This is not the document you are looking for? Use the search form below to find more!

Report home > Science

Cilostazol vs aspirin for secondary prevention of vascular events

0.00 (0 votes)
Document Description
cilostazol vs aspirin for secondary prevention of vascular events
File Details
  • Added: February, 25th 2012
  • Reads: 134
  • Downloads: 1
  • File size: 337.41kb
  • Pages: 29
  • Tags: claudicat, cilostazol, aspirin
  • content preview
Submitter
  • Name: Claudicat
Embed Code:

Add New Comment




Related Documents

Acetylsalicylic Acid for the Prevention of Preeclampsia and Intra-uterine Growth Restriction in Women with Abnormal Uterine Artery Doppler: A Systematic Review and Meta-analysis

by: kinga, 9 pages

Preeclampsia is a major global cause of maternal, neonatal and perinatal mortality. From studies of placental pathophysiology in women with preeclampsia, a potentially important role of low-dose ...

Aspirin for High Blood Pressure: Is it Right for You?

by: craigwilliam, 1 pages

One of the best remedies that hypertensive patients resort to nowadays is taking aspirin for high blood pressure. To learn more about this type of therapy, be sure to check out this article.

A Study to Identify Evidence-Based Strategies for the Prevention of Nursing Errors

by: joline, 58 pages

This study was designed to 1) Describe the characteristics of the nurse, patient and practice setting involved in the complaint case; 2) Categorize the nursing error and harm outcome; 3) Examine ...

Basic Construction of Secondary Parts of a Triangle

by: molly, 5 pages

No transcript available.

GLOBAL BLINDNESS AND THE NATION

by: shinta, 5 pages

In this presentation, the major causes of blindness and blindness according to geographical regions are considered. World blindness has become a global problem and is different in various ...

PREVENTION OF BLINDNESS IN SINGAPORE

by: shinta, 7 pages

Any effective measure to prevent blindness must include the education of the public to create an awareness of ocular diseases espe- cially those which can cause blindness; the ...

Effectiveness of Ginger for Prevention of Nausea and Vomiting after Gynecological Laparoscopy

by: shinta, 7 pages

Nausea and vomiting are common complications after laparoscopic surgery with the incidence ranging from 25-40%. The symptoms usually occur during the first 4 to 6 hours post operation ...

The Prevention of Depressive Symptoms in Children and Adolescents: A Meta-Analytic Review

by: shinta, 15 pages

Research on the prevention of depressive symptoms in children and adolescents was reviewed and synthesized with meta-analysis. When all 30 studies were included, selective prevention programs ...

Prevention of HIV Transmission from Mother to Child

by: lenora, 31 pages

Over 12 million women of childbearing age are now living with HIV and AIDS, and nearly 600,000 children were born with HIV infection in 1997. Since the introduction of zidovudine based preventive ...

The effect of non-cariogenic sweeteners on the prevention of dental caries: A review of the evidence

by: shinta, 12 pages

The role of sugar substitutes such as xylitol and sorbitol in the prevention of dental caries has been investigated in several clinical studies. The purpose of this report is to review the ...

Content Preview
Cilostazol versus aspirin for secondary prevention of vascular
events after stroke of arterial origin (Review)
Kamal AK, Naqvi I, Husain MR, Khealani BA
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2011, Issue 10
http://www.thecochranelibrary.com
Cilostazol versus aspirin for secondary prevention of vascular events after stroke of arterial origin (Review)
Copyright (c) 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.


T A B L E O F C O N T E N T S
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
ABSTRACT
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
PLAIN LANGUAGE SUMMARY
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
BACKGROUND
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
OBJECTIVES
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5
Figure 1.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
DISCUSSION
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8
AUTHORS' CONCLUSIONS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
CHARACTERISTICS OF STUDIES
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
Analysis 1.1. Comparison 1 Cilostazol versus aspirin in patients with ischaemic stroke or TIA, Outcome 1 Stroke, MI or
vascular death during follow-up.
. . . . . . . . . . . . . . . . . . . . . . . . . . .
18
Analysis 1.2. Comparison 1 Cilostazol versus aspirin in patients with ischaemic stroke or TIA, Outcome 2 Stroke (of all
types) during follow-up.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18
Analysis 1.3. Comparison 1 Cilostazol versus aspirin in patients with ischaemic stroke or TIA, Outcome 3 Ischaemic stroke
during follow-up.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
Analysis 1.4. Comparison 1 Cilostazol versus aspirin in patients with ischaemic stroke or TIA, Outcome 4 Haemorrhagic
stroke during follow-up.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
Analysis 1.5. Comparison 1 Cilostazol versus aspirin in patients with ischaemic stroke or TIA, Outcome 5 MI during
follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
Analysis 1.6. Comparison 1 Cilostazol versus aspirin in patients with ischaemic stroke or TIA, Outcome 6 Vascular death
during follow-up.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
Analysis 1.7. Comparison 1 Cilostazol versus aspirin in patients with ischaemic stroke or TIA, Outcome 7 Death from any
cause during follow-up.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
Analysis 1.8. Comparison 1 Cilostazol versus aspirin in patients with ischaemic stroke or TIA, Outcome 8 Extracranial
haemorrhage during follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
Analysis 1.9. Comparison 1 Cilostazol versus aspirin in patients with ischaemic stroke or TIA, Outcome 9 Gastrointestinal
haemorrhage during follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
Analysis 1.10. Comparison 1 Cilostazol versus aspirin in patients with ischaemic stroke or TIA, Outcome 10 Other
outcomes of safety during follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . .
22
Analysis 2.1. Comparison 2 Cilostazol versus aspirin in patients with ischaemic stroke or TIA - sensitivity analysis, Outcome
1 Composite vascular events (stroke, MI or vascular death during follow-up). . . . . . . . . . . . .
24
APPENDICES
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
WHAT'S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
25
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
CONTRIBUTIONS OF AUTHORS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
INDEX TERMS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
Cilostazol versus aspirin for secondary prevention of vascular events after stroke of arterial origin (Review)
i
Copyright (c) 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

