Cilostazol for peripheral arterial disease (Review)

Robless P, Mikhailidis DP, Stansby GP

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2008, Issue 1
http://www.thecochranelibrary.com

Cilostazol for peripheral arterial disease (Review)

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Analysis 1.1. Comparison 1 Initial claudication distance, Outcome 1 ICD 100 mg cilostazol twice daily versus placebo. 19
Analysis 1.2. Comparison 1 Initial claudication distance, Outcome 2 ICD 50 mg cilostazol versus placebo. . . . . 20
Analysis 1.3. Comparison 1 Initial claudication distance, Outcome 3 ICD 150 mg cilostazol versus placebo. . . . 20
Analysis 1.4. Comparison 1 Initial claudication distance, Outcome 4 ICD cilostazol 100 mg twice daily versus ptx 400 mg
three times daily. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Analysis 2.1. Comparison 2 Absolute claudication distance, Outcome 1 ACD 100 mg cilostazol twice daily versus
placebo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Analysis 2.2. Comparison 2 Absolute claudication distance, Outcome 2 ACD 50 mg cilostazol versus placebo. . . . 22
Analysis 2.3. Comparison 2 Absolute claudication distance, Outcome 3 ACD 150 mg cilostazol versus placebo. . . 23
Analysis 2.4. Comparison 2 Absolute claudication distance, Outcome 4 ACD Cilostazol 100 mg twice daily versus ptx 400
mg three times daily. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Analysis 3.1. Comparison 3 ABPI, Outcome 1 ABPI. . . . . . . . . . . . . . . . . . . . . . . 24
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Cilostazol for peripheral arterial disease (Review) i

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Cilostazol for peripheral arterial disease

Peter Robless1 , Dimitris P Mikhailidis2 , Gerard P Stansby3

1
Department of Cardiac, Thoracic and Vascular Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore,
Singapore. 2 Department of Clinical Biochemistry, Royal Free and University College Medical School, London, UK. 3 Department of
Surgery, University of Newcastle upon Tyne, Newcastle upon Tyne, UK

Contact address: Peter Robless, Department of Cardiac, Thoracic and Vascular Surgery, Yong Loo Lin School of Medicine, National Uni-
versity of Singapore, 5 Lower Kent Ridge Road, Singapore, 119074, Singapore. surrpa@nus.edu.sg. peter_robless@btopenworld.com.

Editorial group: Cochrane Peripheral Vascular Diseases Group.

Publication status and date: Edited (no change to conclusions), published in Issue 3, 2008.
Review content assessed as up-to-date: 6 November 2007.

Citation: Robless P, Mikhailidis DP, Stansby GP. Cilostazol for peripheral arterial disease. Cochrane Database of Systematic Reviews
2008, Issue 1. Art. No.: CD003748. DOI: 10.1002/14651858.CD003748.pub3.

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

Background

Peripheral arterial disease (PAD) affects 4% to 12% of people aged 55 to 70 years and 20% of people over 70 years. The most common
complaint is intermittent claudication (IC) characterised by pain in the legs or buttocks that occurs with exercise and which subsides
with rest. Compared with age-matched controls, people with IC have a three- to six-fold increase in cardiovascular mortality. Symptoms
of IC, walking distance, and quality of life can be improved by risk factor modification, smoking cessation, and a structured exercise
program. Antiplatelet treatment is beneficial in patients with IC for the reduction of vascular events but has not been shown to influence
claudication distance.

Objectives

To determine the effect of cilostazol on improving walking distance and in reducing vascular mortality and cardiovascular events in
patients with stable IC.

Search methods

The Cochrane Peripheral Vascular Diseases Group searched their specialised register (last searched August 2007) and the Cochrane
Central Register of Controlled Trials (CENTRAL) (Issue 3, 2007). We searched MEDLINE (1966 to November 2005), EMBASE
(1980 to November 2005), several more specialised databases, and reference lists of articles.

Selection criteria

Double-blind, randomised controlled trials of cilostazol versus placebo, or versus other antiplatelet agents in patients with stable IC or
patients undergoing vascular surgical intervention for PAD.

Data collection and analysis

Two authors independently assessed trials for selection and all three authors independently extracted data.
Cilostazol for peripheral arterial disease (Review) 1
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results

Seven randomised controlled trials comparing cilostazol with placebo were included.

The weighted mean difference (WMD) for the initial claudication distance (ICD) was improved following treatment with cilostazol
100 mg twice daily (WMD 31.1 m; 95% confidence interval (CI): 21.3 to 40.9 m) and 50 mg twice daily (WMD 41.3 m; 95% CI: -
7.1 to 89.7 m) compared with placebo.

Participants receiving cilostazol 150 mg twice daily had an increased ICD (WMD 15.7 m; 95% CI: -9.6 to 41.0 m) compared with
those receiving placebo.

One study also included a comparison with pentoxifylline. In this study, participants receiving cilostazol had significant improvement
in ICD compared with placebo.

There was no increase in major adverse events including cardiovascular events or mortality in patients receiving cilostazol compared
with placebo.

Authors’ conclusions

Patients with IC should receive secondary prevention for cardiovascular disease. Cilostazol has been shown to be of benefit in improving
walking distance in people with IC. There are no data on whether it results in a reduction of adverse cardiovascular events.

PLAIN LANGUAGE SUMMARY

Cilostazol for peripheral arterial disease

Peripheral arterial disease affects 20% of people over 70 years of age and 4% to 12% of the population aged 55 to 70 years. Approximately
40% of those affected with peripheral arterial disease commonly complain of intermittent claudication. Intermittent claudication is
characterised by pain in the legs or buttocks that occurs with exercise and which subsides with rest. Despite the relatively benign
prognosis for the affected leg, the symptoms of intermittent claudication are an indicator for the development of systemic atherosclerosis.
Compared with age-matched controls, people with intermittent claudication have a three- to six- fold increased chance of dying as a
result of cardiovascular events.

The majority of patients with intermittent claudication are treated with best medical management. Symptoms of intermittent clau-
dication, walking distance, and quality of life can be improved by risk factor modification, which includes stopping smoking and a
structured exercise program. Further cardiovascular risk modification includes treatment for hypertension, diabetes and cholesterol
reduction. Antiplatelet treatment is given to reduce the risk of cerebrovascular and coronary events and is effective in the long-term
secondary prevention of vascular events in people at high risk of vascular disease, including those who have had ischaemic stroke or
acute myocardial infarction. However, antiplatelet therapy has not been shown to influence claudication distance (i.e. the distance
walked before the onset of pain). In practice, compliance with best medical treatment is poor and most people continue to have
symptoms of intermittent claudication. Until recently there have been three options; supervised exercise, angioplasty or bypass surgery.
Compliance with supervised exercise is poor; the long-lasting effect of angioplasty is unproven and surgery carries significant morbidity
and mortality. Many pharmacological agents have been advocated for treating intermittent claudication but until recently none have
gained acceptance. Cilostazol has recently been approved for the treatment of intermittent claudication. Cilostazol has been shown to
be of benefit in improving pain-free walking distance in people with intermittent claudication. There are no data on whether it results
in a reduction of cardiovascular events.

BACKGROUND 55 to 70 years. It is the manifestation of atherosclerosis in the

Peripheral arterial disease (PAD) affects 20% of people over 70 lower extremities (Dormandy 1999; PAD 2003). Patients with
years of age and 4% to 12% of the middle-aged population aged PAD commonly complain of intermittent claudication (IC), oc-

