. Diehm C, Schuster A, Allenberg JR, et al. High preva-
lence of peripheral arterial disease and co-morbidity in
6880 primary care patients: cross-sectional study.
Atherosclerosis 2004; 172: 95–105.
5. Meijer WT, Hoes AW, Rutgers D, et al. Peripheral arte-
rial disease in the elderly: the Rotterdam Study.
Arterioscler Thromb Vasc Biol 1998; 18: 185–192.
6. Ahmed O, Hanley M, Bennett SJ, et al. ACR appropri-
RVascular claudication – assessment for
revascularization. J Am Coll Radiol 2017; 14: S372–S379.
7. Berger J, Davies M and Clement D. Overview of lower
extremity peripheral artery disease. Waltham, MA:
8. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA
2005 practice guidelines for the management of patients
with peripheral arterial disease (lower extremity, renal,
mesenteric, and abdominal aortic): a collaborative
report from the American association for vascular sur-
gery/society for vascular surgery,* Society for
Cardiovascular Angiography and Interventions, Society
for Vascular Medicine and Biology, Society of
Interventional Radiology, and the ACC/AHA Task
Force on Practice Guidelines (Writing Committee to
Develop Guidelines for the Management of Patients
With Peripheral Arterial Disease): Endorsed by the
American Association of Cardiovascular and
Pulmonary Rehabilitation; National Heart, Lung, and
Blood Institute; Society for Vascular Nursing;
TransAtlantic Inter-Society Consensus; and Vascular
Disease Foundation. Circulation 2006; 113: e463–e654.
9. Mg D. Management of claudication 2019, www.upto
(accessed 9 January 2019).
10. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016
AHA/ACC guideline on the management of patients with
lower extremity peripheral artery disease: executive sum-
mary: a report of the American College of Cardiology/
American Heart Association Task Force on Clinical
Practice Guidelines. J Am Coll Cardiol 2017; 69:
11. Vitalis A, Lip GY, Kay M, et al. Ethnic differences in the
prevalence of peripheral arterial disease: a systematic
review and meta-analysis. Expert Rev Cardiovasc Ther
2017; 15: 327–338.
12. Takagi H and Umemoto T. Associations of coronary and
peripheral artery disease with presence, expansion, and
rupture of abdominal aortic aneurysm – a grin without
a cat! VASA Zeitschrift Vasa 2017; 46: 151–158.
13. Johner F, Thalhammer C, Jacomella V, et al. Differences
in cardiovascular risk factors between patients with acute
limb ischemia and intermittent claudication. Angiology
2014; 65: 497–500.
14. Baigent C, Blackwell L, Collins R, et al. Aspirin in the
primary and secondary prevention of vascular disease: col-
laborative meta-analysis of individual participant data
from randomised trials. Amsterdam: Elsevier, 2009.
Gaddi et al. 11
15. Berger JS, Krantz MJ, Kittelson JM, et al. Aspirin for the
prevention of cardiovascular events in patients with
peripheral artery disease: a meta-analysis of randomized
trials. JAMA 2009; 301: 1909–1919.
16. Pessah-Rasmussen H. A randomised, blinded, trial of
clopidogrel versus aspirin in patients at risk of ischaemic
events (CAPRIE). CAPRIE Steering Committee. Lancet
1996; 348: 39–1329.
17. Group H. Randomized trial of the effects of cholesterol-
lowering with simvastatin on peripheral vascular and
other major vascular outcomes in 20,536 people with
peripheral arterial disease and other high-risk conditions.
J Vasc Surg 2007; 45: 645–654. e1.
18. O’Donnell TF, Deery SE, Darling JD, et al. Adherence to
lipid management guidelines is associated with lower
mortality and major adverse limb events in patients
undergoing revascularization for chronic limb-
threatening ischemia. J Vasc Surg 2017; 66: 572–578.
19. Bonaca MP, Nault P, Giugliano RP, et al. Low-density
lipoprotein cholesterol lowering with evolocumab and
outcomes in patients with peripheral artery disease:
insights from the FOURIER trial (Further
Cardiovascular Outcomes Research With PCSK9
Inhibition in Subjects With Elevated Risk). Circulation
2018; 137: 338–350.
20. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban
with or without aspirin in stable cardiovascular disease.
N Engl J Med 2017; 377: 1319–1330.
21. Anand SS, Bosch J, Eikelboom JW, et al. Rivaroxaban
with or without aspirin in patients with stable peripheral
or carotid artery disease: an international, randomised,
double-blind, placebo-controlled trial. Lancet 2018; 391:
22. Bendermacher BL, Willigendael EM, Teijink JA, et al.
Supervised exercise therapy versus non-supervised exer-
cise therapy for intermittent claudication. Cochrane
Database Syst Rev 2006; 8: CD005263.
23. Wind J and Koelemay MJ. Exercise therapy and the
additional effect of supervision on exercise therapy in
patients with intermittent claudication. Systematic
review of randomised controlled trials. Eur J Vasc
Endovasc Surg 2007; 34: 1–9.
24. Parmenter BJ, Raymond J, Dinnen P, et al. A systematic
review of randomized controlled trials: walking versus
alternative exercise prescription as treatment for intermit-
tent claudication. Atherosclerosis 2011; 218: 1–12.
25. Parmenter BJ, Dieberg G and Smart NA. Exercise train-
ing for management of peripheral arterial disease: a sys-
tematic review and meta-analysis. Sports Med 2015; 45:
26. Lyu X, Li S, Peng S, et al. Intensive walking exercise for
lower extremity peripheral arterial disease: a systematic
review and meta-analysis. J Diabetes 2016; 8: 363–377.
27. Lane R, Harwood A, Watson L, et al. Exercise for inter-
mittent claudication. Cochrane Database Syst Rev 2017;
28. Duprez D, De Backer T, De Buyzere M, et al. Estimation
of walking distance in intermittent claudication: need for
standardization. Eur Heart J 1999; 20: 641–644.
29. Aung PP, Maxwell HG, Jepson RG, et al. Lipid-lowering
for peripheral arterial disease of the lower limb. Cochrane
Database Syst Rev 2007; 4: CD000123.
30. Thompson PD, Zimet R, Forbes WP, et al. Meta-analysis
of results from eight randomized, placebo-controlled
trials on the effect of cilostazol on patients with intermit-
tent claudication. Am J Cardiol 2002; 90: 1314–1319.
31. Pande RL, Hiatt WR, Zhang P, et al. A pooled analysis
of the durability and predictors of treatment response of
cilostazol in patients with intermittent claudication. Vasc
Med 2010; 15: 181–188.
32. Stevens JW, Simpson E, Harnan S, et al. Systematic
review of the efﬁcacy of cilostazol, naftidrofuryl oxalate
and pentoxifylline for the treatment of intermittent clau-
dication. Br J Surg 2012; 99: 1630–1638.
33. Bedenis R, Stewart M, Cleanthis M, et al. Cilostazol for
intermittent claudication. Cochrane Database Syst Rev
2014; 10: CD003748.
34. Hood SC, Moher D and Barber GG. Management of
intermittent claudication with pentoxifylline: meta-
analysis of randomized controlled trials. CMAJ 1996;
35. Salhiyyah K, Senanayake E, Abdel-Hadi M, et al.
Pentoxifylline for intermittent claudication. Cochrane
Database Syst Rev 2012; 1: CD005262.
36. Reilly MP and Mohler ER 3rd. Cilostazol: treatment of
intermittent claudication. Ann Pharmacother 2001; 35:
37. Jacoby D and Mohler ER 3rd. Drug treatment of inter-
mittent claudication. Drugs 2004; 64: 1657–1670.
38. Jung F, Kiesewetter H, Mrowietz C, et al.
Hemorrheological, micro- and macrocirculatory effects
of naftidrofuryl in an acute study: a randomized,
placebo-controlled, double-blind individual comparison.
Int J Clin Pharmacol Ther Toxicol 1987; 25: 507–514.
39. Lasierra-Cirujeda J, Coronel P, Aza M, et al. Use of
sulodexide in patients with peripheral vascular disease.
J Blood Med 2010; 1: 105.