[Intervention Review]
Cilostazol versus aspirin for secondary prevention of vascular
events after stroke of arterial origin

Ayeesha K Kamal1, Imama Naqvi1, Muhammad R Husain2, Bhojo A Khealani2
1Stroke Service, International Cerebrovascular Translational Clinical Research Training Program, Section of Neurology, Department
of Medicine, Aga Khan University Hospital, Karachi, Pakistan. 2Stroke Service, Section of Neurology, Department of Medicine, Aga
Khan University Hospital, Karachi, Pakistan
Contact address: Ayeesha K Kamal, Stroke Service, International Cerebrovascular Translational Clinical Research Training Program,
Section of Neurology, Department of Medicine, Aga Khan University Hospital, Stadium Road, PO Box 3500, Karachi, 74800, Pakistan.
ayeesha.kamal@aku.edu.
Editorial group: Cochrane Stroke Group.
Publication status and date: Edited (no change to conclusions), published in Issue 10, 2011.
Review content assessed as up-to-date: 13 July 2011.
Citation:
Kamal AK, Naqvi I, Husain MR, Khealani BA. Cilostazol versus aspirin for secondary prevention of vascular
events after stroke of arterial origin. Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD008076. DOI:
10.1002/14651858.CD008076.pub2.
Copyright (c) 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
Aspirin is widely used for secondary prevention after stroke. Cilostazol has shown promise as an alternative to aspirin in Asian people
with stroke.
Objectives
To determine the relative effectiveness and safety of cilostazol compared directly with aspirin in the prevention of stroke and other
serious vascular events in patients at high vascular risk for subsequent stroke, those with previous transient ischaemic attack (TIA) or
ischaemic stroke of arterial origin.
Search strategy
We searched the Cochrane Stroke Group Trials Register (last searched September 2010), the Cochrane Central Register of Controlled
Trials (CENTRAL) (The Cochrane Library 2009, Issue 4), MEDLINE (1950 to May 2010) and EMBASE (1980 to May 2010). In an
effort to identify further published, ongoing and unpublished studies we searched journals, conference proceedings and ongoing trial
registers, scanned reference lists from relevant studies and contacted trialists and Otsuka Pharmaceutical Co Ltd.
Selection criteria
We selected all randomised controlled trials (RCTs) comparing cilostazol with aspirin where participants were treated for at least one
month and followed systematically for development of vascular events.
Data collection and analysis
Data extracted from eligible studies included: (1) a composite outcome of vascular events (stroke, myocardial infarction or vascular
death) during follow up (primary outcome); (2) separate outcomes of stroke (ischaemic or haemorrhagic, fatal or non-fatal), myocardial
infarction (MI) (fatal or non-fatal), vascular death and death from all causes; and (3) main outcomes of safety including any intracranial,
extracranial or gastrointestinal (GI) haemorrhage and other outcomes during treatment follow up (secondary outcomes). We computed
an estimate of treatment effect and performed a test for heterogeneity between trials. We analysed data on an intention-to-treat basis
and assessed bias for all included studies.
Cilostazol versus aspirin for secondary prevention of vascular events after stroke of arterial origin (Review)
1
Copyright (c) 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Main results
We included two RCTs with 3477 Asian participants. Compared with aspirin, cilostazol was associated with a significantly lower risk
of composite outcome of vascular events (6.77% versus 9.39%, risk ratio (RR) 0.72, 95% confidence interval (CI) 0.57 to 0.91), and
lower risk of haemorrhagic stroke (0.53% versus 2.01%, RR 0.26, 95% CI 0.13 to 0.55). In terms of outcome of safety compared with
aspirin, cilostazol was significantly associated with minor adverse effects (8.22% versus 4.95%, RR 1.66, 95% CI 1.51 to 1.83).
Authors' conclusions
