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Sulodexide improves pain-free walking distance in patients with lower extremity peripheral arterial disease: A systematic review and meta-analysis

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Peripheral arterial disease is associated with very high cardiovascular risk. The main symptom is intermittent claudication, 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 improvement 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 +68.9 (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.
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Review Article
Sulodexide improves pain-free walking
distance in patients with lower extremity
peripheral arterial disease: A systematic
review and meta-analysis
Antonio Vittorino Gaddi
1
, Fabio Capello
2
,
Oana Florentina Gheorghe-Fronea
3
, Simone Fadda
4
and
Roxana Oana Darabont
5
Abstract
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.
Keywords
Peripheral arterial disease, lower extremity arterial disease, drug therapy, intermittent claudication, meta-analysis,
walking distance
Date received: 23 June 2019; revised: 22 December 2019; accepted: 7 January 2020
Introduction
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.
1
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
a
– ranges from 8% in the
general population
2
to approximately 20% in high-risk
populations.
3,4
In the last decade, the total number of
1
EuroGenLab, Bologna, Italy
2
Department of Paediatrics, AUSL della Romagna, Ospedale Morgagni-
Pierantoni, Forlı
`, Italy
3
Discipline of Cardiology, Clinical Emergency Hospital Bucharest,
University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
4
Department of Cardiology, ATS Sardegna, Italy
5
Discipline of Internal Medicine and Cardiology, University Emergency
Hospital Bucharest, University of Medicine and Pharmacy “Carol Davila”,
Bucharest, Romania
Corresponding author:
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.
Email: dr.fronea79@gmail.com
JRSM Cardiovascular Disease
Volume 9: 1–14
!The Author(s) 2020
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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
countries.
1
Most patients with PAD are asymptomatic.
Intermittent claudication (IC) is a lead symptom in
approximately 20% of the people affected.
5
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-
ities muscles.
6,7
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-
mia.
8
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.
3,9,10
Patients with PAD are included in the very high
category of cardiovascular risk.
6,10–13
The evolution
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
arteries.
11–13
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
use
3,10
– sustain the use of antiplatelet therapy (aspi-
rin
14,15
and clopidogrel
16
) or lipid-lowering therapy
(statins
17
) for the reduction of cardiovascular events,
specifically in patients with PAD.
Statins,
18
evolocumab,
19
and rivaroxaban in low doses
addedtoaspirin
20
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.
21
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),
4–6
namely, the
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,
7
is
considered a positive prognostic factor.
Supervised exercise programmes are known to give
the most convincing benefits.
22–28
In fact, lifestyle mod-
ifications, particularly exercise (walking, intensive
walking, and supervised exercise), are effective in
increasing the ICD
18–22
: supervised exercise
programmes can increase the ICD by 81.2–143.8 m,
whereas free exercise shows inferior results.
23,24
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
3,7,9,10
months.
Recently, new approaches have also been tried: sur-
gical treatment, such as percutaneous transluminal
angioplasty (PTA) and revascularization;
8–11
use of
autologous, stem and embryogenic cells for critical
limb ischemia;
12,13
mixed surgical and pharmacological
intervention, such as drug-eluting balloons;
8,14,15
new
resorbable stent;
16
or promising extracorporeal shock-
wave therapy (ESW).
17
Medical treatments used for cardiovascular risk con-
trol, such as statins, might slightly contribute to ICD
improvement.
29
Along with these, data from random-
ized trials and meta-analyses indicate three drug ther-
apies as symptom relievers in patients with IC:
cilostazol,
30–33
naftidrofuryl
33
and pentoxifylline.
34,35
Cilostazol is a phosphodiesterase inhibitor that sup-
presses platelet aggregation and has direct vasodilatory
activity.
36
It has serious side effects and is contraindi-
cated in heart failure of any grade.
37
Naftidrofuryl is a
5-hydroxytryptamine-2-receptor antagonist whose
mechanism of action is still unclear; it might promote
glucose uptake and increase adenosine triphosphate
levels.
38
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
than pentoxifylline.
