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Dipyridamole for preventing stroke and other vascular events
in patients with vascular disease (Review)
De Schryver ELLM, Algra A, van Gijn J
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2010, Issue 9
http://www.thecochranelibrary.com
Dipyridamole for preventing stroke and other vascular events in patients with vascular disease (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1 ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6 AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7 ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Dipyridamole vs control (in the presence or absence of other identical antiplatelet drugs):
dipyridamole dose, Outcome 1 vascular death. . . . . . . . . . . . . . . . . . . . . . . 42
Analysis 1.2. Comparison 1 Dipyridamole vs control (in the presence or absence of other identical antiplatelet drugs):
dipyridamole dose, Outcome 2 vascular event. . . . . . . . . . . . . . . . . . . . . . . 44
Analysis 2.1. Comparison 2 Dipyridamole plus aspirin versus placebo, Outcome 1 vascular death. . . . . . . . 46 Analysis 2.2. Comparison 2 Dipyridamole plus aspirin versus placebo, Outcome 2 vascular event. . . . . . . . 47
Analysis 3.1. Comparison 3 Dipyridamole versus other antiplatelet drug, Outcome 1 vascular death. . . . . . . 48
Analysis 3.2. Comparison 3 Dipyridamole versus other antiplatelet drug, Outcome 2 vascular event. . . . . . . 49
Analysis 4.1. Comparison 4 Dipyridamole vs control (in the presence or absence of other identical antiplatelet drugs):
presenting disease, Outcome 1 vascular death. . . . . . . . . . . . . . . . . . . . . . . . 50
Analysis 4.2. Comparison 4 Dipyridamole vs control (in the presence or absence of other identical antiplatelet drugs):
presenting disease, Outcome 2 vascular event. . . . . . . . . . . . . . . . . . . . . . . . 52
Analysis 5.1. Comparison 5 Dipyridamole plus aspirin versus aspirin, Outcome 1 vascular death. . . . . . . . 54
Analysis 5.2. Comparison 5 Dipyridamole plus aspirin versus aspirin, Outcome 2 vascular event. . . . . . . . 55
Analysis 6.1. Comparison 6 Dipyridamole versus control: bleeding complications, Outcome 1 major extracranial bleeding
complication plus fatal extracranial bleeding complication. . . . . . . . . . . . . . . . . . . 56
Analysis 7.1. Comparison 7 Dipyridamole versus control (dipyridamole formulation), Outcome 1 vascular death. . 58
Analysis 7.2. Comparison 7 Dipyridamole versus control (dipyridamole formulation), Outcome 2 vascular event. . 5960 APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63 WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
64DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
64SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
64INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iDipyridamole for preventing stroke and other vascular events in patients with vascular disease (Review)
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[Intervention Review]
Dipyridamole for preventing stroke and other vascular eventsin patients with vascular disease
Els LLM De Schryver2, Ale Algra 1, Jan van Gijn3
1 Julius Centre for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands. 2Department of
Neurology, Rijnland Ziekenhuis Leiderdorp, Leiderdorp, Netherlands. 3Department of Neurology, University Medical Center Utrecht,
Utrecht, Netherlands
Contact address: Ale Algra, Julius Centre for Health Sciences and Primary Care, University Medical Center Utrecht, PO Box 85500,
Utrecht, 3508 GA, Netherlands. [email protected].
Editorial group: Cochrane Stroke Group.
Publication status and date: Edited (no change to conclusions), comment added to review, published in Issue 9, 2010.
Review content assessed as up-to-date: 15 October 2006.
Citation: De Schryver ELLM, Algra A, vanGijnJ. Dipyridamolefor preventing strokeand other vascular eventsin patients with vascular
disease. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD001820. DOI: 10.1002/14651858.CD001820.pub3.
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
Patients with limited cerebral ischaemia of arterial origin are at risk of serious vascular events (4% to 11% annually). Aspirin reduces
that risk by 13%. In one trial, adding dipyridamole to aspirin was associated with a 22% risk reduction compared with aspirin alone.However, a systematic review of all trials of antiplatelet agents by the Antithrombotic Trialists’ Collaboration showed that, in high-risk
patients, there was virtually no difference between the aspirin-dipyridamole combination and aspirin alone.