Cilostazol is more effective than aspirin in the prevention of vascular events secondary to stroke. Cilostazol has more minor adverse
effects, although there is evidence of fewer bleeds.
P L A I N L A N G U A G E S U M M A R Y
Cilostazol versus aspirin for secondary prevention of vascular events after a stroke of arterial origin
Stroke is a public health problem. As lower and middle income countries make rapid economic progress they face the additional
health burden of diseases of affluence like stroke and heart attacks. Unlike heart attack, stroke is a disease caused by more than one
mechanism. In Asians, a larger proportion of ischaemic stroke is due to narrowing of the arteries at the base of the brain. Compared to
Caucasians, Asians are more likely to have bleeds into their brain matter causing stroke, because of uncontrolled high blood pressure.
The medication cilostazol thins the blood by blocking platelet accumulation and appears, from early reports, to be more effective than
aspirin in the prevention of stroke, heart attacks and death from vascular causes in patients with stroke. This may be due to its inherent
effectiveness, as well as chances of fewer brain bleeds. In this review of two randomised trials involving 3477 participants, we found
that cilostazol was more effective for the prevention of stroke, heart attack and death from vascular causes in Asian patients with stroke.
In terms of safety, it causes more side effects than aspirin but less serious bleeding in the brain and the body.
B A C K G R O U N D
and appears to contribute to fewer intracranial haemorrhages than
with aspirin while maintaining a significant reduction in the risk
of recurrent strokes. In the Cilostazol Stroke Prevention Study,
Description of the condition
a phase III clinical trial involving more than 1000 Japanese pa-
Stroke is the leading cause of sustained disability in the world to-
tients, cilostazol was found to reduce the risk of secondary stroke
day. Two-thirds of all strokes now occur in the developing world
by 41.7% compared with placebo (Matsumoto 2005). In a phase
(Lopez 2006). It is important to study interventions that are rel-
II clinical trial comparing the efficacy of cilostazol versus aspirin
evant to the Asian population as it bears the brunt of the burden
among 720 Chinese patients, stroke recurrence was reported in 12
of global stroke mortality (Feldmann 1990). Moreover the distri-
patients in the cilostazol group and in 20 patients in the aspirin
bution of types of strokes is different in this region, with a sig-
group. The estimated hazard ratio was 0.62 (95% confidence in-
nificantly higher proportion of intracranial haemorrhages (ICH)
terval (CI) 0.30 to 1.26; P = 0.185). Also, cerebral haemorrhagic
than in the developed world (Liu 2007). Individuals suffering from
events were significantly more common in the aspirin group than
stroke are already at a very high risk of developing subsequent
in the cilostazol group (7 versus 1; P = 0.034) (Huang 2008).
stroke (Wong 2002). In addition, they are at higher risk of mor-
bidity from other clinical manifestations of atherosclerotic disease
such as myocardial infarction (MI), angina or peripheral arterial
Description of the intervention
disease (PAD) (Burke 1995). Although aspirin is beneficial for the
secondary prevention of a wide spectrum of cardiovascular inci-
Cilostazol is a selective and potent phosphodiesterase type 3
dents, including stroke, it is also known to be associated with a risk
(PDE3) inhibitor (Minami 1997) that is both an antiplatelet and
of ICH. Cilostazol, a phosphodiesterase type 3 (PDE3) inhibitor,
a vasodilating agent. PDE 3 increases the breakdown of cyclic
has been tested in this population for secondary stroke prevention
adenosine monophosphate (cAMP) (Ikeda 1999). Inhibition of
Cilostazol versus aspirin for secondary prevention of vascular events after stroke of arterial origin (Review)
2
Copyright (c) 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