32
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
cofactor.
39
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.
40,41
These
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
affected patients.
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.
42,43
We published the complete protocol in PROSPERO
44,b
(ID¼CRD42017076473).
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
(all types).
A combination of the following key words (includ-
ing Medical Subject Headings 2017)
c
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;
45
the JADAD score was evaluated by the Oxford QSS.
d
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.
46–49
Furthermore, it relates to the quality of life of patients
affected by IC,
50
and it is strongly linked with its prog-
nosis expressed as the progression of the disease
according to Leriche-Fontaine staging classification.
51
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
IC.
33,34,52
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).
53,54
We used
a random effect model when I
2
was >50%; otherwise,
we used a fixed effect model, as suggested by a recent
Cochrane meta-analysis on ICD in patients with clau-
dication.
33
When useful, we followed the recommenda-
tions of Zwetsloot:
55
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
56,57
and the number of
patients with a clinical improvement were expressed
according to other indexes.
40,58
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.
Results
Study selection for meta-analysis and quality
assessment
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
44
(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
inadequate protocol.
Table 1 shows the demographic characteristics of the
included studies: Bodula,
59
Bonalumi,
60
Borreani,
61
Coccheri,
40
Corsi,
58
Cospite,
62
Della Marchina,
63
Di
Stefano,
64
Liguori,
65
Palmieri,
66
Shustov.
67
Gaddi et al. 3
All the studies included in the table refer to patients
with type II IC according to Leriche-Fontaine; in two
studies,
61,66
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;
61
in
the Della-Marchina study, patients with diabetes were
included,
63
whereas the Palmieri study included
patients with hyperlipoproteinemia only (phenotype
IV or IIb according to Fredrickson).
66
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
62
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-
glycerides;
59
the prevalence of hyperlipoproteinemia is
not stated.
Effect size of ICD differences between and within
groups
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
2
¼0,0%
(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,
p¼0,153, I
2
¼0,0%).
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
I
2
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
60
paper),
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),
65
and a very short administra-
tion period
59
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
2
¼20.2%), both
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.
Patient
enrolled (N)
Patient
analysed (N)
Patient
analysed (%g
Age (mean–
SD/range)
Age (mean-
SD/range) Males (%) Diabetes (%)
Hyperlipoproteinemias
(%)
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
65
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-
parable.
32,68
The Borreani study
61
was excluded
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
61
in the analysis because
of high heterogeneity among data (overall, placebo
and pentoxifenilline as controls, I
2
¼94.2%); moreover,
a funnel plot of precision by raw difference in means
also confirms the presence of publication bias
(Figure 5).
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-
dose sulodexide
60,65
), resulted in þ58.2 15.7 m,
favouring sulodexide (z ¼3.709, p ¼0.001; I
2
72.7%).
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
2
¼82%); how-
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.
Author
JADAD
score Study design
Intention
to treat
Homogeneity
check
Inclusion
criteria
description
Randomization
bias
Allocation
concealment
Performance
bias
Detection
bias
Attrition
bias
Reporting
bias
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
2
¼0%)
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
Miscellanea
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).
Discussion
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
effect size.
The one-study influence and cumulative analyses
reflect the stability of the effect-size results reported
above.
As stated before, we also found a slight rise of ICD in
placebo-treated controls; several studies reported in
other reviews
33,69
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;
27,70
this was particularly evi-
dent when the placebo group went through supervised
and personalized physical activity programmes
26,71
or
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-
lines;
51,72
in one study, a progressive walking pro-
gramme was strongly recommended.
40
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
73
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.
73
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,
68
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
59
and in Shustov
67
study,
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;
33
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.
74
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.
3
In terms of increment of ICD, the naftidrofuryl
(nafronyl) had a better ranking,
32,68
with a percentage
increase of ICD similar to that of sulodexide as per our
meta-analysis.
5
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,
75
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
atherosclerosis.
56,76
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
review.
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
77
– 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.
Conclusions
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
the literature.
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.
Contributorship
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
article.