Cilostazol for peripheral arterial disease (Review) 2

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
curring in 40% of patients (Dormandy 1999). Intermittent clau-
dication is characterised by pain in the legs or buttocks that occurs
with exercise and subsides with rest. Despite the relatively benign
prognosis for the affected limb, the symptoms of IC are an indica-
tor for systemic atherosclerosis. Compared with age-matched con-
trols, people with IC have a three- to six-fold increase in cardio-
vascular mortality (Leng 1996). The majority of patients with IC
are treated with best medical management (Khan 2005). Smoking
cessation must be encouraged and a prescribed exercise program is
beneficial (Leng 2000). Further cardiovascular risk modification
includes treatment for hypertension, diabetes and cholesterol re-
duction. Antiplatelet treatment is given to reduce the risk of cere-
brovascular and coronary events. Antiplatelet therapy is effective
in long term secondary prevention of vascular events in patients
at high risk of vascular disease, including those who have had is-
chaemic stroke or acute myocardial infarction. There is a benefit
of antiplatelet treatment in patients with IC in the reduction of
vascular events (ATT 2002; PAD 2003; Robless 2001).
In practice, compliance with best medical treatment is poor and
most people remain symptomatic with IC. Until recently there
have been three options; supervised exercise, angioplasty or by-
pass surgery. Compliance with supervised exercise is poor. The
durability of angioplasty is unproven and surgery carries signifi-
cant morbidity and mortality (Fowkes 1998). Many pharmaco-
logical agents have been advocated for the symptomatic treatment
of IC but until recently none have gained acceptance. Cilostazol
(PLETAL), a phosphodiesterase III inhibitor, has been recently
approved for the treatment of IC and has been shown to improve
pain-free walking distance (PFWD) (Barnett 2004). While it is
not clear exactly how cilostazol reduces the symptoms of IC, its
two main physiologic effects are vasodilation and inhibition of
platelet aggregation (Chapman 2003).
OBJECTIVES
To determine the effect of cilostazol on improving initial and ab-
solute claudication distances and in reducing vascular events (my-
ocardial infarction and stroke) in patients with stable intermittent
claudication (Fontaine stage II) (Fontaine 1954) or undergoing
vascular surgical intervention (surgery or percutaneous translumi-
nal angioplasty (PTA)) for PAD.
METHODS
Criteria for considering studies for this review
Cilostazol for peripheral arterial disease (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Types of studies
Double-blind,randomised controlled trials of cilostazol versus
placebo, or versus other antiplatelet agents in patients with stable
IC (Fontaine stage II), or undergoing vascular surgical interven-
tion (surgery or PTA) for PAD.
Types of participants
Patients with stable IC (Fontaine stage II) for more than six months
or undergoing vascular surgical intervention (surgery or PTA) for
PAD.
Types of interventions
Cilostazol versus placebo, or versus an alternative drug therapy.
The antiplatelet or placebo intervention must have been given for
at least four weeks. We recorded the type of therapy, dosage, time
of starting and duration of therapy. Comparisons with exercise,
anticoagulants or surgery were not included.
Types of outcome measures
Primary
Initial claudication distance (the distance walked on a treadmill
before the onset of calf pain).
Secondary
The absolute claudication distance (the maximum distance walked
on a treadmill) among patients with moderate intermittent claudi-
cation. Mortality, cardiovascular events (i.e. myocardial infarction
and stroke), ankle brachial pressure index (ABPI), progression to
surgery, quality of life, and side effects were included.
Search methods for identification of studies
The Cochrane Peripheral Vascular Diseases (PVD) Group
searched their trials register (last searched August 2007) and the
Cochrane Central Register of Controlled Trials (CENTRAL), (last
searched The Cochrane Library Issue 3, 2007). Briefly, the trials
register of the PVD Group has been constructed from regular elec-
tronic searches of MEDLINE (1966 to date) and EMBASE (1980
to date), and CINAHL (1982 to date), as well as from handsearch-
ing journals. The full list of journals that have been handsearched,
and the search strategies for the electronic databases, are described
in the editorial information about the Cochrane PVD Group in
the ’Search strategies for the identification of studies’ section in
The Cochrane Library (http://www.mrw.interscience.wiley.com/
cochrane/clabout/articles/PVD/frame.html). For details of the
3
search strategy used to search CENTRAL for this review, see
Appendix 1.
In addition, we also searched the following sources:
1. MEDLINE: January 1966 to November 2005 including
established searches using a Cochrane Randomised Controlled
Trials filter for identification of randomised controlled trials
combined with terms that will include intermittent claudication.
2. EMBASE: 1980 to November 2005.
3. All reference lists of identified studies.
4. The register of trials held by the Antiplatelet Trialists’
Collaboration.
5. Proceedings from the following vascular surgical society
meetings: Vascular Surgical Society of Great Britain and Ireland,
European Vascular Surgical Society, North American Society of
Vascular Surgery.
6. The pharmaceutical companies that market cilostazol for
details of any trials, particularly unpublished ones (Otsuka
Pharmaceutical Europe Ltd and Otsuka Pharmaceutical Co Ltd,
Japan). For this update we again contacted Otsuka
Pharmaceutical Co Ltd, Japan for further information (October
2007).
We searched MEDLINE on DIALOG (November 2005, period
1966 to date) and EMBASE on DIALOG (November 2005, pe-
riod 1980 to date). For details of the search strategy we used see
Appendix 2.
Data collection and analysis
Study selection
PR and GS independently selected the studies.
Methodological quality
Two authors (PR, GS) independently assessed the methodologi-
cal rigour and clinical significance of each trial using the checklist
provided by the PVD Group, with emphasis on concealment of
allocation and gave an allocation score of A (clearly concealed), B
(unclear if concealed), C (not concealed) or D (not used). Any dis-
crepancies between the authors in the above scores were discussed
and consensus reached. Each trial was allocated a summary score
of A (low risk of bias), B (moderate risk), or C (high risk). Trials
scoring A or B were included and those scoring C were excluded.
In the absence of consensus over the inclusion of a trial, we sought
the opinion of the third author (DM).
We sought information regarding quality of randomisation, al-
location concealment, description of dropouts and withdrawals,
intention-to-treat analysis, and blinding procedures at treatment
and outcome assessment. We excluded studies if they were not
randomised, were quasi-randomised controlled trials, or if they
Cilostazol for peripheral arterial disease (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
made comparisons other than those pre-specified by the authors
and included patients with either acute or critical ischaemia.
Data extraction
All three authors independently extracted the data. From each in-
cluded trial we collected information regarding the trial design,
patient characteristics, dosages and treatment periods. Informa-
tion for initial claudication distance (ICD) and absolute walking
distance (ACD) and for any other available outcomes was also col-
lected. Additional information on side effects from each trial was
documented. Where necessary, we contacted the principal authors
of the included studies for information.
Statistical analyses
Data on the initial and absolute claudication distances and any
other available outcomes from each trial were pooled to obtain an
overall estimate of the effectiveness of cilostazol therapy. The data
are presented both as a weighted mean difference (WMD) and an
effect size.
All of the analyses were based on the intention-to-treat data from
the individual clinical trials. We evaluated trial heterogeneity using
chi-square testing. If there was no evidence of statistical hetero-
geneity then we used a fixed-effect model. If we detected statistical
heterogeneity then we used a random-effects model.
We performed statistical analyses according to the statistical guide-
lines for reviews outlined in the Cochrane PVD Group’s mod-
ule (http://www.mrw.interscience.wiley.com/cochrane/clabout/
articles/PVD/frame.html). Odds ratios were used as the measure
of effect for each dichotomous outcome. Where sufficient data
were available, we calculated a summary statistic for each outcome
using a fixed-effect model. Heterogeneity was noted in the data
and cautiously explored using previously identified characteristics
of the studies, particularly assessments of quality. We undertook
sensitivity analyses to examine the stability of the results in relation
to a number of factors including study quality, the source of the
data, and patient type. Where continuous scales of measurement
were used to assess the effects of treatment, we analysed the data
using continuous form (i.e. WMD).
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
Summary details of included studies are given in the ’Character-
istics of included studies’ table.
4
Seven randomised controlled trials fulfilled the inclusion criteria
for consideration in the present review. Six were published in peer
reviewed journals (Beebe 1999; Dawson 1998; Dawson 2000;
Elam 1998; Money 1998; Strandness 2002), and one study was
an in-house unpublished studies (Otsuka 21-95-201). All seven
studies included a comparison between 100 mg cilostazol versus
placebo. Two studies included a separate comparison with 50 mg
cilostazol twice daily (Beebe 1999; Strandness 2002). One study
compared 150 mg cilostazol twice daily (Otsuka 21-95-201). Only
one study compared cilostazol with 400 mg of pentoxifylline (
Dawson 2000).
These studies involved over 1500 patients with stable IC treated
over a period of 12 to 24 weeks. Men and women were included
in all studies and were > 40 years in age with stable claudication of
at least six months duration without significant progression over
the previous three months.
All patients had peripheral arterial disease confirmed by a resting
ankle brachial pressure index (ABPI) of < 0.9 (seven trials) or
< 0.8 (one trial). Additional confirmation was obtained by a >
10 mm Hg drop in post-exercise systolic ankle pressure. Patients
lacking ABPI criteria but with a > 20 mm Hg drop in post-exercise
systolic ankle pressure were also considered eligible. Patients were
required to demonstrate stable reproducible exercise ability and
were enrolled if their pre-randomisation ABPI varied by less than
20%.
The primary endpoint in most of these studies was the absolute
claudication distance (ACD; also known as the maximum walk-
ing distance). Secondary endpoints included the initial claudica-
tion distance (ICD) defined as the distance walked until the ini-
tial onset of pain, the ankle brachial pressure index (ABPI) and
patient-perceived changes in quality of life (QoL) or functional
status. Treadmill tests were used to evaluate ACD and ICD. The
treadmill protocols used involved either constant (four studies) or
progressive loads (three studies). Progressive workloads involved
patients walking 2.0 mph (3.2 km/h) at a 0 degree gradient with
3.5 deg increase every three minutes. Constant workload testing
involved patients walking at 2.0 mph (3.2 km/h) at a constant
12.5 degree gradient. In one trial a 100 gradient was used. The
ABPI was estimated from ratio of ankle and brachial systolic blood
pressure measured with Doppler ultrasound.
Several QoL assessment tools including the Walking Impairment
Questionnaire (WIQ), Claudication Outcome Measure (COM)
and Medical Outcomes Scale Short Form 36 (SF36) were used
to measure patients’ responses to therapy. In a number of trials
subjective assessments of functional status were made.
Outcome measures were evaluated at baseline then from week two
at four-weekly intervals to study end. Intention-to-treat (ITT)
analysis were performed on all patients randomised to treatment
who underwent baseline testing using the last observation carried
forward. In this review the WMD in walking distance from base-
line was used to compare results from the trials.
Patient demographics were similar in all trials and between treat-
Cilostazol for peripheral arterial disease (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ment groups. Men and women aged 40 years and above were in-
cluded in all trials. All patients had moderate to severe stable inter-