Objectives
To assess the efficacy and safety of dipyridamole versus control in the secondary prevention of vascular events in patients with vascular
disease.
Search methods
We searched the Cochrane Stroke Group trials register (searched June 2006), the Cochrane Central Register of Controlled Trials
(CENTRAL) (The Cochrane Library Issue 2, 2006), MEDLINE (1966 to May 2006) and EMBASE (1980 to May 2006). We contactedauthors and pharmaceutical companies in the search for further data on published and unpublished studies.
Selection criteria
We selected randomised long-term secondary prevention trials with concealed treatment allocation, treatment for more than one month,
starting within six months after presentation of an arterial vascular disease. Treatment consisted of dipyridamole with or without other
antiplatelet drugs compared with no drug or an antiplatelet drug other than dipyridamole.
Data collection and analysis
Two review authors independently selected trials for inclusion, assessed trial quality and extracted data. Data were analysed according
to the intention-to-treat principle.
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Main results
Twenty-nine trials were included, with 23019 participants, among whom 1503 vascular deaths and 3438 fatal and non-fatal vascular
events occurred during follow up. Compared with control, dipyridamole had no clear effect on vascular death (relative risk (RR) 0.99,
95% confidence interval (CI) 0.87 to 1.12). This result was not influenced by the dose of dipyridamole or type of presenting vascular
disease. Compared with control, dipyridamole appeared to reduce the risk of vascular events (RR 0.88, 95% CI 0.81 to 0.95). This
effect was only statistically significant in patients presenting with cerebral ischaemia.
Authors’ conclusions
For patients who presented with arterial vascular disease, there was no evidence that dipyridamole, in the presence or absence of another
antiplatelet drug reduced the risk of vascular death, though it reduces the risk of further vascular events. This benefit was found only
in patients presenting after cerebral ischaemia. There was no evidence that dipyridamole alone was more efficacious than aspirin.
P L A I N L A N G U A G E S U M M A R Y
Dipyridamole for preventing stroke and other vascular events in patients with vascular disease
Patients with symptoms of arterial disease have a high risk of getting a (possibly fatal) stroke or heart attack (myocardial infarction). Antiplatelet therapy with drugs like aspirin prevents blood clotting and reduces the risk of strokes, heart attacks, and death from
vascular disease. Dipyridamole, another antiplatelet drug, given on its own or together with aspirin might reduce the risk even further.
This review included 29 studies involving 23019 participants. When we compared the effects of dipyridamole (alone or together with
aspirin) with aspirin alone there was no evidence of an effect on death from vascular causes. When we compared the effects on the
occurrence of vascular events (strokes, heart attacks, and deaths from vascular diseases) the combination of aspirin and dipyridamole
had an advantage over aspirin alone. This result holds particularly true for patients with ischaemic stroke.
B A C K G R O U N DPatients with transient ischaemic attacks (TIA) and minor is-
chaemic strokes are at risk of serious vascular events (death from
all vascular causes, non-fatal stroke, or non-fatal myocardial in-
farction). A systematic review of all trials of antiplatelet agents by
the Antithrombotic Trialists’ Collaboration (ATT) provided very
strong evidence that, in patients with a history of a vascular dis-
ease, antiplatelet drugs reduce the risk of serious vascular events by
about a quarter ( ATT 2002). Aspirin was the most widely tested
antiplatelet drug. By comparison with the very large number of
trials of aspirin, there were relatively few trials which assessed the
efficacy of dipyridamole. A number of trials included in the re-
view tested the hypothesis that the combination of dipyridamole
with aspirin might be more effective than aspirin alone, but it ap-peared that, in high risk patients, there was virtually no difference
between the aspirin-dipyridamole combination and aspirin alone
( ATT 2002). We therefore sought to examine the trial data with a
somewhat different approach to assess the effects of dipyridamole
in greater detail.
The most appropriate way to make a more detailed assessment has
been the subject of some debate. Is it better to assess the efficacy of
medication for secondary prevention of vascular complications by
looking at subgroups of high risk patients, or at all these patients
together ( Algra 1999a )? A similar discussion applies to the most
appropriate combination of vascular outcome events, that is, vas-
cular death, non-fatal myocardial infarction and non-fatal stroke.