Ethical approval
None.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
Guarantor
Prof. AV Gaddi.
ORCID iD
Fabio Capello https://orcid.org/0000-0002-1074-6979
Notes
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
disease.
70
b. http://www.crd.york.ac.uk/PROSPERO/display_record.
php?ID=CRD42017076473
c. https://meshb.nlm.nih.gov/search
d. http://www.pmidcalc.org/?sid=8721797&newtest=Y
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).
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14 JRSM Cardiovascular Disease
... Although Sulodexide does not have a direct action on blood circulation, cardiac ejection fraction, blood pressure, or peripheral resistance, in patients with chronic venous disease, Sulodexide improves various parameters of venous hemodynamics (39)(40)(41). Clinical improvement with the use of Sulodexide has been repeatedly demonstrated in occlusive atherosclerosis of the lower limbs in observational, prospective, double-blind, randomized, multicenter, placebo-controlled trials (42)(43)(44)(45)(46)(47)(48). Sulodexide-induced positive hemorrheological changes are likely due to improvement of venous and arterial circulation. ...
Article
Objectives: To review the current knowledge regarding the mechanisms of action and the clinical indications of Sulodexide, a glycosaminoglycan with established efcacy for the prevention of recurrent venous thromboembolism, with reduced bleeding risk. A critical review of the Methods: literature regarding Sulodexide in several data sources between 1975 and 2020. A total of 481 articles were found and analyzed but only 21 articles were considered for this review. Antithrombotic effects of Sulodexide include vas Results: cular endothelial protection, diminished platelet aggregation in response to several stimuli, inhibition of plasma coagulation factors Xa and thrombin, enhancement of brinolysis secondary to reducing PAI-1 and increasing of tPA, and decreased blood viscosity. Compared with other extended treatments, Sulodexide decreases mortality and bleeding episodes. Due to its broad range of pleiotropic effects and mainly a Conclusions: ntithrombotic, Sulodexide has emerged as a therapeutic option for the prevention of recurrent venous thromboembolism in subjects with high risk of bleeding, including elderly patients.
Article
Background: medical correction of the hemostatic system is one of the most important directions for complex treatment of obliterating diseases of lower limbs arteries (ODLLA), including cases of chronic limb-threatening ischaemia (CLTI).Aim: to evaluate the efficacy and safety of the sulodexide use in patients with ODLLA when conducting a comprehensive treatment of CLTI.Patients and Methods: 520 patients underwent two-center prospective study, 318 of whom (211 — with signs of ODLLA, 107 — without signs of CLTI) underwent revascularization interventions, whereas, 202 patients with CLTI received multicomponent complex conservative treatment. In addition to standard treatment, 30 patients who underwent surgery interventions and the group of 50 patients receiving conservative treatment received sulodexide orally in 2 capsules bis in day (1000 LE/day). The severity of the pain syndrome, the distance of pain-free walking, some laboratory indicators of hemostatic system, as well as the presence of adverse events and complications were evaluated before and after treatment. Results: in operated patients with both CLTI and without it, regardless of the sulodexide use, there was a significant decrease in the severity of pain syndrome and an increase in the distance of pain-free walking. Sulodexide use was accompanied by reduced fibrinogen, D-dimer, soluble fibrin monomer complexes (SFMC) and plasminogen activator inhibitor (PAI-1) in the subgroup of patients with CLTI, and indicators of fibrinogen and PAI-1 in the subgroup of patients without CLTI (p<0.05). In non-operated patients with CLTI, sulodexide use was accompanied by a decrease in pain syndrome and indicators of fibrinogen, D-dimer, SFMC, and PAI-1 (p<0.05). However, it was less significant after performed revascularization. There were no adverse events or complications associated with the sulodexide use.Conclusions: improvement of clinical and laboratory parameters was mainly determined by the efficacy of performed limb revascularization. In the complex treatment of patients with ODLLA, the sulodexide use was safe and effective, which was manifested by a decrease in the pain severity, an increase in the distance of pain-free walking and normalization of some coagulogram indicators.KEYWORDS: chronic limb-threatening ischaemia, critical limb ischemia, obliterating diseases of lower limb arteries, complex treatment, sulodexide.FOR CITATION: Katelnitsky I.I., Darvin V.V., Zorkin A.A. Comprehensive treatment of patients with chronic limb-threatening ischaemia: are we using all the possibilities of anticoagulant therapy? Russian Medical Inquiry. 2020;4(7):445–451. DOI: 10.32364/2587-6821-2020-4-7-445-451.