PDE3 increases the levels of cAMP. Since both platelets and vas-
(Algra 1996). A study of 720 Chinese patients that compared
cular smooth muscle cells contain PDE 3A, inhibition leads to
treatment with a standard dose of aspirin at 100 mg per day to
decreased platelet aggregation. Cilostazol inhibits the uptake of
cilostazol 100 mg twice a day was associated with a reduction of
adenosine (Liu 2000). This leads to an enhanced adenosine ac-
recurrent stroke by 30% (95% CI -26% to 70%) (Huang 2008).
tion via A1 and A2 receptors. In platelets and vascular smooth
A systematic review is necessary to evaluate the strength of these
muscle cells A2 mediated increases in cAMP enhance the conse-
claims.
quences of PDE inhibition, that is result in additional increases in
cAMP. Aspirin is a non-selective irreversible inhibitor of cyclooxy-
genase (COX) and has anti-inflammatory and antiplatelet effects.
It decreases the formation of prostaglandins (PGs) and thrombox-
O B J E C T I V E S
anes, which leads to decreased platelet aggregation and stabiliza-
tion (Abramson 1989).
The objective of this review was to determine the relative ef-
fectiveness and safety of the phosphodiesterase inhibitor (PDE
3A) cilostazol, compared directly with aspirin (frequently used
as monotherapy for secondary prevention), in the prevention of
How the intervention might work
stroke and other serious vascular events in patients at high vascu-
In addition to platelet inhibition, cilostazol has other effects on
lar risk for subsequent stroke. That is, those people with previous
the circulatory system that may be relevant to stroke prevention.
transient ischaemic attack (TIA) and ischaemic stroke of arterial
Both PDE inhibition and possibly inhibition of adenosine up-
origin.
take act in concert to relax vascular smooth muscle cells and lead
to vasodilatation. Monocyte chemoattractant protein 1 (MCP-
1) plays a significant role in mediating monocyte recruitment in
M E T H O D S
atherosclerotic lesions. Interestingly, cilostazol also inhibits the cy-
tokine induced expression of MCP-1 probably due to cAMP el-
evation, which might contribute to an anti-inflammatory action
Criteria for considering studies for this review
(Nishio 1997).
Cilostazol acts as an antimitogenic agent by several mechanisms.
It blocks the surface expression of the platelet fibrinogen receptor
(G2b/3a) as well as alpha-granule secretion of P-selectin (Inoue
Types of studies
1999). P-selectin is assumed to be involved in platelet dependent
We included all truly randomised trials in which cilostazol was
mitogenesis. This effect might contribute to inhibition of re-steno-
compared directly with aspirin and in which patients were followed
sis. Heparin binding epidermal growth factor (HBEGF), which is
up prospectively and systematically for at least one month for the
also inhibited by cilostazol, is one the most potent mitogens for
occurrence of serious vascular events.
vascular smooth muscle cells and is found in macrophages and
vascular smooth muscle cells (Kayanoki 1997). Cilostazol used
for a period of 12 weeks has been shown to increase high density
Types of participants
lipoproteins (HDL) by 10% and decrease triglycerides by 15%
Eligible patients were those at high risk of stroke and other serious
(Elam 1998). These multiple potential mechanisms of action may
vascular events due to previous clinical manifestations of TIA or
explain the efficacy of cilostazol.
ischaemic stroke of arterial origin.
Types of interventions
Why it is important to do this review
Orally administered cilostazol at a minimum dose of 50 mg twice
Cilostazol has shown promise as an alternative to aspirin for Asian
a day compared with aspirin at a minimum dose of 81 mg once a
populations with ischaemic stroke (Shinohara 2008). The risk
day.
of primary intracranial haemorrhage (ICH) in people from these
regions is 30% compared to 10% in the developed world (Liu
2007). Cilostazol appears to prevent more ischaemic strokes and
Types of outcome measures
cause less ICH than aspirin when used for secondary prevention
of ischaemic stroke (Huang 2008).
Aspirin is the most widely prescribed agent for the prevention of
Primary outcomes
stroke in the world today (Rother 2008). Aspirin overall reduces
The main outcome measure of effectiveness was the composite
the risk of major vascular events by 13% (95% CI 6% to 19%)
outcome of stroke, myocardial infarction (MI), and vascular death.
Cilostazol versus aspirin for secondary prevention of vascular events after stroke of arterial origin (Review)
3
Copyright (c) 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Secondary outcomes
4. Contacted Otsuka Pharmaceutical Co Ltd, the
The secondary outcomes of effectiveness were the separate out-
manufacturer of cilostazol (May 2010).