mittent claudication of at least six months duration due to PAD.
Stable IC was defined as reproducible ACD with a variance of less
than 20% in the screening treadmill tests. Patients with ischaemic
rest pain, deep venous thrombosis, hypertension, morbid obesity,
malignancy, symptomatic ischaemic heart disease, bleeding dis-
orders and pregnancy were excluded from the studies. Patients
on antiplatelet agents, anticoagulants or anti-inflammatory agents
were also excluded. (See Table of Included Studies.)
Excluded studies
Two unpublished randomised studies were not included due
the data not being available at the time of publication (Otsuka
21-94-301; Otsuka 21-98-214-01). One study comparing cilosta-
zol with pentoxifylline (Rodin 1998 ) has been described in the
FDA report on cilostazol and mentioned (without reference) in
another review (Rodin 1998; Thompson 2002). Another multi-
centre study involving over 1400 patients randomised to cilostazol
or placebo to asses the morbidity and mortality was not included
due the data not being available at the time of publication (Otsuka
21-98-214-01). To date we have been unable to obtain further
data on these unpublished studies from Otsuk a and have therefore
been unable to assess its quality, and include it in this review.
A third study was a non-randomised study and was therefore ex-
cluded (Samra 2003). (See Table of Excluded studies.)
Risk of bias in included studies
Three of the seven studies were classified as category A (Beebe
1999; Dawson 1998; Dawson 2000). In the remaining four trials
the methods of randomisation was not stated and were classified
as category B (Elam 1998; Money 1998; Otsuka 21-95-201;
Strandness 2002). All included trials were double blinded.
Effects of interventions
Cilostazol 100 mg twice daily versus placebo
Seven randomised controlled trials compared 100 mg twice daily
cilostazol versus placebo in this review involving over 1500 patients
(Beebe 1999; Dawson 1998; Dawson 2000; Elam 1998; Money
1998; Otsuka 21-95-201; Strandness 2002). Data on ICD were
available in only six trials (Beebe 1999; Dawson 1998; Dawson
2000; Money 1998; Otsuka 21-95-201; Strandness 2002). Chi-
squared testing for heterogeneity was not significant therefore a
fixed-effect model was used for ICD. The WMD for the ICD
was in favour of treatment with cilostazol (WMD 31.1 m; 95%
confidence interval (CI) 21.3 to 40.9 m) compared with placebo.
(Comparison 1-01)
5
Data on ACD were available from the seven included trials (Beebe
1999; Dawson 1998; Dawson 2000; Elam 1998; Money 1998;
Otsuka 21-95-201; Strandness 2002). Chi-squared testing for het-
erogeneity was significant therefore a random-effects model was
used. The WMD for the ACD was in favour of treatment of
cilostazol (WMD 49.7 m; 95% CI 24.2 to 75.2 m) compared
with placebo (Comparison 2-01)
Cilostazol 50 mg twice daily versus placebo
Two trials in this review involving 475 patients compared 50
mg twice daily cilostazol versus placebo (Beebe 1999; Strandness
2002). Data on ICD were available in only two trials involving
475 patients (Beebe 1999; Strandness 2002). Chi-squared testing
for heterogeneity was significant therefore a random-effects model
was used. The WMD for the ICD was in favour of treatment with
cilostazol (WMD 41.3 m; 95% CI: -7.1 to 89.7 m) compared with
placebo. However this difference was not statistically significant.
(Comparison 1-02)
The results for ACD, chi-squared testing for heterogeneity was
not significant and therefore a fixed-effect model was used. The
WMD for the ACD was in favour of treatment with cilostazol
(WMD 31.9 m; 95% CI: 12.4 to 51.5 m) compared with placebo.
(Comparison 2-02)
Cilostazol 150 mg twice daily versus placebo
One trial compared 150 mg cilostazol twice daily versus placebo
in 104 patients (Otsuka 21-95-201). At the end of the 12 week
study, patients receiving cilostazol 150 mg twice daily had a mean
change in absolute claudication distance from baseline of 89.9 m
compared with 38 m in patients receiving placebo (WMD 51.8
m; 95% CI: -13.9 to 117.5 m). Patients receiving cilostazol 150
mg twice daily had a mean change in ICD from baseline of 50.1 m
compared with 34.4 m in patients receiving placebo (WMD 15.7
m; 95%CI: -9.6 to 41.0 m). This difference was not statistically
significant. (Comparisons 2-03 and 1-03 respectively)
Cilostazol 100 mg twice daily versus pentoxifylline 400 mg
three times daily
One trial compared cilostazol 100 mg twice daily versus pentox-
ifylline 400 mg three times daily and placebo in 698 patients
(Dawson 2000). Patients receiving cilostazol 100 mg twice daily
had a mean improvement in ICD of 94 m from baseline compared
to 73.6 m in patients receiving pentoxifylline 400 mg three times
daily (WMD 20.0 m; 95% CI: -1.5 to 41.5). Patients receiving
cilostazol 100 mg twice daily had a mean improvement in ACD
from baseline of 107 m compared to 64.4 m in patients receiving
pentoxifylline 400 mg three times daily (WMD 42.9 m; 95% CI:
15.3 to 70.5 m). These differences in ICD and ACD showed sig-
nificant improvement for the cilostazol group over patients taking
pentoxifylline. (Comparisons 1-04 and 2-04)
Ankle brachial pressure index (ABPI)
Only three trials reported mean ABPI before and after treatment
Cilostazol for peripheral arterial disease (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
with cilostazol (Dawson 2000; Elam 1998; Money 1998). All
three compared 100 mg cilostazol twice daily with placebo. In one
trial there was a third arm where patients received pentoxifylline
(Dawson 2000). Chi-squared testing for heterogeneity was signif-
icant therefore a random-effects model was used. The WMD for
the mean change in ABPI was in favour of treatment with cilosta-
zol (WMD 0.06; 95% CI: 0.03 to 0.09) compared with placebo.
(Comparison 3)
Functional status/Quality of Life
Patients receiving cilostazol (50 mg and 100 mg twice daily) in
three trials reported improvements in the physical health compo-
nents of the SF-36 questionnaires compared with patients receiv-
ing placebo (Beebe 1999; Money 1998; Strandness 2002). These
included significant improvements in the physical health sub scales
of physical function (P = 0.002) and bodily pain (P < 0.05). There
were no significant differences in mental health components of
the SF-36 quality of life questionnaires between cilostazol and
placebo.
One trial reported significant changes in the Claudication Out-
come Measure (COM) for walking pain/discomfort, change in
pain/discomfort and pain/discomfort during physical activity (P
< 0.01) (Beebe 1999). Regarding the Walking Impairment Ques-
tionnaire (WIQ), there were two trials that reported significant
improvement in patients perception of walking speed (P < 0.05)
with cilostazol (Beebe 1999; Money 1998). However, only one
trial reported improvement in walking distance with cilostazol
(Beebe 1999).
Three trials reported subjective assessments of response to treat-
ment. Significantly more patients receiving cilostazol reported im-
proved outcomes (better or much better) compared with base-
line (50% to 55% versus 19% to 39%; P < 0.05) (Beebe 1999;
Strandness 2002; Money 1998).
Side effects
The side effect profile of cilostazol included symptoms of
headache, diarrhoea, pain, infection, rhinitis, pharyngitis, periph-
eral oedema and nausea in 5% or more of patients receiving cilosta-
zol. Headaches, diarrhoea and peripheral oedema were reported
more frequently in patients receiving cilostazol (100 and 50 mg
twice daily) compared with placebo (P < 0.05). Patients receiving
50 mg cilostazol twice daily reported symptoms of rhinitis and
infection more frequently than patients on placebo (P < 0.05)
(Chapman 2003). A separate review by Pratt summarizes the safety
data from the eight included studies (Pratt 2001). There were a to-
tal of 475 patient-exposure years on cilostazol, 357 patient-expo-
sure years on placebo, and 135 patient-exposure years on pentoxi-
fylline. Headache, diarrhoea, and other gastrointestinal complaints
were seen more often in cilostazol-treated than placebo-treated
patients; pharyngitis and nausea were more common in pentoxi-
fylline-treated than placebo-treated patients. Headache requiring
discontinuation occurred in 1.3% of patients taking cilostazol 50
6
mg twice daily and 3.7% of those receiving cilostazol 100 mg twice
daily, compared with 0.3% of placebo-treated patients. Discon-
tinuations due to diarrhoea, palpitations, or myocardial infarction
were similar in cilostazol-, placebo-, and pentoxifylline-treated pa-
tients. The incidence of cardiovascular events was similar in all
three treatment groups. Myocardial infarction occurred in 1.0%
of cilostazol-treated, 0.8% of placebo-treated, and 1.1% of pen-
toxifylline-treated patients. Similarly the incidence of stroke was
0.5% in both cilostazol- and placebo-treated patients and 1.1%
in pentoxifylline-treated patients.
Cardiovascular morbidity and mortality
Total cardiovascular morbidity and all-cause mortality was 6.5%
for cilostazol 100 mg twice daily, 6.3% for cilostazol 50 mg twice
daily, and 7.7% for placebo (Pratt 2001). There were 16 deaths
occurring in 0.6%, 0.5%, and 0.6% of cilostazol-, placebo-, and
pentoxifylline-treated patients, respectively.
DISCUSSION
The results of this meta-analysis of seven randomised double
blind controlled studies demonstrate that cilostazol significantly
improves the ICD and ACD in patients with stable, moderate
to severe intermittent claudication (Beebe 1999; Dawson 1998;
Dawson 2000; Elam 1998; Money 1998; Otsuka 21-95-201;
Strandness 2002). The trials were well designed and conformed to
the accepted standards for trials of IC. All trials included patients
receiving 100 mg cilostazol twice daily or placebo. In the meta-
analysis involving over 1500 patients, there were significant im-
provements in ACD and ICD in patients receiving 100 mg cilosta-
zol twice daily compared with placebo. Two trials also compared
50 mg cilostazol with placebo (Beebe 1999; Strandness 2002). In-
terestingly, there was a consistent increase in WMD in both groups
receiving cilostazol for ACD and ICD compared with placebo.
One trial involved patients receiving 150 mg cilostazol twice daily
compared with placebo showed a significant improvement in ACD
and ICD (Otsuka 21-95-201). However, the wide confidence in-
tervals and the small numbers make it difficult to prove any real
benefit using high dose cilostazol. Only one trial compared pen-
toxifylline with placebo and cilostazol (Dawson 2000). In this trial
there was no significant improvement in walking distance between
patients receiving pentoxifylline and placebo.
Three studies used a graded treadmill protocol and a constant work
load protocol. These protocols have different test characteristics
in that patients tend to walk longer on the graded relative to the
constant load protocol. Therefore an absolute change in distance
with treatment on one protocol does not directly translate into a
similar change in distance on the other protocol. In this review the
treadmill results are presented together to demonstrate an overall
effect. Regensteiner et al have done a subgroup analysis looking at
the results for graded and constant load (Regensteiner 2002). They
Cilostazol for peripheral arterial disease (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
found a significant improvement in walking distance in patients
receiving 100 mg cilostazol twice daily in both the constant load
and graded treadmill protocol groups.
The benefits in improved walking distances were observed within
a few weeks of starting the treatment and continued for the du-
ration of these short studies (12 to 24 weeks). There was a small
improvement in ABPI reported in three trials comparing cilosta-
zol with placebo (Dawson 2000; Elam 1998; Money 1998). Sim-
ilarly, there was an improvement in the physical function but
not the mental health status as assessed by quality of life ques-
tionnaires (Beebe 1999; Money 1998; Strandness 2002 ). Regen-
steiner et al (Regensteiner 2002) performed a meta-analysis of
treadmill walking, community-based walking ability, and health-
related quality of life in patients with IC due to peripheral arterial
disease in six of the included studies (Beebe 1999; Dawson 2000;
Elam 1998; Otsuka 21-95-201; Money 1998; Strandness 2002).
Walking Impairment Questionnaire (WIQ) and SF-36 physical
summary scores improved significantly more with cilostazol than
with placebo (for instance, WIQ distance score, P <.0001 and SF-
36 physical summary score, P <.0001, comparing persons taking
cilostazol with controls) (Regensteiner 2002). Improved MWD
correlated with improvements in WIQ (correlation with distance
score, r = 0.34, P <.0001) and SF-36 physical summary scores (r
= 0.29, P <.0001). They concluded that treatment with cilostazol