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Background: The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). We investigated the efficacy and safety of evolocumab in patients with peripheral artery disease (PAD) as well as the effect on major adverse limb events. Methods: FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2 years. Patients were identified as having PAD at baseline if they had intermittent claudication and an ankle brachial index of <0.85, or if they had a prior peripheral vascular procedure. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularization. The key secondary end point was a composite of cardiovascular death, myocardial infarction, or stroke. An additional outcome of interest was major adverse limb events defined as acute limb ischemia, major amputation, or urgent peripheral revascularization for ischemia. Results: Three thousand six hundred forty-two patients (13.2%) had PAD (1505 with no prior myocardial infarction or stroke). Evolocumab significantly reduced the primary end point consistently in patients with PAD (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.66-0.94; P=0.0098) and without PAD (HR 0.86; 95% CI, 0.80-0.93; P=0.0003; Pinteraction=0.40). For the key secondary end point, the HRs were 0.73 (0.59-0.91; P=0.0040) for those with PAD and 0.81 (0.73-0.90; P<0.0001) for those without PAD (Pinteraction=0.41). Because of their higher risk, patients with PAD had larger absolute risk reductions for the primary end point (3.5% with PAD, 1.6% without PAD) and the key secondary end point (3.5% with PAD, 1.4% without PAD). Evolocumab reduced the risk of major adverse limb events in all patients (HR, 0.58; 95% CI, 0.38-0.88; P=0.0093) with consistent effects in those with and without known PAD. There was a consistent relationship between lower achieved low-density lipoprotein cholesterol and lower risk of limb events (P=0.026 for the beta coefficient) that extended down to <10 mg/dL. Conclusions: Patients with PAD are at high risk of cardiovascular events, and PCSK9 inhibition with evolocumab significantly reduced that risk with large absolute risk reductions. Moreover, lowering of low-density lipoprotein cholesterol with evolocumab reduced the risk of major adverse limb events. Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633.
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Meta-analyses are increasingly used for synthesis of evidence, and often include an assessment of publication bias based on detection of asymmetry in funnel plots. We studied the influence of different normalisation approaches, sample size and intervention effects on funnel plot asymmetry, using empirical datasets and illustrative simulations. We found that funnel plots of the Standardized Mean Difference (SMD) plotted against the standard error (SE) are susceptible to distortion, leading to overestimation of the existence and extent of publication bias. Distortion was more severe when the primary studies had a small sample size and when an intervention effect was present. We show that using the Normalised Mean Difference (when possible), or plotting the SMD against a sample size-based precision estimate, are more reliable alternatives. We conclude that funnel plots using the SMD in combination with the SE are unsuitable for publication bias assessments and can lead to false-positive results.