Patients who enrolled in clinical trials after a TIA or non-disabling
ischaemic stroke have an annual risk of important vascular events
(death from all vascular causes, non-fatal stroke, or non-fatal my-
ocardial infarction) of between 4% and 11% ( Algra 1996; APT I
1994). The corresponding estimate for population-based studies
is 9% per year ( Warlow 1992). The Antithrombotic Trialists’ Col-
laboration ( ATT 2002) showed an absolute risk reduction of 22to 36 per 1000 high risk patients treated with antiplatelet therapy
for two years; this number was 36 per 1000 patients after cerebral
ischaemia. Aspirin alone, in a daily dose of 30 mg or more, offers
only modest protection after cerebral ischaemia: it reduces the in-
cidence of major vascular events by 13% in such patients ( Algra
1996; Algra 1999b). In direct comparisons of different doses of
aspirin no differences were found in the efficacy between doses
of 300 mg and 1200 mg (UK-TIA Trial 1991) nor between 30
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mg and 283 mg (Dutch TIA Trial 1991). The efficacy of dipyri-
damole, an alternative antiplatelet agent, was assessed in the Eu-
ropean Stroke Prevention Study 2 (ESPS-2 1997a ), a randomised,
placebo-controlled, double-blind trial, with four treatment arms:
aspirin (50 mg daily), dipyridamole (400 mg daily), both drugs
or neither. The combination treatment showed a relative risk re-duction of 22% of major vascular events over aspirin. However,
a meta-analysis of the four previous studies that compared the
efficacy of the combination therapy with aspirin alone ( ACCSG
1985; AICLA 1983a ; Kaye 1990; Toulouse 1982a ), showed a rel-
ative risk of 0.97 ( Algra 1999a ; APT I 1994). In 2006 the results
of ESPRIT 2006 were published and showed a hazard ratio (HR)
of 0.80 in favour of the combination therapy of dipyridamole 400
mg daily combined with aspirin 30 mg to 325 mg daily compared
with aspirin alone.
O B J E C T I V E S
(1) To assess the efficacy of dipyridamole versus control in the
secondary prevention of vascular events in patients with vascular
disease in the presence and absence of other antiplatelet drugs.
(2) To assess the safety of dipyridamole versus control in the sec-
ondary prevention of vascular events in patients with vascular dis-
ease in the presence and absence of other antiplatelet drugs.
M E T H O D S
Criteria for considering studies for this review
Types of studies
Randomised long-term secondary prevention trials with concealed
treatment allocation, for more than one month, started within six
months after presentation of a vascular disease.
Types of participants
Patients who presented with an arterial vascular disease: coronary
artery disease, myocardial infarction, angina pectoris, retinopathy,
nephropathy, peripheral arterial disease, stroke, TIA, amaurosis
fugax. Patients with presumed embolism from the heart were ex-
cluded.
Types of interventions
• Dipyridamole in any dose in the presence or absence of
other antiplatelet drugs
• No drug or an antiplatelet drug(s) other than dipyridamole
(control group)
Types of outcome measures
Efficacy outcome measures
(1) The composite event ’vascular death, non-fatal stroke, non-
fatal myocardial infarction or major bleeding complication’(2) Vascular death, non-fatal stroke or non-fatal myocardial in-
farction
(3) Death (all causes)
(4) Vascular death
(5) Ischaemic stroke or intracranial haemorrhage
(6) Myocardial infarction
(7) Death or dependent at end of follow up
Safety outcome measures
(8) Major bleeding complication; that is, any fatal or non-fatal
intracranial or major extracranial haemorrhage
(9) Fatal bleed (intra or extracranial)(10) Intracranial bleed
(11) Major extracranial bleed, according to the definition of the
original investigator
Search methods for identification of studies
See: ’Specialized register’ section in Cochrane Stroke Group
We searched the Cochrane Stroke Group trials register, which was
last searched by the Review Group Co-ordinator in June 2006.
To access the trials registers of the Cochrane Heart Group and
the Cochrane Peripheral Vascular Diseases Group we searched the
Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2006). In addition, we searched MED-
LINE (1966 to May 2006) and EMBASE (1980 to May 2006)
( Appendix 1).