40. Coccheri S, Scondotto G, Agnelli G, et al. Arterial arm of
the Suavis g. sulodexide in the treatment of intermittent
claudication. Results of a randomized, double-blind,
multicentre, placebo-controlled study. Eur Heart J
2002; 23: 1057–1065.
41. Gaddi A, Galetti C, Illuminati B, et al. Meta-analysis of
some results of clinical trials on sulodexide therapy in
peripheral occlusive arterial disease. J Int Med Res
1996; 24: 389–406.
42. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA
statement for reporting systematic reviews and meta-
analyses of studies that evaluate health care interven-
tions: explanation and elaboration. J Clin Epidemiol
2009; 62: e1–e34.
43. Volmink J, Siegfried N, Robertson K, et al. Research
synthesis and dissemination as a bridge to knowledge
management: the Cochrane Collaboration. Bull World
Health Organ 2004; 82: 778–783.
44. Capello F, Gaddi AV, Darabont RA, et al. Effect of
sulodexide on claudication in patients with peripheral
vascular disease. Prospero 2017; 2013: CRD42017076473.
12 JRSM Cardiovascular Disease
45. Higgins JP, Altman DG, Gotzsche PC, et al. The
Cochrane Collaboration’s tool for assessing risk of bias
in randomised trials. BMJ 2011; 343: d5928.
46. Hafner HM, Junger I, Geyer A, et al. Inﬂuence of con-
trolled vascular training on the pain free walking distance
and plasmaviscosity in patients suffering from peripheral
arterial occlusive disease. Clin Hemorheol Microcirc 2009;
47. Mazzone A, Di Salvo M, Mazzuca S, et al. Effects of
iloprost on pain-free walking distance and clinical out-
come in patients with severe stage IIb peripheral arterial
disease: the FADOI 2bPILOT Study. Eur J Clin Invest
2013; 43: 1163–1170.
48. Carrero JJ, Lopez-Huertas E, Salmeron LM, et al. Daily
supplementation with (n-3) PUFAs, oleic acid, folic acid,
and vitamins B-6 and E increases pain-free walking dis-
tance and improves risk factors in men with peripheral
vascular disease. J Nutr 2005; 135: 1393–1399.
49. Arosio E, De Marchi S, Zannoni M, et al. Effect of glu-
tathione infusion on leg arterial circulation, cutaneous
microcirculation, and pain-free walking distance in
patients with peripheral obstructive arterial disease: a
randomized, double-blind, placebo-controlled trial.
Mayo Clin Proc 2002; 77: 754–759.
50. Ponte E and Cattinelli S. Quality of life in a group of
patients with intermittent claudication. Angiology 1996;
51. Lawall H, Huppert P, Espinola-Klein C, et al. German
guideline on the diagnosis and treatment of peripheral
artery disease – a comprehensive update 2016. VASA
2017; 46: 79–86.
52. de Backer TL and Vander Stichele. R. Buﬂomedil for
intermittent claudication. Cochrane Database Syst Rev
2013; 3: CD000988.
53. Borenstein M, Hedges LV, Higgins JP, et al. A basic
introduction to ﬁxed-effect and random-effects models
for meta-analysis. Res Synth Methods 2010; 1: 97–111.
54. Riley RD, Higgins JP and Deeks JJ. Interpretation of
random effects meta-analyses. BMJ 2011; 342: d549.
55. Zwetsloot PP, Van Der Naald M, Sena ES, et al.
Standardized mean differences cause funnel plot distor-
tion in publication bias assessments. Elife 2017; 6. DOI:
56. Xu D, Zou L, Xing Y, et al. Diagnostic value of ankle-
brachial index in peripheral arterial disease: a meta-anal-
ysis. Can J Cardiol 2013; 29: 492–498.
57. Lin JS, Olson CM, Johnson ES, et al. The ankle-brachial
index for peripheral artery disease screening and cardio-
vascular disease prediction among asymptomatic adults:
a systematic evidence review for the U.S. Preventive
Services Task Force. Ann Intern Med 2013; 159: 333–341.
58. Corsi C, Bocci L, Cipriani C, et al. The effectiveness of
glycosaminoglycans in peripheral vascular disease thera-
py: a clinical and experimental trial. J Int Med Res 1985;
59. Bodula A, Malecki R and Adamiec R. Comparative eval-
uation of pentoxyphylline and sulodexide effectiveness in
the treatment of symptomatic arteriosclerosis obliterans.