was associated with improvements in community-based walking
ability and health-related quality of life in patients with IC than
treatment with placebo. These improvements also correlated with
increased MWD.
The side effect profile of cilostazol appears to offer an acceptable
risk-benefit ratio in patients with IC (Chapman 2003; Pratt 2001).
A separate analysis of the cilostazol safety database by Pratt showed
no trend toward increased cardiovascular morbidity or mortality
risk in patients receiving cilostazol (Pratt 2001). However the Scot-
tish Medicines Consortiums assessment of the efficacy and safety
profile of cilostazol in patients with IC have not recommended its
use in the management of Scottish patients with IC. They con-
cluded that although the ICD and ACD were improved in clinical
trials with limited effects on quality of life, physical function and
pain, the efficacy and safety profile of cilostazol in Scottish patients
with IC who are treated concomitantly with an antiplatelet drug
was unclear( SMC 2005).
Approximately 4% to 12% of the middle-aged population suf-
fer with IC. The mainstay of treatment for patients with PAD is
cardiovascular risk factor modification. This consists of smoking
cessation, prescribed exercise, antiplatelet treatment, lipid-lower-
ing therapy and control of blood pressure and diabetes. Only two
thirds of compliant patients will achieve symptomatic relief from
the symptoms of IC after three to six months. Some patients may
not be able to comply with prescribed exercise due to associated
co-morbidity or social reasons. As angioplasty or surgery are only
used in severe disabling or progressive IC these symptomatic pa-
7
tients may benefit from adjunctive therapy. Cilostazol has been
shown in this and several other reviews to be of benefit in the symp-
tomatic relief of IC (Barnett 2004; Chapman 2003; Thompson
2002). Other drugs that are used to improve the symptoms of IC
are pentoxifylline, naftidrofuryl and buflomedil. Pentoxifylline is
a non-selective phosphodiesterase inhibitor that improves blood
flow by increasing erythrocyte deformability, decreasing blood vis-
cosity and inhibiting platelet aggregation. Two meta-analyses of
trials involving pentoxifylline showed a small increase in walking
distance (Pratt 2001; Regensteiner 2002). This was thought to
be due to the small number of patients in the trials involved. In
this review there was no significant difference in walking distance
between patients receiving pentoxifylline or placebo. In one large
trial, patients receiving cilostazol showed a significant improve-
ment in absolute and initial claudication distances compared with
pentoxifylline or placebo. This difference was seen as early as four
weeks after commencing treatment. The withdrawal of cilostazol
treatment at 24 weeks also resulted in a deterioration of walking
distances.
Naftidrofuryl is a serotonin antagonist with vasoactive properties.
A review of randomised controlled trials showed a significant in-
crease in initial claudication distances at three and six months com-
pared with placebo (Barradell 1996). Improvements in quality of
life were also seen with naftidrofuryl in patients with IC after six
months. Buflomedil is a weak calcium antagonist and vasodila-
tor. Several small placebo-controlled studies demonstrated small
increases in walking distances (Dawson 2001).
Cilostazol was well tolerated with an acceptable side effect profile.
The most common side effects reported were headaches, nausea,
diarrhoea, pain, infection, upper respiratory symptoms and pe-
ripheral oedema. These symptoms were mild to moderate in in-
tensity and resolved with symptomatic treatment without requir-
ing cessation of therapy. However, cilostazol is contraindicated
REFERENCES
References to studies included in this review
Beebe 1999 {published data only}
Beebe HG, Dawson DL, Cutler BS, Herd JA, Strandness
DE Jr Bortey EB, et al.A new pharmacological treatment
for intermittent claudication: results of a randomized,
multicenter trial. Archives of Internal Medicine 1999;159
(17):2041–50.
Dawson 1998 {published data only}
Dawson DL, Cutler BS, Meissner MH, Strandness DE Jr.
Cilostazol has beneficial effects in treatment of intermittent
claudication : results from a multicenter, randomized,
prospective, double-blind trial. Circulation 1998;98(7):
678–86.
Cilostazol for peripheral arterial disease (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
in patients with congestive cardiac failure due to its mechanism
of action as a PD III inhibitor. Cilostazol is also contraindicated
in patients with moderate to severe renal or hepatic impairment
(Chapman 2003).
In summary, it is well established that patients with IC should re-
ceive secondary prevention for cardiovascular disease. The results
of eight randomised controlled trials show that cilostazol improves
initial and absolute claudication distances as well as some improve-
ment in quality of life in patients who remain symptomatic despite
these measures.
AUTHORS’ CONCLUSIONS
Implications for practice
Cilostazol (50 to 100 mg twice daily) has been shown to improve
walking distance compared with placebo. It is probably the drug of
choice for a subset of claudicants where conservative or interven-
tional treatments have failed to alleviate sufficiently their symp-
toms There are no data on whether treatment with cilostazol re-
sults in a reduction of adverse cardiovascular events.
Implications for research
Further studies in relation to the impact of cilostazol on Quality
of Life, health economics and prevention of adverse cardiovascular
events are required.
ACKNOWLEDGEMENTS
We would like to thank Professor Gordon Lowe for providing ex-
ternal peer referee comments. We would also like to thank Otsuka
Pharmaceuticals for providing unpublished trial data.
Dawson 2000 {published data only}
Dawson DL, Cutler BS, Hiatt WR, Hobson RW 2nd,
Martin JD, Bortey EB, et al.A comparison of cilostazol
and pentoxifylline for treating intermittent claudication.
American Journal of Medicine 2000;109(7):523–30.
Elam 1998 {published data only}
Elam MB, Heckman J, Crouse JR, Hunninghake DB,
Herd JA, Davidson M, et al.Effect of the novel antiplatelet
agent cilostazol on plasma lipoproteins in patients with
intermittent claudication. Arteriosclerosis, Thrombosis &
Vascular Biology 1998;18(12):1942–7.
Money 1998 {published data only}
Money SR, Herd JA, Isaacsohn JL, Davidson M, Cutler B,
8
 Heckman J, et al.Effect of cilostazol on walking distances in
patients with intermittent claudication caused by peripheral
vascular disease. Journal of Vascular Surgery 1998;27(2):
267–74.
Otsuka 21-95-201 {unpublished data only}
Otsuka 21-95-201. A randomised double-blind study of
the safety and efficacy of two different doses of cilostazol
versus placebo in patients with intermittent claudication
secondary to peripheral vascular disease. Internal report.
Otsuka Pharmaceuticals 1996.
Strandness 2002 {published data only}
Otsuka 21-94-201. A randomised double blind study of
the effect of cilostazol versus placebo on walking distances
in patients with intermittent claudication secondary to
peripheral vascular disease. Internal report. Otsuka
Pharmaceuticals 1996.
∗
Strandness DE Jr, Dalman RL, Panian S, Rendell MS,
Comp PC, Zhang P, et al.Effect of cilostazol in patients with
intermittent claudication: a randomized, double-blind,
placebo-controlled study. Vascular & Endovascular Surgery
2002;36(2):83–91.
References to studies excluded from this review
Otsuka 21-94-301 {published data only (unpublished sought but not
used)}
Otsuka 21-94-301. Pletal (Cilostazol) Tablets. Medical
Review of NDA. Internal report. Otsuka Pharmaceuticals
1998.
Otsuka 21-98-214-01 {published data only (unpublished sought but
not used)}
Otsuka 21-98-214-01. CASTLE . A randomized, double-
blind, placebo-controlled, multicenter, parallel-arm, study
to assess the long-term effects of Pletal® (Cilostazol) versus
placebo administered orally to patients with intermittent
claudication secondary to peripheral arterial disease.
Internal report. Otsuka Pharmaceuticals 1998.
Samra 2003 {published data only}
Samra SS, Bajaj P, Vijayaraghavan KS, Potdar NP, Vyas D,
Devani RG, et al.Efficacy and safety of cilostazol, a novel
phosphodiesterase inhibitor in patients with intermittent
claudication. Journal of the Indian Medical Association 2003;
101(9):561–4.
Additional references
ATT 2002
Antithrombotic Trialists’ Collaboration. Collaborative
meta-analysis of randomised trials of antiplatelet therapy for
prevention of death, myocardial infarction, and stroke in
high risk patients. BMJ 2002;324(7329):71–86.
Barnett 2004
Barnett AH, Bradbury AW, Brittenden J, Crichton B,
Donnelly R, Homer-Vanniasinkam S, et al.The role of
cilostazol in the treatment of intermittent claudication.
Current Medical Research & Opinion 2004;20(10):1661–70.
Cilostazol for peripheral arterial disease (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Barradell 1996
Barradell LB, Brogden RN. Oral naftidrofuryl. A review of
its pharmacology and its therapeutic use in the management
of peripheral occlusive arterial disease. Drugs and Aging
1996;8(4):299–322.
Chapman 2003
Chapman TM, Goa KL. Cilostazol: a review of its
use in intermittent claudication. American Journal of
Cardiovascular Drugs 2003;3(2):117–38.
Dawson 2001
Dawson DL. Comparative effects of cilostazol and other
therapies for intermittent claudication. American Journal of
Cardiology 2001;87(12A):19D–27D.
Dormandy 1999
Dormandy J, Heeck L, Vig S. The natural history of
claudication: risk to life and limb. Seminars in Vascular
Surgery 1999;12(2):123–37.
Fontaine 1954
Fontaine VR, Kim M, Kieny R. Surgical treatment for
peripheral vascular disease [Die chirurgische Behandlung
der peripheren Durchblutungsstorungen]. Helvetica
Chirurgica Acta 1954;5/6:499–533.
Fowkes 1998
Fowkes FG, Gillespie IN. Angioplasty (versus non surgical
management) for intermittent claudication. Cochrane
Database of Systematic Reviews 1998, Issue 2. [Art. No.:
CD000017. DOI: 10.1002/14651858.CD000017]
Khan 2005
Khan S, Cleanthis M, Smout J, Flather M, Stansby G. Life-
style modification in peripheral arterial disease. European
Journal of Vascular & Endovascular Surgery 2005;29(1):2–9.
Leng 1996
Leng GC, Lee AJ, Fowkes FG, Whiteman M, Dunbar
J, Housley E, et al.Incidence, natural history and
cardiovascular events in symptomatic and asymptomatic
peripheral artery disease in the general population.
International Journal of Epidemiology 1996;25(6):1172–81.
Leng 2000
Leng GC, Fowler B, Ernest E. Exercise for intermittent
claudication. Cochrane Database of Systematic Reviews
2000, Issue 2. [Art. No.: CD000990. DOI: 10.1002/
14651858.CD000990]
PAD 2003
Peripheral Arterial Diseases Antiplatelet Consensus Group.
Antiplatelet therapy in peripheral arterial disease. Consensus
statement. European Journal of Vascular & Endovascular
Surgery 2003;26(1):1–16.
Pratt 2001
Pratt CM. Analysis of the cilostazol safety database.
American Journal of Cardiology 2001;87(12A):28D–33D.
Regensteiner 2002
Regensteiner JG, Ware JE Jr, McCarthy WJ, Zhang
P, Forbes WP, Heckman J, et al.Effect of cilostazol on
treadmill walking, community-based walking ability, and
9
 health-related quality of life in patients with intermittent
claudication due to peripheral arterial disease: meta-analysis
of six randomized controlled trials. Journal of the American
Geriatrics Society 2002;50(12):1939–46.
Robless 2001
Robless P, Mikhailidis D, Stansby G. Systematic review of
antiplatelet therapy for prevention of myocardial infarction,
stroke or vascular death in patients with peripheral vascular
disease. British Journal of Surgery 2001;88(6):787–800.
Rodin 1998
Rodin SM. Pletal (Cilostazol) Tablets. Medical Review of
NDA. Otsuka America YR:1998. Study 21–94–301 Vol.
Study 21–94–301:58–72.
SMC 2005
Scottish Medicines Consortium. NHS
Scotland. Cilostazol 100mg tablets (Pletal).
http://www.scottishmedicines.org.uk/updocs/
Cilostazol for peripheral arterial disease (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
cilostazol%20100mg%20tablets%20_Pletal_
%20resubmission%20_86-04_.pdf (accessed 14 July 2006)
2005; Vol. 86–04.
Thompson 2002
Thompson PD, Zimet R, Forbes WP, Zhang P. Meta-
analysis of results from eight randomized, placebo-
controlled trials on the effect of cilostazol on patients with
intermittent claudication. American Journal of Cardiology
2002;90(12):1314–9.
References to other published versions of this review
Robless 2007
Robless P, Mikhailidis DP, Stansby GP. Cilostazol for
peripheral arterial disease. Cochrane Database of Systematic
Reviews 2007, Issue 1. [Art. No.: CD003748. DOI:
10.1002/14651858.CD003748.pub2]
∗
Indicates the major publication for the study
10
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Beebe 1999