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Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events
Article
Background: Intermittent claudication (IC) is a symptom of peripheral arterial disease (PAD) and is associated with high morbidity and mortality. Pentoxifylline, one of many drugs used to treat IC, acts by decreasing blood viscosity, improving erythrocyte flexibility and promoting microcirculatory flow and tissue oxygen concentration. Many studies have evaluated the efficacy of pentoxifylline in treating individuals with PAD, but results of these studies are variable. This is an update of a review first published in 2012. Objectives: To determine the efficacy of pentoxifylline in improving the walking capacity (i.e. pain-free walking distance and total (absolute, maximum) walking distance) of individuals with stable intermittent claudication, Fontaine stage II. Search methods: For this update, the Cochrane Vascular Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2015) and the Cochrane Register of Studies (2015, Issue 3). Selection criteria: All double-blind, randomised controlled trials (RCTs) comparing pentoxifylline versus placebo or any other pharmacological intervention in patients with IC Fontaine stage II. Data collection and analysis: Two review authors separately assessed included studies,. matched data and resolved disagreements by discussion. Review authors assessed the methodological quality of studies by using the Cochrane 'Risk of bias' tool and collected results related to pain-free walking distance (PFWD) and total walking distance (TWD). Comparison of studies was based on duration and dose of pentoxifylline. Main results: We included in this review 24 studies with 3377 participants. Seventeen studies compared pentoxifylline versus placebo. In the seven remaining studies, pentoxifylline was compared with flunarizine (one study), aspirin (one study), Gingko biloba extract (one study), nylidrin hydrochloride (one study), prostaglandin E1 (two studies) and buflomedil and nifedipine (one study). The quality of the evidence was generally low, with large variability in reported findings. Most included studies did not report on random sequence generation and allocation concealment, did not provide adequate information to allow selective reporting to be judged and did not report blinding of assessors. Heterogeneity between included studies was considerable with regards to multiple variables, including duration of treatment, dose of pentoxifylline, baseline walking distance and participant characteristics; therefore, pooled analysis was not possible. Of 17 studies comparing pentoxifylline with placebo, 14 reported TWD and 11 reported PFWD; the difference in percentage improvement in TWD for pentoxifylline over placebo ranged from 1.2% to 155.9%, and in PFWD from -33.8% to 73.9%. Testing the statistical significance of these results generally was not possible because data were insufficient. Most included studies suggested improvement in PFWD and TWD for pentoxifylline over placebo and other treatments, but the statistical and clinical significance of findings from individual trials is unclear. Pentoxifylline generally was well tolerated; the most commonly reported side effects consisted of gastrointestinal symptoms such as nausea. Authors' conclusions: Given the generally poor quality of published studies and the large degree of heterogeneity evident in interventions and in results, the overall benefit of pentoxifylline for patients with Fontaine class II. intermittent claudication remains uncertain. Pentoxifylline was shown to be generally well tolerated. Based on total available evidence, high-quality data are currently insufficient to reveal the benefits of pentoxifylline for intermittent claudication.
Article
This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the effectiveness of screening for PAD in asymptomatic and undiagnosed individuals in terms of reduction of all-cause mortality, cardiovascular events (e.g. myocardial infarction and stroke), morbidity from PAD (intermittent claudication, amputation, reduced walking distance) and improvement in quality of life.
Article
Background: Exercise programmes are a relatively inexpensive, low-risk option compared with other, more invasive therapies for treatment of leg pain on walking (intermittent claudication (IC)). This is the fourth update of a review first published in 1998. Objectives: Our goal was to determine whether an exercise programme was effective in alleviating symptoms and increasing walking treadmill distances and walking times in people with intermittent claudication. Secondary objectives were to determine whether exercise was effective in preventing deterioration of underlying disease, reducing cardiovascular events, and improving quality of life. Search methods: For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (last searched 15 November 2016) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 10) via the Cochrane Register of Studies Online, along with trials registries. Selection criteria: Randomised controlled trials of an exercise regimen versus control or versus medical therapy for people with IC due to peripheral arterial disease (PAD). We included any exercise programme or regimen used for treatment of IC, such as walking, skipping, and running. Inclusion of trials was not affected by duration, frequency, or intensity of the exercise programme. Outcome measures collected included treadmill walking distance (time to onset of pain or pain-free walking distance and maximum walking time or maximum walking distance), ankle