comes of stroke (ischaemic or haemorrhagic, non-fatal or fatal),
5. Screened reference lists from relevant articles.
MI (non-fatal or fatal), vascular death, and death from all causes.
We searched for trials in all languages and arranged translation of
We classified deaths as due to ischaemic stroke, intracranial haem-
potentially relevant trial reports that were published in languages
orrhage (ICH), MI, other vascular causes (for example sudden
other than English.
cardiac death, cardiac failure, pulmonary embolism, extracranial
haemorrhage), non-vascular causes, and unknown causes (deaths
that could not be assigned to any of the foregoing categories).
Data collection and analysis
The main outcomes of safety were any ICH, extracranial haemor-
We reviewed all potentially eligible studies. We extracted data on
rhage, and gastrointestinal haemorrhage. Other outcomes measur-
types of patients enrolled; entry and exclusion criteria; method of
ing safety were headache, gastrointestinal intolerance, palpitation,
randomisation; process of treatment allocation concealment; the
dizziness, tachycardia, precipitation of angina, and cardiac failure.
original numbers of patients assigned to the treatment and aspirin
groups; number of patients lost to follow up in each treatment
group; degree of adherence to treatment; method and duration of
Search methods for identification of studies
follow up; whether patients and trial staff were blinded to treat-
See the 'Specialized Register' section in the Cochrane Stroke
ment allocation and, if so, what methods of blinding to treatment
Group module.
of patients, treating clinicians, and outcome assessors allocation
were employed; definitions of outcome events; and treatment-spe-
cific side effects. We analysed data on the basis of an intention-to-
Electronic searches
treat analysis.
We searched the Cochrane Stroke Group Trials Register, which
was last searched by the Managing Editor in September 2010, the
Cochrane Central Register of Controlled Trials (CENTRAL) (The
Selection of studies
Cochrane Library 2009, Issue 4), MEDLINE (1950 to May 2010)
We considered that all RCTs comparing cilostazol with aspirin in
(Appendix 1), and EMBASE (1980 to May 2010) (Appendix 2).
patients with a qualifying stroke or TIA were eligible for inclusion
in this review. These patients should have been on treatment for at
least one month and followed systematically for the development
Searching other resources
of vascular events.
In an effort to identify further published, unpublished, and ongo-
ing trials we undertook the following.
1. Handsearched journals and conference proceedings:
Data extraction and management
i) Proceedings of the International Stroke Conference
We extracted data from published reports or from the original re-
2010, 24 to 26 February 2010, USA, San Antonio Texas (July
searchers by using a pre-designed data collection form. One review
2010);
author (IN) independently extracted data and reviewed studies.
ii) Proceedings of the 18th European Stroke Conference
Another review author (AKK) reviewed the studies, verified data
2009, 26 to 29 May 2009, Sweden, Stockholm (May 2010);
entry and numbers to double check for errors. We resolved all dis-
iii) Proceedings of the International Stroke Conference
agreements by discussion and with a third review author as needed
2009, 18 to 20 February 2009, USA, San Diego, California
(BAK).
(May 2010);
iv) Proceedings of the 2nd International Conference on
Hypertension, Lipids, Diabetes and Stroke Prevention 2008, 6 to
Assessment of risk of bias in included studies
8 March 2008, Czech Republic, Prague (May 2010).
We used the 'Risk of bias' table, part of the 'Characteristics of in-
2. Searched the following international trials registers:
cluded studies' table, to delineate assessment of risk of bias in the
i) ClinicalTrials.gov (http://www.clinicaltrials.gov/)
included studies. This helped to address issues of bias including se-
(May 2010);
lection, allocation concealment, blinding, performance, attrition,
ii) Current Controlled Trials (www.controlled-trials.com)
detection, incomplete outcome data processing, and selective re-
(May 2010);
porting. The content expert (AKK) reviewed the table. We scored
iii) Stroke Trials Registry (www.strokecenter.org/trials/)
each entry as 'low risk', 'high risk' or 'unclear risk' of bias. For
(May 2010).
each entry, we provided text detailing the description of design,
3. Contacted authors of identified trials and other researchers
conduct, or observation leading to the judgement. We incorpo-
in the field (April 2010).
rated bias assessment in the analyses by reporting an estimated
Cilostazol versus aspirin for secondary prevention of vascular events after stroke of arterial origin (Review)
4
Copyright (c) 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