Methods Study design: multicentre, randomised, double-blind, placebo-controlled, clinical trial.

Method of randomisation: randomisation list developed using a permuted-block design, stratified by each
clinical centre.
Concealment of allocation: randomisation list forwarded to the drug packaging company.
Intention to treat: yes.

Participants Country: USA.

Setting: outpatient vascular medicine clinics.
Number randomised: 516
Treatment group (100 mg)
Number: 175.
Age: mean 64.3 years.
Sex M/F: 130/45.
Treatment group (50 mg)
Number: 171.
Age: mean 64.5 years.
Sex M/F: 131/40.
Control group
Number: 170.
Age: mean 65.1 years.
Sex M/F: 131/39.
Inclusion criteria: > 40 years of age with at least 6 months history of stable symptomatic IC secondary
to PAOD.
Exclusion criteria: ischaemic pain at rest; gross obesity; childbearing potential; hypertension; current
metastic malignant neoplasm; exercise-limiting cardiac disease; history of bleeding tendencies; or con-
comitant use of antiplatelet, anticoagulant, vasoactive or NSAIDs

Interventions Treatment: cilostazol 100 mg twice daily.

Treatment: cilostazol 50 mg twice daily.
Control: placebo.
Duration: 24 weeks.

Outcomes PFWD and MWD by treadmill testing; patient-based QoL questionnaires; cardiovascular morbidity; all-
cause mortality; and adverse events

Notes Efficacy intent-to-treat population in each group: 100 mg = 140; 50 mg = 139; placebo = 140

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Yes A - Adequate

Cilostazol for peripheral arterial disease (Review) 11

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Dawson 1998

Methods Study design: multicentre, randomised, double-blind, placebo-controlled, clinical trial.

Method of randomisation: method not stated but randomisation was stratified by treatment centre and
patient’s use of calcium channel blocker.
Concealment of allocation: method not stated.
Intention to treat: yes.