Acta Angiol 2010; 16: 18–29.
60. Bonalumi F, Sarcina A, Bonadeo P, et al. A randomized
protocol for the management of chronic peripheral arte-
rial disease by means of sulodexide. Riv Eur Sci Med
Farmac 1986; VIII: 123–129.
61. Borreani B, Brizio L, Cianfanelli G, et al. Valutazione
`del Sulodexide nell’arteropatia cronica peri-
ferica scleroateromatosa. Arch Sci Med (Torino) 1993;
62. Cospite M, Milio G, Ferrara F, et al. Double-blind study
of the pharmacological effects of sulodexide in patients
with multiple atherosclerotic vascular disease. Riv Europ
Sci Med Farmac 1985; VII: 97–106.
63. Della Marchina M, Bellucci M and Palazzini E. Medium
term oral Sulodexide Treatment of diabetic patients suf-
fering from peripheral arterial disease: a double-blind
placebo-controlled study. Progr Rep 1992; 4: 5–16.
64. Di Stefano F, Patan
e S, Vinci M, et al. Medical treatment
of atherosclerosis controlled clinical trial with new gly-
cosaminoglycan: sulodexide. Riv Europ Sci Med Farmac
1984; VI: 525–532.
65. Liguori L, Saviano M, Lampugnani R, et al. Efﬁcacy,
tolerability, and dose-effect relationship of oral sulodex-
ide in obstructive peripheral arterial disorders. Adv Ther
1993; 10: 53–66.
66. Palmieri G, Nazzari M, Ambrosi G, et al. Sulodexide in
the treatment of peripheral arterial diseases. Clin Trials J
1984; 21: 411–427.
67. Shustov SB. Controlled clinical trial on the efﬁcacy and
safety of oral sulodexide in patients with peripheral
occlusive arterial disease. Curr Med Res Opin 1997; 13:
68. Girolami B, Bernardi E, Prins MH, et al. Treatment of
intermittent claudication with physical training, smoking
cessation, pentoxifylline, or nafronyl: a meta-analysis.
Arch Intern Med 1999; 159: 337–345.
69. Stewart M, Morling JR and Maxwell H. Padma 28 for
intermittent claudication. Cochrane Database Syst Rev
2016; 3: CD007371.
70. McDermott MM. Exercise training for intermittent clau-
dication. J Vasc Surg 2017; 66: 1612–1620.
71. Vemulapalli S, Dolor RJ, Hasselblad V, et al. Supervised
vs unsupervised exercise for intermittent claudication: a
systematic review and meta-analysis. Am Heart J 2015;
169: 924–937 e3.
72. Writing Committee M, Gerhard-Herman MD,
Gornik HL, et al. 2016 AHA/ACC guideline on the man-
agement of patients with lower extremity peripheral
artery disease: executive summary. Vasc Med 2017; 22:
73. Momsen AH, Jensen MB, Norager CB, et al. Drug ther-
apy for improving walking distance in intermittent clau-
dication: a systematic review and meta-analysis of robust
randomised controlled studies. Eur J Vasc Endovasc Surg
2009; 38: 463–474.
74. Meng Y, Squires H, Stevens JW, et al. Cost-effectiveness
of cilostazol, naftidrofuryl oxalate, and pentoxifylline
for the treatment of intermittent claudication in people
with peripheral arterial disease. Angiology 2014; 65:
Gaddi et al. 13
75. Chaudru S, de Mullenheim PY, Le Faucheur A, et al.
Training to perform ankle-brachial index: systematic
review and perspectives to improve teaching and learn-
ing. Eur J Vasc Endovasc Surg 2016; 51: 240–247.
76. Hajibandeh S, Hajibandeh S, Shah S, et al.
Prognostic signiﬁcance of ankle brachial pressure index:
a systematic review and meta-analysis. Vascular 2017; 25:
77. Andras A and Ferket B. Screening for peripheral
arterial disease. Cochrane Database Syst Rev 2014; 4:
14 JRSM Cardiovascular Disease