intervention effect based on all available studies, with a narrative
Sensitivity analysis
discussion on the risk of bias in individual domains.
We performed sensitivity analysis by removing studies that ap-
peared to dominate the data set in terms of the primary outcome
and analysed the results without them.
Measures of treatment effect
We determined treatment effect primarily by calculating effect es-
timators for signal trials, which were then combined by means
of the Mantel-Haenszel (MH) method. The treatment effect was
measured in terms of risk ratio (RR). The absolute risk reduc-
R E S U L T S
tion (ARR) and number needed to treat (NNT) were also cal-
culated. For this purpose we used the calculator available on the
Cochrane Stroke Group website (http://www.dcn.ed.ac.uk/csrg/
NNT2.asp).
Description of studies
See: Characteristics of included studies; Characteristics of excluded
Unit of analysis issues
studies.
We did not include studies with crossover design or cluster ran-
domisation in this analysis.
Results of the search
We retrieved a total of 15 hits by the search strategies employed.
Dealing with missing data
After screening we considered two trials relevant for inclusion, and
We performed an intention-to-treat analysis; we included all those
we excluded the remaining 13 that did not meet the inclusion
participants that were 'lost' in the appropriate assigned arm.
criteria.
Assessment of heterogeneity
Included studies
We used the I2 statistic to test for heterogeneity between trials.
See: Characteristics of included studies
We identified two completed trials that fulfilled our eligibility
criteria and these have been included in this review (CASISP 2008;
Assessment of reporting biases
CSPS II 2010). The trials included a total of 3477 participants,
We constructed a funnel plot and looked for asymmetry to assess
of which 2757 participated in CSPS II 2010.
reporting bias.
Both studies were RCTs conducted in Asia: CASISP 2008 in China
and CSPS II 2010 in Japan. The patients on average were 62 years
of age and approximately two-thirds were men.
Data synthesis
Cilostazol was compared with aspirin in 3477 patients with a his-
tory of ischaemic stroke of arterial origin within the previous one
We used a fixed-effect model to perform meta-analysis. Since there
to 6.5 months, of which 1697 patients belonged to the cilosta-
was no extreme heterogeneity within trials, we were able to perform
zol arm and 1694 patients belonged to the aspirin arm in the in-
meta-analysis.
tention-to-treat analysis. All medication was given orally, though
dosage differed for each trial. Cilostazol was given at 100 mg twice
a day and aspirin at 81 mg once a day in the CSPS II 2010 trial,
Subgroup analysis and investigation of heterogeneity
and at 100 mg twice a day and 100 mg once a day respectively in
Pre-specified subgroups included investigating any differences in
the CASISP 2008 trial.
the primary outcome in Caucasians versus Asians. For analysis of
The duration of follow up varied from one year (CASISP 2008)
the differences of effect between subgroups, we planned to com-
to five years (CSPS II 2010).
pare confidence intervals between subgroups and look for over-
Both trials recorded stroke (of all types) as a primary outcome,
lap. Since there were no studies from Caucasian populations, this
while CASISP 2008 also included MI and vascular death as major
could not be carried out.
outcome events.
We determined statistical significance with the Chi2 test for het-
A summary of the details of each trial is described in the
erogeneity.
Characteristics of included studies table.
Cilostazol versus aspirin for secondary prevention of vascular events after stroke of arterial origin (Review)
5
Copyright (c) 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Excluded studies
Other potential sources of bias
See: Characteristics of excluded studies
No other potential sources of bias were noted.
We excluded 13 studies as they did not meet the eligibility cri-
In the CSPS II 2010 trial the sponsor, Otsuka Pharmaceutical Ltd,
teria for this review. Of these, four studies compared cilostazol
had a role in the study design, data collection, and data analysis
with placebo (Ahn 2001; CSPS 2000; Mitsuhashi 2004; TOSS
but was not involved in the data interpretation or writing of the
2005) and six other studies used a confounded comparison of
report.
interest (CATHARSIS 2009; ECLIPse 2009; Kohriyama 1994;
Kikuchi 1985; Terayama 2008; TOSS II 2009). Moreover, eight
of the excluded studies did not examine a clinical vascular event
Effects of interventions
as the primary outcome (Ahn 2001; DAPC 2006; ECLIPse 2009;
Kikuchi 1985; Kohriyama 1994; TOSS 2005; TOSS II 2009;
Of the 3477 randomised participants with a history of previous
Yasunaga 1985). In one excluded study the patient population did
stroke in the past one to 6.5 months, intention-to-treat analysis
not present with ischaemic stroke or TIA (Suzuki 2010).
included 1697 patients in the cilostazol group and 1694 patients
in the aspirin group.
The results given below are a culmination of those presented in
the two trials (CASISP 2008; CSPS II 2010). They address the
Risk of bias in included studies
composite outcome of vascular events (stroke, MI, or vascular
See: Characteristics of included studies
death) and each of these separately as specific outcome events.