Participants Country: USA.

Setting: university medical centres.
Number randomised: 81.
Treatment group
Number: 54.
Age: mean ± SE, 66 ± 1.1 years.
Sex M/F: 38/16.
Contol group
Number: 27.
Age: mean ± SE, 67 ± 2.0 years.
Sex M/F: 24/3.
Inclusion criteria: > 40 years; stable IC secondary to chronic occlusive arterial disease > 6 months; ICD
on treadmill between 30 and 200 m; confirmation of diagnosis of PAOD.
Exclusion criteria: limb-threatening chronic limb ischaemia (ischaemic rest pain, ulceration or gangrene)
; lower extremity surgical or endovascular reconstruction or sympathectomy in previous 6 months; un-
controlled hypertension; inability to complete the treadmill walking test; MI within previous 6 months;
DVT within previous 3 months; severe concomitant disease; substance abuse; or gross obesity

Interventions Treatment: cilostazol 100 mg twice daily .

Control: placebo.
Duration: 12 weeks.

Outcomes Primary: PFWD, MWD on a treadmill.

Secondary: ABPI, subjective assessments of symptoms by patient and physician, safety

Notes 81 patients randomized, 4 did not participate in the trial long enough to have more than 1 treadmill test
after initiation of treatment

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Dawson 2000

Methods Study design: multicentre, randomised, double-blind, placebo-controlled, clinical trial.

Method of randomisation: stratified by clinical centre using permuted block design.
Concealment of allocation: interactive voice randomisation system.
Intention to treat: yes.

Cilostazol for peripheral arterial disease (Review) 12

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Dawson 2000 (Continued)

Participants Country: USA.

Setting: outpatient vascular clinics.
Number randomised: 698
Treatment group
Number:227.
Age: mean age 66 ± 9 years.
Sex M/F: 172/55.
Pentoxifylline group
Number: 232.
Age: mean age 66 ± 9 years.
Sex M/F: 181/51.
Control group
Number: 239.
Age: mean age 66 ± 9 years.
Sex M/F: 176/63.
Inclusion criteria: stable moderate to severe symptoms of IC for previous 6 months; confirmed PAD;
baseline PFWD more than or equal to 53.6 m; MWD less than or equal to 537.6 m.
Exclusion criteria: patients with Buerger’s disease; critical ischaemia; lower extremity surgical or endovas-
cular reconstruction or sympathectomy in previous 3 months; limited exercise capacity due to conditions
other than IC

Interventions Treatment: cilostazol 100 mg twice daily.

Treatment: pentoxifylline 400 mg three times.
Contol: placebo.
Duration: 24 weeks.

Outcomes Primary: MWD.

Secondary: PFWD, ABPI, QoL questionnaires.

Notes Intention-to-treat analysis population in each group: cilostazol = 205; pentoxifylline = 212; placebo = 226

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Yes A - Adequate

Elam 1998

Methods Study design: multicentre, randomised, double-blind, placebo-controlled, clinical trial.

Method of randomisation: not stated.
Concealment of allocation: not stated.
Intention to treat: yes.

Participants Country: USA.

Setting: hospital.
Number randomised: 189.
Treatment group

Cilostazol for peripheral arterial disease (Review) 13

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Elam 1998 (Continued)

Number: 95.
Age: mean 66.7 years.
Sex M/F: 83/12.
Control group
Number: 94.
Age: mean 65.8 years.
Sex M/F: 76/18.
Inclusion criteria: men and women > 40 years; chronic stable IC secondary to PAD.
Exclusion criteria: women with childbearing potential; gross obesity; poorly controlled hypertension or
diabetes; current alcohol or drug abuse; or renal disease

Interventions Treatment: cilostazol 100 mg twice daily.

Control: placebo.

Outcomes MWD, PFWD, ABPI,

Notes

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Money 1998

Methods Study design: multicentre, randomised, double-blind, placebo-controlled, clinical trial.

Method of randomisation: not stated.
Concealment of allocation: not stated.
Intention to treat: yes.

Participants Country: USA.

Setting: hospital.
Number randomised: 239.
Treatment group
Number: 119.
Age: mean ± SD 64.8 ± 9.4 years.
Sex M/F: 90/29.
Control group
Number: 120.
Age: mean ± SD 64.5 ± 8.8.
Sex M/F: 90/30.
Inclusion criteria: > 40 years; PAOD for at least 6 months.
Exclusion criteria: limb-threatening PAOD including gangrene or ischaemic rest pain; surgical or
endovascular procedures during previous 3 months; gross obesity; hypertension; current malignancy;
Buerger’s disease, DVT in previous 3 months; inability to complete treadmill testing for reasons unrelated
to IC; or bleeding problems

Cilostazol for peripheral arterial disease (Review) 14

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Money 1998 (Continued)

Interventions Treatment: 100mg cilostazol twice daily.

Control: placebo.
Duration: 16 weeks.

Outcomes MWD, PFWD, ABPI, QoL

Notes

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Otsuka 21-95-201

Methods Study design: multicentre, randomised, double-blind, placebo-controlled, clinical trial.

Method of randomisation: not stated.
Concealment of allocation: not stated.
Intention to treat: yes.

Participants Country: USA

Setting: hospital.
Number randomised: 215.
Treatment group (150 mg)
Number: 73.
Age: mean 65 years.
Sex M/F: 81% / 19%.
Treatment group (100 mg)
Number: 72.
Age: mean 68 years.
Sex M/F: 75% / 25%.
Control group
Number: 70.
Age: mean 66 years.
Sex M/F: 81% / 19%.
Inclusion criteria: > 40 years; stable, PAOD-induced IC for at least 6 months.
Exclusion criteria: women of childbearing potential; sympathectomy or lower extrmeity arterial reparitive
surgery, including endovascular procedures in previous 3 months; greater than 60% above ideal body
wieght; current metatastic malignancy; DVT within previous 3 months; exercise-limiting disease; tedency
to bleeding; pericarditis; platelet count < 130,000/cm3 or haematocrit < 30%

Interventions Treatment: cilostazol 150 mg twice daily.

Treatment: cilostazol 100 mg twice daily.
Placebo twice daily.
Duration: 12 weeks.

Outcomes MWD, PFWD, ABPI, QoL

Cilostazol for peripheral arterial disease (Review) 15

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Otsuka 21-95-201 (Continued)

Notes

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Strandness 2002

Methods Study design: multicentre, randomised, double-blind, placebo-controlled, clinical trial.

Method of randomisation: not stated.
Concealment of allocation: not stated.
Intention to treat: yes.

Participants Country: USA.

Setting: medical centres.
Number randomised:394.
Treatment group (100 mg)
Number: 133.
Age: mean ± SE, 63.1 ± 10.2 years.
Sex M/F: 102/31.
Treatment group (50 mg)
Number: 132.
Age: mean ± SE, 63.9 ± 8.7 years.
Sex M/F: 98/34.
Control group
Number: 129.
Age: mean ± SE, 64.4 ± 10.2 years.
Sex M/F: 100/29.
Inclusion criteria: >40 years; at least 6 month hisotry of stable symptomatic IC secondary to PAD; and
reproducible walking distances on screening treadmill.
Exclusion criteria: ischaemic pain at rest; gross obesity; childbearing potential; hypertension; malignancy;
exercise limiting cardiac disease; hisotry of bleeding tendencies; or concomitant use of antiplatelet, anti-
coagulant, haemoreologic or NSAIDs

Interventions Treatment: cilostazol 100 mg twice daily.

Treatment: cilostazol 50 mg twice daily.
Placebo twice daily.
Duration: 24 weeks.

Outcomes MWD, PFWD, QoL

Notes Intention-to-treat analysis population for treadmill analysis = 377; 286 completed all 24 weeks of therapy

Risk of bias

Item Authors’ judgement Description

Cilostazol for peripheral arterial disease (Review) 16

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Strandness 2002 (Continued)

Allocation concealment? Unclear B - Unclear

ABPI: ankle brachial pressure index

DVT: deep vein thrombosis
IC: intermittent claudication
ICD: initial claudication distance
m: metres
MI: myocardial infarction
MWD: maximum walking distance
NSAIDs: non-steroidal anti-inflammatory agents
PAD: peripheral arterial disease
PAOD: peripheral arterial occlusive disease
PFWD: pain-free walking distance
QoL: quality of life
SE: standard error

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Otsuka 21-94-301 Insufficient data available.Unable to assess the quality of the study. Otsuka Pharmaceutical Co Ltd, Japan
contacted requesting further information

Otsuka 21-98-214-01 Insufficient data available.Unable to assess the quality of the study. Otsuka Pharmaceutical Co Ltd, Japan
contacted requesting further information

Samra 2003 Non randomised study.