For a previous version of this review, carried out in April 2002,
we searched the trials register of the Antithrombotic Trialists’ Col-
laboration and contacted the following Dutch manufacturers of
dipyridamole in the search for other published and unpublished
studies: Boehringer Ingelheim, Centrafarm, Dumex, Genfarma,
ICN Pharmaceuticals, Katwijk Farma, Multipharma, Pharbita,
Pharmachemie, and Stephar.
Data collection and analysisTwo review authors (EDS and AA) independently selected those
trials which met the inclusion criteria and extracted details of
randomisation methods, blinding of treatments and assessments,
whether intention-to-treat analysis was possible from the pub-
lished data, whether treatment groups were comparable with re-
gard to major prognostic factors, the number of patients who were
excluded or lost to follow up, definition of outcome events, and
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entry and exclusion criteria. The methodological quality of each
trial was assessed by the two review authors on the basis of these
extracted data. In addition, dose and type of antiplatelet treat-
ments, duration of follow up and the numbers of defined outcome
events were also recorded. Unpublished data, collected by the An-
tithrombotic Trialists’ Collaboration, were used. The remaining data were extracted independently by the same two review authors
and cross checked.
The following subgroup analyses were planned in advance: pre-
senting disease, age (less than or equal to 65 year versus 65 years
plus), sex, history of ischaemicheart disease, dose of dipyridamole,
methodological quality and type of cerebral ischaemia (large vessel
disease versus small vessel disease). Separate analyses on the use
of dipyridamole in the presence and absence of other antiplatelet
drugs were carried out. The data were analysed according to the
intention-to-treat principle. If outcome data on some randomised
patients were lacking, both a best and worst case scenario were
planned: the bestcase scenario (with regardsto treatment) assumed
that none of the patients excluded from the reference group hadthe outcome of interest whilst all those excluded from the refer-
ence group did, and vice versa for the worst case analysis. Relative
risk reductions were calculated by means of the Cochrane Review
Manager software (RevMan 4.2).The results are presented as rela-
tive risk (RR) ratios with a 95% confidence interval (CI), analysed
with a fixed-effect model. Heterogeneity was tested with the I-
squared (I2) heterogeneity statistic. We assessed the presence of sta-
tistical differences between the pre-specified subgroups by means
of the methods for subgroup analysis as described in the Cochrane
Handbook for Systematic Reviews of Interventions (Deeks 2005).
R E S U L T S
Description of studies
See: Characteristics of included studies.
Twenty-nine randomised controlled trials (RCTs) were included,
which studied 42 comparisonsof treatments, with a total of 23,019
participants, among whom 1503 vascular deaths and 3438 vas-
cular events (fatal and non-fatal) occurred during follow up. The
mean follow-up duration of the trials ranged from one month
to seven years. Data from two trials (Caneschi 1985a /Caneschi
1985b; Igloe 1970) were not published and not used in the meta-
analysis of the second cycle of the Antiplatelet Trialists’ Collabora-
tion ( ATT 2002). Sixteen trials were performed in Europe, seven
in North America, two in both Europe and North America, one
in Australia, one in the Middle East and two in Asia. The mean
age of the patients ranged from 47 to 67 years. In the included
studies 42% to 100% of the patients were male. In 13 studies,
the patients presented with a cardiac disease, in nine with (tran-
sient) cerebral ischaemia, in four with arterial peripheral vascular
diseases, in two studies patients on haemodialysis were included
and in one study patients with diabetic retinopathy were included.
Daily dipyridamole doses varied between 150 mg and 800 mg:
four trials used 150 mg per day, 16 trials 200 mg to 300 mg per
day and nine trials at least 400 mg per day of which one trial partly
used 800 mg per day. Three trials used a modified-release (retard)preparation of dipyridamole. Other antiplatelet drugs were aspirin
and sulfinpyrazone.
Not all trials had vascular events as a primary outcome. However,
most of these trials published additional data about vascular death
or vascular events. Primary published data were used, but miss-
ing data were completed from the publication of the second cycle
of the Antiplatelet Trialists’ Collaboration, which published addi-
tional data not available in the original publications. Therefore,
the authors of the source publications were not contacted again to
obtain missing data. The mean follow-up time ranged from one
month to 60 months. Information about the description of each
included study can be found in Characteristics of included studies.