Methodological quality of the two included studies (CASISP
2008; CSPS II 2010) was generally high in terms of treatment al-
location and blinding. In these trials both the cilostazol and aspirin
Stroke, myocardial infarction (MI), or vascular death
arms were well balanced for major prognostic factors at baseline
during follow up
(such as age, history of stroke, and use of diagnostic tools).
Data indicated that cilostazol was associated with a significantly
lower risk of composite outcome of vascular events (stroke, MI, or
vascular death): cilostazol 115/1697 (6.77%) versus aspirin 159/
Allocation
1694 (9.39%), RR 0.72 (95% CI 0.57 to 0.91). This corresponds
Treatment allocation was randomised in both studies, and the
to the avoidance of about 26 vascular events (95% CI 9 to 40)
methods of randomisation and allocation concealment were
per 1000 patients treated for an average of three years when com-
stated. In both trials (CASISP 2008; CSPS II 2010) double-
pared to aspirin. It meant that for each vascular event prevented
dummy concealment was performed and all pills, placebo and
by cilostazol 39 patients (95% CI 26 to 117) needed to be treated
other made to look alike.
for an average of three years (Analysis 1.1).
Blinding
Stroke (all types) during follow up
Blinding was adequately addressed in each trial, with reference
The two trials collectively showed that cilostazol significantly de-
to participant, caregiver, investigator, and outcome assessor. The
creased stroke of all types compared to aspirin, and therefore it
CASISP study (CASISP 2008) stated that radiologists assigned to
is an even more effective intervention for the secondary preven-
report diagnoses for the enrolled patients were blinded to clinical
tion of stroke: cilostazol 94/1697 (5.54%) versus aspirin 141/1694
data. The CSPS II trial (CSPS II 2010) ensured blinding by sealing
(8.32%), RR 0.67 (95% CI 0.52 to 0.86). This corresponds to
assignment lists immediately after assignment until the designated
the avoidance of about 27 strokes (95% CI 12 to 41) per 1000
time of unmasking.
patients treated for an average of three years. For each stroke to
be prevented 37 patients (95% CI 25 to 87) needed to be treated
with cilostazol for an average of thee years (Analysis 1.2).
Incomplete outcome data
Both trials addressed incomplete outcome data, reporting on par-
ticipants that were lost to follow up for different reasons.
Ischaemic stroke during follow up
Both trials provided data on stroke subtypes. With respect to
reduction of ischaemic stroke (fatal and non-fatal) there was a
Selective reporting
non-significant trend in favour of cilostazol: cilostazol 83/1697
All patients that were selected were accounted for and all the data
(4.89%) versus aspirin 103/1694 (6.08%), RR 0.80 (95% CI 0.61
recorded were presented in both studies.
to 1.07) (Analysis 1.3).
Cilostazol versus aspirin for secondary prevention of vascular events after stroke of arterial origin (Review)
6
Copyright (c) 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Haemorrhagic stroke (ICH) during follow up
Other outcome measures of safety during follow up
Data pooled from both trials identified a significant trend towards
Adverse effects of the interventional treatments were addressed in
a reduction of haemorrhagic stroke among patients treated with
both studies. There was statistically significant evidence to indicate
cilostazol: 9/1697 (0.53%) versus aspirin 34/1694 (2.01%), RR
that more adverse effects were experienced by participants enrolled
0.26 (95% CI 0.13 to 0.55) (Analysis 1.4).
in the cilostazol arm: cilostazol 977/11,879 (8.22%) versus aspirin
587/11,858 (4.95%), RR 1.66 (95% CI 1.51 to 1.83) (Analysis
Myocardial infarction (MI) during follow up
1.10).
Cilostazol was significantly more likely to cause each of the fol-
Available data from both studies provided inconclusive evidence
lowing adverse effects.
of a reduction in MI among patients treated with cilostazol: 15/
1.10.1. Headaches: cilostazol events 362/1697 (21.3%) versus as-
1697 (0.88%) versus aspirin 13/1694 (0.77%), RR 1.15 (95% CI
pirin 236/1694 (13.9%), RR 1.53 (95% CI 1.32 to 1.78).
0.55 to 2.41) (Analysis 1.5).
1.10.2. Gastrointestinal intolerance: cilostazol 164/1697 (9.66%)
versus aspirin 85/1694 (5.02%), RR 1.93 (95% CI 1.50 to 2.48).
Vascular death during follow up
1.10.3. Palpitations: cilostazol 161/1697 (9.49%) versus aspirin
106/1694 (6.26%), RR 1.52 (95% CI 1.20 to 1.92).
Data from the CCSPS II 2010 study did not indicate a significant
1.10.4. Dizziness: cilostazol 161/1697 (9.49%) versus aspirin 114/
reduction in vascular death during follow up: cilostazol 6/1697
1694 (6.73%), RR 1.41 (95% CI 1.12 to 1.77).
(0.35%) versus aspirin 5/1694 (0.30%), RR 1.20 (95% CI 0.37
1.10.5. Tachycardia: cilostazol 111/1697 (6.54%) versus aspirin
to 3.92). There were no data reported on this outcome event in
28/1694 (1.65%), RR 3.96 (95% CI 2.63 to 5.96).
the CASISP study (Analysis 1.6).
With respect to cardiac adverse effects, results were inconclusive.
Angina was reported in both arms: cilostazol 10/1697 (0.59%)
Death from any cause during follow up
versus aspirin 11/1694 (0.65%), RR 0.91 (95% CI 0.39 to 2.13);
along with cardiac failure: cilostazol 8/1697 (0.47%) versus aspirin
Both trials reported death during the follow-up periods. How-
7/1694 (0.41%), RR 1.14 (95% CI 0.41 to 3.14).
ever, these results did not point towards a difference in mortality:
cilostazol 16/1697 (0.94%) versus aspirin 18/1694 (1.06%), RR
0.89 (95% CI 0.45 to 1.74) (Analysis 1.7).
Sensitivity analysis
Extracranial haemorrhage during follow up
In both trials, patients that were given cilostazol had significantly
We performed sensitivity analysis by excluding the trial that ap-
fewer extracranial haemorrhagic events than those on aspirin:
peared to dominate the data set (CSPS II 2010). This did not
cilostazol 155/1697 (9.10%) versus aspirin 209/1694 (12.3%),
definitively change treatment effect but did render it imprecise.
RR 0.74 (95% CI 0.61 to 0.90) (Analysis 1.8).
Outcome events were reduced in patients given cilostazol com-
pared with aspirin but results were no longer statistically signif-
icant: cilostazol 13/360 (3.61%) versus aspirin 24/359 (6.69%),
Gastrointestinal (GI) haemorrhage during follow up
RR 0.54 (95% CI 0.28 to 1.04) (Analysis 2.1).
Patients in both arms of treatment reported GI haemorrhage
We did not note any statistically significant heterogeneity between
events: cilostazol 17/1697 (1.00%) versus aspirin 30/1694
the two included trials except in terms of palpitations as an out-
(1.77%), RR 0.57 (95% CI 0.31 to 1.02) (Analysis 1.9). The
come measure of safety, where the larger study (CSPS II 2010)
results were statistically inconclusive. In the CASISP 2008 study
dominated and changed the outcome of safety in favour of the
more people reported GI bleeding versus fecal occult blood on
aspirin arm.
treatment with cilostazol than for those on aspirin, where only one
We detected no evidence of reporting bias after analysing a funnel
event of upper GI bleeding was reported.
plot constructed for this purpose (Figure 1).
Cilostazol versus aspirin for secondary prevention of vascular events after stroke of arterial origin (Review)
7
Copyright (c) 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Figure 1. Funnel plot of comparison: 1 Cilostazol versus aspirin in patients with ischaemic stroke or TIA,
outcome: 1.1 Stroke, MI or vascular death during follow-up.
Combining the main outcome of serious vascular events into a
composite outcome of stroke, MI and vascular death not only
increases the statistical power and reliability of the analysis, but
also provides a more cohesive measure of effectiveness. Analysis
D I S C U S S I O N
revealed that, compared to aspirin, cilostazol is significantly more
effective in preventing vascular events (stroke, MI and vascular
Summary of main results
death) and stroke of all types, in patients with a history of stroke
We undertook this review to determine if, compared to aspirin,
or TIA. Cilostazol showed an overall reduction in the composite
cilostazol is a better alternative for secondary prevention of vas-
outcome of 28%, ranging between 9% to 43% (95% CI), which
cular events in patients with a previous ischaemic stroke or TIA.
corresponds to comparative avoidance of 26 events (ranging be-
We analysed the available data from two randomised trials directly
tween nine to as high as 40 events) per 1000 patients treated for
comparing cilostazol to aspirin. The larger trial (CSPS II 2010)
an average of three years. Thus for each vascular event to be pre-
contributed about 80% of the patients randomised. It studied pa-
vented, 39 patients needed to be treated with cilostazol for an av-
tients at high vascular risk (those with previous TIA or ischaemic
erage of three years compared with aspirin, with a wider range of
stroke of arterial origin) and primarily evaluated the outcome of
between 26 and 117 patients per event (95% CI).
stroke of all types, with ischaemic stroke, death from all causes and
In patients with a previous history of stroke or TIA, the propor-
a composite outcome as secondary endpoints. It also examined
tional benefit of cilostazol over aspirin on the outcome of strokes
safety endpoints in terms of all significant haemorrhagic events.
of all type was very similar to that of the composite outcome of
The smaller study, contributing about 20% of patients (CASISP
vascular events. Cilostazol demonstrated a reduction of about 33%
2008), assessed the composite outcome of vascular events (stroke,
(14% to 48%) compared with aspirin, corresponding to compar-
MI, and vascular death) and provided adequate data on each sub-
ative avoidance of 27 events (95% CI 12 to 41) per 1000 patients
type of vascular events, along with outcomes of safety.
treated for an average of three years. Thus for each stroke event to
Cilostazol versus aspirin for secondary prevention of vascular events after stroke of arterial origin (Review)
8
Copyright (c) 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Download
Cilostazol vs aspirin for secondary prevention of vascular events

 

 

Your download will begin in a moment.
If it doesn't, click here to try again.

Share Cilostazol vs aspirin for secondary prevention of vascular events to:

Insert your wordpress URL:

example:

http://myblog.wordpress.com/
or
http://myblog.com/

Share Cilostazol vs aspirin for secondary prevention of vascular events as:

From:

To:

Share Cilostazol vs aspirin for secondary prevention of vascular events.

Enter two words as shown below. If you cannot read the words, click the refresh icon.

loading

Share Cilostazol vs aspirin for secondary prevention of vascular events as:

Copy html code above and paste to your web page.

loading