brachial index (ABI), quality of life, morbidity, or amputation; if none of these was reported, we did not include the trial in this review. Data collection and analysis: For this update (2017), RAL and AH selected trials and extracted data independently. We assessed study quality by using the Cochrane 'Risk of bias' tool. We analysed continuous data by determining mean differences (MDs) and 95% confidence intervals (CIs), and dichotomous data by determining risk ratios (RRs) and 95% CIs. We pooled data using a fixed-effect model unless we identified significant heterogeneity, in which case we used a random-effects model. We used the GRADE approach to assess the overall quality of evidence supporting the outcomes assessed in this review. Main results: We included two new studies in this update and identified additional publications for previously included studies, bringing the total number of studies meeting the inclusion criteria to 32, and involving a total of 1835 participants with stable leg pain. The follow-up period ranged from two weeks to two years. Types of exercise varied from strength training to polestriding and upper or lower limb exercises; supervised sessions were generally held at least twice a week. Most trials used a treadmill walking test for one of the primary outcome measures. The methodological quality of included trials was moderate, mainly owing to absence of relevant information. Most trials were small and included 20 to 49 participants. Twenty-seven trials compared exercise versus usual care or placebo, and the five remaining trials compared exercise versus medication (pentoxifylline, iloprost, antiplatelet agents, and vitamin E) or pneumatic calf compression; we generally excluded people with various medical conditions or other pre-existing limitations to their exercise capacity.Meta-analysis from nine studies with 391 participants showed overall improvement in pain-free walking distance in the exercise group compared with the no exercise group (MD 82.11 m, 95% CI 71.73 to 92.48, P < 0.00001, high-quality evidence). Data also showed benefit from exercise in improved maximum walking distance (MD 120.36 m, 95% CI 50.79 to 189.92, P < 0.0007, high-quality evidence), as revealed by pooling data from 10 studies with 500 participants. Improvements were seen for up to two years.Exercise did not improve the ABI (MD 0.04, 95% CI 0.00 to 0.08, 13 trials, 570 participants, moderate-quality evidence). Limited data were available for the outcomes of mortality and amputation; trials provided no evidence of an effect of exercise, when compared with placebo or usual care, on mortality (RR 0.92, 95% CI 0.39 to 2.17, 5 trials, 540 participants, moderate-quality evidence) or amputation (RR 0.20, 95% CI 0.01 to 4.15, 1 trial, 177 participants, low-quality evidence).Researchers measured quality of life using Short Form (SF)-36 at three and six months. At three months, the domains 'physical function', 'vitality', and 'role physical' improved with exercise; however this was a limited finding, as it was reported by only two trials. At six months, meta-analysis showed improvement in 'physical summary score' (MD 2.15, 95% CI 1.26 to 3.04, P = 0.02, 5 trials, 429 participants, moderate-quality evidence) and in 'mental summary score' (MD 3.76, 95% CI 2.70 to 4.82, P < 0.01, 4 trials, 343 participants, moderate-quality evidence) secondary to exercise. Two trials reported the remaining domains of the SF-36. Data showed improvements secondary to exercise in 'physical function' and 'general health'. The other domains - 'role physical', 'bodily pain', 'vitality', 'social', 'role emotional', and 'mental health' - did not show improvement at six months.Evidence was generally limited in trials comparing exercise versus antiplatelet therapy, pentoxifylline, iloprost, vitamin E, and pneumatic foot and calf compression owing to small numbers of trials and participants.Review authors used GRADE to assess the evidence presented in this review and determined that quality was moderate to high. Although results showed significant heterogeneity between trials, populations and outcomes were comparable overall, with findings relevant to the claudicant population. Results were pooled for large sample sizes - over 300 participants for most outcomes - using reproducible methods. Authors' conclusions: High-quality evidence shows that exercise programmes provided important benefit compared with placebo or usual care in improving both pain-free and maximum walking distance in people with leg pain from IC who were considered to be fit for exercise intervention. Exercise did not improve ABI, and we found no evidence of an effect of exercise on amputation or mortality. Exercise may improve quality of life when compared with placebo or usual care. As time has progressed, the trials undertaken have begun to include exercise versus exercise or other modalities; therefore we can include fewer of the new trials in this update.
Article
Background: Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications. Methods: This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants. Findings: Between March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0·72, 95% CI 0·57-0·90, p=0·0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0·54 95% CI 0·35-0·82, p=0·0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0·86, 95% CI 0·69-1·08, p=0·19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0·67, 95% CI 0·45-1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17-2·40; p=0·0043). Interpretation: Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding. Funding: Bayer AG.