Cilostazol for peripheral arterial disease (Review) 17

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DATA AND ANALYSES

Comparison 1. Initial claudication distance

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 ICD 100 mg cilostazol twice 7 1326 Mean Difference (IV, Fixed, 95% CI) 31.14 [21.34, 40.93]
daily versus placebo
2 ICD 50 mg cilostazol versus 2 475 Mean Difference (IV, Random, 95% CI) 41.31 [-7.09, 89.71]
placebo
3 ICD 150 mg cilostazol versus 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
placebo
4 ICD cilostazol 100 mg twice 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
daily versus ptx 400 mg three
times daily

Comparison 2. Absolute claudication distance

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 ACD 100 mg cilostazol twice 7 1579 Mean Difference (IV, Random, 95% CI) 49.70 [24.23, 75.18]
daily versus placebo
2 ACD 50 mg cilostazol versus 2 497 Mean Difference (IV, Fixed, 95% CI) 31.94 [12.35, 51.53]
placebo
3 ACD 150 mg cilostazol versus 1 Mean Difference (IV, Random, 95% CI) Totals not selected
placebo
4 ACD Cilostazol 100 mg twice 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected
daily versus ptx 400 mg three
times daily

Comparison 3. ABPI

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 ABPI 3 859 Mean Difference (IV, Random, 95% CI) 0.06 [0.03, 0.09]

Cilostazol for peripheral arterial disease (Review) 18

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 1.1. Comparison 1 Initial claudication distance, Outcome 1 ICD 100 mg cilostazol twice daily
versus placebo.

Review: Cilostazol for peripheral arterial disease

Comparison: 1 Initial claudication distance

Outcome: 1 ICD 100 mg cilostazol twice daily versus placebo

Mean Mean
Study or subgroup Cilostazol Placebo Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Beebe 1999 140 67.5 (130.4) 140 23.04 (63.78) 16.6 % 44.46 [ 20.41, 68.51 ]

Dawson 1998 52 38.9 (68.34) 25 8.3 (33.5) 18.5 % 30.60 [ 7.85, 53.35 ]

Dawson 2000 205 93.6 (127.4) 226 56.5 (93.1) 21.2 % 37.10 [ 15.85, 58.35 ]

Elam 1998 1 0 (0) 1 0 (0) Not estimable

Money 1998 119 85.9 (108) 120 54.2 (114) 12.1 % 31.70 [ 3.55, 59.85 ]

Otsuka 21-95-201 54 41.4 (63.2) 60 34.4 (57.3) 19.4 % 7.00 [ -15.23, 29.23 ]

Strandness 2002 89 58.5 (128.3) 94 17.2 (43.6) 12.2 % 41.30 [ 13.23, 69.37 ]

Total (95% CI) 660 666 100.0 % 31.14 [ 21.34, 40.93 ]

Heterogeneity: Chi2 = 6.52, df = 5 (P = 0.26); I2 =23%
Test for overall effect: Z = 6.23 (P < 0.00001)
Test for subgroup differences: Not applicable

-100 -50 0 50 100

Favours placebo Favours cilostazol

Cilostazol for peripheral arterial disease (Review) 19

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 1.2. Comparison 1 Initial claudication distance, Outcome 2 ICD 50 mg cilostazol versus placebo.

Review: Cilostazol for peripheral arterial disease

Comparison: 1 Initial claudication distance

Outcome: 2 ICD 50 mg cilostazol versus placebo

Mean Mean
Study or subgroup Cilostazol Placebo Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Beebe 1999 139 115.1 (93.13) 140 48.6 (76.9) 49.0 % 66.50 [ 46.45, 86.55 ]

Strandness 2002 102 34.3 (60.6) 94 17.2 (43.6) 51.0 % 17.10 [ 2.40, 31.80 ]

Total (95% CI) 241 234 100.0 % 41.31 [ -7.09, 89.71 ]

Heterogeneity: Tau2 = 1139.75; Chi2 = 15.17, df = 1 (P = 0.00010); I2 =93%
Test for overall effect: Z = 1.67 (P = 0.094)

-100 -50 0 50 100

Favours placebo Favours cilostazol

Analysis 1.3. Comparison 1 Initial claudication distance, Outcome 3 ICD 150 mg cilostazol versus placebo.

Review: Cilostazol for peripheral arterial disease

Comparison: 1 Initial claudication distance

Outcome: 3 ICD 150 mg cilostazol versus placebo

Mean Mean
Study or subgroup Cilostazol Placebo Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Otsuka 21-95-201 44 50.1 (70.3) 66 34.4 (60.1) 15.70 [ -9.63, 41.03 ]

-100 -50 0 50 100

Favours placebo Favours cilostazol

Cilostazol for peripheral arterial disease (Review) 20

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 1.4. Comparison 1 Initial claudication distance, Outcome 4 ICD cilostazol 100 mg twice daily
versus ptx 400 mg three times daily.

Review: Cilostazol for peripheral arterial disease

Comparison: 1 Initial claudication distance

Outcome: 4 ICD cilostazol 100 mg twice daily versus ptx 400 mg three times daily

Mean Mean
Study or subgroup Cilostazol Pentoxifylline Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Dawson 2000 205 93.6 (127.4) 212 73.6 (93.1) 20.00 [ -1.48, 41.48 ]

-100 -50 0 50 100

Favours Ptx Favours Cilostazol

Analysis 2.1. Comparison 2 Absolute claudication distance, Outcome 1 ACD 100 mg cilostazol twice daily
versus placebo.

Review: Cilostazol for peripheral arterial disease

Comparison: 2 Absolute claudication distance

Outcome: 1 ACD 100 mg cilostazol twice daily versus placebo

Mean Mean
Study or subgroup Cilostazol Placebo Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Beebe 1999 140 129.1 (463.3) 140 26.82 (148.5) 6.9 % 102.28 [ 21.69, 182.87 ]

Dawson 1998 52 84.6 (144.94) 25 4.56 (61.5) 12.8 % 80.04 [ 33.85, 126.23 ]

Dawson 2000 205 107.36 (158.4) 226 64.7 (134.61) 17.5 % 42.66 [ 14.76, 70.56 ]

Elam 1998 95 79.05 (134.5) 94 36.1 (141.55) 14.5 % 42.95 [ 3.58, 82.32 ]

Money 1998 119 101.1 (154.9) 120 47.1 (124.88) 15.4 % 54.00 [ 18.31, 89.69 ]

Otsuka 21-95-201 54 35.2 (72.05) 60 38.1 (69.7) 18.0 % -2.90 [ -28.98, 23.18 ]

Strandness 2002 124 96.41 (200.44) 125 23.2 (78.26) 14.9 % 73.21 [ 35.36, 111.06 ]

Total (95% CI) 789 790 100.0 % 49.70 [ 24.23, 75.18 ]

Heterogeneity: Tau2 = 762.54; Chi2 = 19.16, df = 6 (P = 0.004); I2 =69%
Test for overall effect: Z = 3.82 (P = 0.00013)

-100 -50 0 50 100

Favours placebo Favours cilostazol

Cilostazol for peripheral arterial disease (Review) 21

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 2.2. Comparison 2 Absolute claudication distance, Outcome 2 ACD 50 mg cilostazol versus
placebo.

Review: Cilostazol for peripheral arterial disease

Comparison: 2 Absolute claudication distance

Outcome: 2 ACD 50 mg cilostazol versus placebo

Mean Mean
Study or subgroup Cilostazol Placebo Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Beebe 1999 139 67.26 (120.72) 140 26.8 (148.49) 38.1 % 40.46 [ 8.71, 72.21 ]

Strandness 2002 110 49.9 (111.17) 108 23.2 (72.75) 61.9 % 26.70 [ 1.80, 51.60 ]

Total (95% CI) 249 248 100.0 % 31.94 [ 12.35, 51.53 ]

Heterogeneity: Chi2 = 0.45, df = 1 (P = 0.50); I2 =0.0%
Test for overall effect: Z = 3.20 (P = 0.0014)
Test for subgroup differences: Not applicable

-100 -50 0 50 100

Favours placebo Favours cilostazol

Cilostazol for peripheral arterial disease (Review) 22

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 2.3. Comparison 2 Absolute claudication distance, Outcome 3 ACD 150 mg cilostazol versus
placebo.

Review: Cilostazol for peripheral arterial disease

Comparison: 2 Absolute claudication distance

Outcome: 3 ACD 150 mg cilostazol versus placebo

Mean Mean
Study or subgroup Cilostazol Placebo Difference Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Otsuka 21-95-201 44 89.9 (214.25) 60 38.1 (69.7) 51.80 [ -13.92, 117.52 ]

-100 -50 0 50 100

Favours placebo Favours cilostazol

Analysis 2.4. Comparison 2 Absolute claudication distance, Outcome 4 ACD Cilostazol 100 mg twice daily
versus ptx 400 mg three times daily.

Review: Cilostazol for peripheral arterial disease

Comparison: 2 Absolute claudication distance

Outcome: 4 ACD Cilostazol 100 mg twice daily versus ptx 400 mg three times daily

Mean Mean
Study or subgroup Cilostazol Pentoxifylline Difference Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Dawson 2000 205 107.3 (158.4) 212 64.4 (126.6) 42.90 [ 15.32, 70.48 ]

-100 -50 0 50 100

Favours Ptx Favours Cilostazol

Cilostazol for peripheral arterial disease (Review) 23

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 3.1. Comparison 3 ABPI, Outcome 1 ABPI.

Review: Cilostazol for peripheral arterial disease

Comparison: 3 ABPI

Outcome: 1 ABPI

Mean Mean
Study or subgroup Cilostazol Placebo Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Dawson 2000 205 0.04 (0.18) 226 0.01 (0.19) 26.5 % 0.03 [ 0.00, 0.06 ]

Elam 1998 95 0.09 (0.02) 94 0 (0.02) 36.7 % 0.09 [ 0.08, 0.10 ]

Money 1998 119 0.06 (0.02) 120 0.01 (0.02) 36.8 % 0.05 [ 0.04, 0.06 ]

Total (95% CI) 419 440 100.0 % 0.06 [ 0.03, 0.09 ]

Heterogeneity: Tau2 = 0.00; Chi2 = 109.95, df = 2 (P<0.00001); I2 =98%
Test for overall effect: Z = 3.47 (P = 0.00052)

-0.5 -0.25 0 0.25 0.5

Favours placebo Favours cilostazol

APPENDICES

Appendix 1. Search strategy used to search CENTRAL

#1 MeSH descriptor ARTERIAL OCCLUSIVE DISEASES this term only

#2 (peripheral in All Text near/6 arterial in All Text near/6 occlusive in All Text near/6 dis* in All Text)
#3 (arterial in All Text near/6 occlusive in All Text near/6 dis* in All Text)
#4 MeSH descriptor INTERMITTENT CLAUDICATION this term only
#5 intermittent next claudication in All Text
#6 (#1 or #2 or #3 or #4 or #5)
#7 cilostazol in All Text
#8 pletal in All Text
#9 (#7 or #8)
#10 (#6 and #9)

Cilostazol for peripheral arterial disease (Review) 24

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Appendix 2. Search strategy used to search MEDLINE and EMBASE on DIALOG

1) INTERMITTENT CLAUDICATION!(L)DT
2) INTERMITTENT CLAUDICATION(N)DRUG THERAPY
3) INTERMITTENT CLAUDICATION(N)DT
4) CILOSTAZOL
5) S4/HUMAN
6) DT=RANDOMIZED CONTROLLED TRIAL OR DT=CONTROLLED CLINICAL TRIAL OR DT=CLINICAL TRIAL
OR DT=MAJOR CLINICAL STUDY OR DT=CLINICAL ARTICLE OR DT=CONTROLLED STUDY
7) RANDOMIZED CONTROLLED TRIALS/DE OR RANDOM ALLOCATION/DE OR DOUBLE-BLIND METHOD/DE
OR SINGLE-BLIND METHOD/DE OR CLINICAL TRIALS! OR PLACEBOS/DE OR PLACEBO?/TI,AB OR RANDOM?/
TI,AB OR RANDOMI?ED/TI,AB
8) COMPARATIVE STUDY/DE OR FOLLOW UP STUDIES/DE OR PROSPECTIVE STUDIES/DE OR MULTICENTER
STUDY/DE OR DRUG COMPARISON/DR,DE OR CROSSOVER PROCEDURE/DE OR PHASE 3 CLINICAL TRIAL/DE
OR INTERMETHOD COMPARISON/DE OR SINGLE BLIND PROCEDURE/DE
9) DT=FOLLOW UP STUDIES OR PROSPECTIVE STUDIES OR MULTICENTER STUDY/DE OR PROSPECTIVE STUD-
IES/DE OR DRUG COMPARISON/DE OR CROSSOVER PROCEDURE/DE OR PHASE 3 CLINICAL TRIAL OR INTER-
METHOD COMPARISON/DE OR SINGLE BLIND PROCEDURE/DE
10) PROSPECTIVE STUDY/DE OR FOLLOW-UP/DE OR PLACEBO/DE OR LONGITUDINAL STUDY/DE
11) S6 OR S7 OR S8 OR S9 OR S10
12) S5 AND S11

FEEDBACK

Unpublished trials

Summary
The Cochrane review of cilostazol (1/2007) includes only one study of cilostazol (CLZ) and pentoxifylline (PTX, TRENTAL), (Dawson
DL 2000), and states: the differences in ICD and ACD showed significant improvement for the cilostazol group over patients taking
pentoxifylline.
Already in 1998 eight pivotal trials with cilostazol were analysed in the medical review by the FDA. One of these was trial 21-94-301 (p.
58), an unpublished trial of Otsuka with 370 patients: 247 CLZ or placebo, 123 pentoxifylline. In this study CLZ was not statistically
distinguishable from either placebo or oxpentifylline (=pentoxyfylline). A second study comparing cilostazol with pentoxifylline was
the Dawson DL 2000 (trial 21-96-202). The FDA states (p.231): There is not yet a convincing basis with which to conclude that CLZ
is more efficious than pentoxifylline in this regard (anti claudication efficacy).
Pentoxifylline is not recommended for claudication in some guidelines (SIGN 10/2006, CHEST 2/2007), therefore it is important to
note that there is no difference between CLZ and PTX.
In a reply (21 March 2007) to my mail (23 February 2007) to the Cochrane peripheral vascular diseases group Prof. Stansby stated
that “the medical review (of the FDA) does not come up if you put cilostazol into the FDA web page search”.
This Cochrane review was published at the same time as marketing of cilostazol started in Germany and was part of the promotional
material Schwarz Pharma sent to us. Prof. Stansby declared a conflict of interest with Otsuka pharmaceuticals, the developing company.
For me this may be a problem. What does Cochrane think about it?
Submitter agrees with default conflict of interest statement:
I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of
my feedback.

Cilostazol for peripheral arterial disease (Review) 25

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Reply
We agree that there appears to be an additional and unpublished trial comparing cilostazol with pentoxifylline, referred to as study 21-
94-301 in the FDA document of 1998. We were unaware of this when we prepared our original review. It did not come to light using
standard search strategies. Unfortunately the data currently available to us is still not sufficient to allow inclusion of this trial at present.
Otsuka have not made the data available to us, although it has been requested. The review has been altered to make it clear that this
additional study exists and that any conclusions about a comparison with pentoxifylline should be guarded based on the one published
trial. If in the future Otsuka do release further data to us, and the methodological quality is acceptable, we will consider including it
in future updates.
The production of this review and its timing was entirely coincidental to the release date of cilostazol in Germany. Likewise there was
no contact with Otsuka concerning these matters. Professor Stansby has declared his conflicts of interest, but has not had any contact
with Otsuka in relation to the timing and release of this review. The main conclusions of the review are not altered by this additional
trial but we have updated the review to include this study under “excluded studies”.

Contributors
Feedback contributed by:
Dr. Heide Rose GIECK
Editorial staff arznei-telegramm
A.T.I. Arzneimittelinformation Berlin GmbH
Bergstr. 38A, Wasserturm, D-12169 Berlin
Response contributed by:
Professor Gerry Stansby
Professor of Vascular Surgery
Department of Surgery
University of Newcastle upon Tyne
Framlington Place
Newcastle upon Tyne NE24HH
UK

WHAT’S NEW
Last assessed as up-to-date: 6 November 2007.

Date Event Description

9 May 2008 Amended Converted to new review format.

HISTORY
Protocol first published: Issue 3, 2002
Review first published: Issue 1, 2007

Cilostazol for peripheral arterial disease (Review) 26

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Date Event Description

11 November 2007 Feedback has been incorporated Feedback and authors’ response to feedback added.
Unpublished trial Otsuka 1996b (Otsuka 21-94-201)
is a duplicate reference to Strandness 2002

7 November 2007 New citation required but conclusions have not Two excluded studies added. No change to conclu-
changed sions.

21 February 2007 Amended Edited update. Abstract edited to include unit of mea-
surement in results section

CONTRIBUTIONS OF AUTHORS
PR selected studies, assessed the methodological quality of studies and extracted data.
GS selected studies, assessed the methodological quality of studies and extracted data.
DM resolved any conflicts regarding inclusion of trials and extracted data.

DECLARATIONS OF INTEREST
G Stansby has received lecturer’s fees and research funding from Otsuka pharmaceuticals.
DP Mikhailidis and G Stansby were members of the expert panel that produced the following publication:
Barnett AH, Bradbury AW, Brittenden J, Crichton B, Donnelly R, Homer-Vanniasinkam S, Mikhailidis DP, Stansby G. The role of
cilostazol in the treatment of intermittent claudication. Current Medical Research Opinion 2004 ;20:1661-70.
DP Mikhailidis attended an Advisory Board meeting held by Otsuka UK after the publication of the initial Cochrane review in Issue
1, 2007 (January 2007).

SOURCES OF SUPPORT

Internal sources
• No sources of support supplied

Cilostazol for peripheral arterial disease (Review) 27

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
External sources
• Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.

INDEX TERMS

Medical Subject Headings (MeSH)

∗ Walking; Intermittent Claudication [∗ drug therapy]; Myocardial Infarction [prevention & control]; Peripheral Vascular Diseases [drug

therapy]; Platelet Aggregation Inhibitors [adverse effects; ∗ therapeutic use]; Randomized Controlled Trials as Topic; Stroke [prevention
& control]; Tetrazoles [adverse effects; ∗ therapeutic use]

MeSH check words

Aged; Humans; Middle Aged

Cilostazol for peripheral arterial disease (Review) 28

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.