Article
Objective: The objective of this study was to provide an overview of evidence regarding exercise therapies for patients with lower extremity peripheral artery disease (PAD). Methods: This manuscript summarizes the content of a lecture delivered as part of the 2016 Crawford Critical Issues Symposium. Results: Multiple randomized clinical trials demonstrate that supervised treadmill exercise significantly improves treadmill walking performance in people with PAD and intermittent claudication symptoms. A meta-analysis of 25 randomized trials demonstrated a 180-meter increase in treadmill walking distance in response to supervised exercise interventions compared with a nonexercising control group. Supervised treadmill exercise has been inaccessible to many patients with PAD because of lack of medical insurance coverage. However, in 2017, the Centers for Medicare and Medicaid Services issued a decision memorandum to support health insurance coverage of 12 weeks of supervised treadmill exercise for patients with walking impairment due to PAD. Recent evidence also supports home-based walking exercise to improve walking performance in people with PAD. Effective home-exercise programs incorporate behavioral change interventions such as a remote coach, goal setting, and self-monitoring. Supervised treadmill exercise programs preferentially improve treadmill walking performance, whereas home-based walking exercise programs preferentially improve corridor walking, such as the 6-minute walk test. Clinical trial evidence also supports arm or leg ergometry exercise to improve walking endurance in people with PAD. Treadmill walking exercise appears superior to resistance training alone for improving walking endurance. Conclusions: Supervised treadmill exercise significantly improves treadmill walking performance in people with PAD by approximately 180 meters compared with no exercise. Recent evidence suggests that home-based exercise is also effective and preferentially improves over-ground walking performance, such as the 6-minute walk test.
Article
Objective: The 2013 American College of Cardiology/American Heart Association lipid management guidelines recommend high-intensity statins for all patients ≤75 years old with chronic limb-threatening ischemia (CLTI) and moderate-intensity statins for CLTI patients >75 years old without contraindications or on dialysis, but these recommendations are based primarily on coronary and stroke data. We aimed to validate these guidelines in patients with CLTI and to assess current adherence to these recommendations. Methods: We identified all patients with CLTI who underwent first-time revascularization (endovascular or surgical) at Beth Israel Deaconess Medical Center from 2005 to 2014. Patients were classified as taking high-intensity, moderate-intensity, low-intensity, or no statin postoperatively. Outcomes included death and major adverse limb event (MALE). Propensity scores were calculated for the probability of receiving guideline-recommended intensity of statin therapy to account for nonrandom assignment of treatments. Cox regression models were constructed and adjusted for the propensity scores and further adjusted for strong potential confounders. Results: After excluding patients on hemodialysis (n = 252), we identified 1019 limbs from 931 patients with a median follow-up of 380 days. Patients discharged on the recommended statin intensity had higher rates of preoperative statin use, coronary artery disease, chronic kidney disease, stroke, atrial fibrillation, congestive heart failure, and coronary artery bypass grafting; they had lower smoking rates and were less likely to be ambulatory preoperatively. Overall, only 35% were taking the recommended statin dosage: 55% of those >75 years old and 20% of those ≤75 years old. In multivariable analysis including propensity scores where appropriate, discharge on any statin was associated with lower mortality (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.60-0.90; P < .01). Discharge on the recommended intensity of statin therapy was associated with lower mortality (HR, 0.73; 95% CI, 0.60-0.99; P < .05) and lower MALE rate (HR, 0.71; 95% CI, 0.51-0.97; P < .05). Patients >75 years old and ≤75 years old accrued similar benefit. In patients >75 years old, moderate-intensity statin therapy was associated with lower rates of death and MALE compared with high-intensity therapy but did not reach statistical significance. Conclusions: Use of the recommended intensity of statin therapy in compliance with 2013 American College of Cardiology/American Heart Association lipid management guidelines is associated with significantly improved survival and lower MALE rate in patients undergoing revascularization for CLTI. Adherence to current guidelines is an appealing target for quality improvement.