Risk of bias in included studies
All 29 trials were stated to be randomised, but the method of
concealment was unclear in 18 trials. In seven trials baseline data
were not sufficiently described to conclude whether there was good
baseline comparability between treatment groups. All trials, except
five, were stated to be double-blind studies. For 15 trials we could
not determine whether intention-to-treat analysis was performed
or might be reconstructed from the published data. In eight trials
the number of lost or excluded patients was not described. Sev-
enteen studies did not describe exactly the method of monitoring
compliance and in 12 trials nothing was reported on the compli-
ance of the patients. All trials defined criteria for the inclusion of
patients; eight trials did not contain any information about exclu-
sion criteria.
Information about the methodological quality of each included
study can be found in Characteristics of included studies.
Effects of interventions
The 29 included trials mostly did not separately report on the
11 types of outcome measures; data on outcome measures were
available or could be extracted for:
(1) the composite event ’vascular death, non-fatal stroke, non-
fatal myocardial infarction or major bleeding complication’ in two
trials;
(2) vascular death, non-fatal stroke or non-fatal myocardial infarc-
tion in two trials;
(3) death (all causes) in 19 trials;
(4) vascular death in 15 trials;
(5) ischaemic stroke or intracranial haemorrhage in four trials;
(6) myocardial infarction in 14 trials;
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(7) death or dependent at end of follow up in none of the trials;
(8) major bleeding complication, that is any fatal or non-fatal
intracranial or major extracranial haemorrhage, in six trials;
(9) fatal bleed (intra or extracranial) in two trials;
(10) intracranial bleed in five trials;
(11) major extracranial bleed, according to the definition of theoriginal investigator, in five trials.
In some trials the number of patients with a stroke during follow
up was described; however, no furtherinformation could be found
on whether this number included haemorrhagic strokes. Also it
was often unclear whether the fatal strokes were calculated as sep-
arate outcome events or were included in this number of reported
strokes.
The outcome data extracted from the original publications did
not always match exactly the data from the Antithrombotic Tri-
alists’ Collaboration, which used individual patient data at the
end of scheduled follow up, obtained from the trial investigators.
Since most of our defined outcome events could not be extracted
from the original publications, we pragmatically decided to anal-yse two outcome measures: vascular death and vascular events.
The definitionof vascular events, according to the Antithrombotic
Trialists’ Collaboration, is ’vascular death or any death from un-
known cause, non-fatal stroke or non-fatal myocardial infarction’.
The safety measure was, according the Antithrombotic Trialists’
Collaboration, the combination of all major extracranial bleeding
complications plus all fatal extracranial bleeds. We used the data
from the Antithrombotic Trialists’ Collaboration for this review
and checked the observed inconsistencies.
For the analyses we assumed that the published outcome events
could be used in an intention-to-treat model in all trials and that
no patient was lost if no lost to follow up was reported. Since
not many patients were described as lost, no worst or best casescenario wasperformed. A fixed-effect model wasused. Some trials
were split up (extension a, b, etc) because they contained different
treatment comparisons. However, no patient has been included
twice in the same analysis. No significant heterogeneity between
the studies was found.
Comparisons 1, 4, 6: Dipyridamole versus control
Compared with control, there was no evidence that, in patients
who presented with an arterial vascular disease, dipyridamole, in
the presence or absence of other antiplatelet drugs, had any effect
on vascular death (RR 0.99, 95% CI 0.87 to 1.12) in 21 trials
(23 comparisons). This result was not influenced by the dose of
dipyridamole (P value for differences between subgroups = 0.86)
or by the type of presenting vascular disease (P = 0.85). However,
there was a reduction in the risk of vascular events (RR 0.88, 95%
CI 0.81 to 0.95). This result reached statistical significance in
patients presenting after cerebral ischaemia, who were randomly
allocated to receive 400 mg dipyridamole at least. Again, there
were no statistical differences according to dose of dipyridamole (P
= 0.20) or qualifying disease (P = 0.78). There were no differences
in major extracranial and fatal extracranial bleeding complications
in patients allocated to dipyridamole, compared with controls (RR
1.01, 95% CI 0.73 to 1.38).
Comparison 2: Dipyridamole plus aspirin versus
placebo
Combination treatment of dipyridamole and aspirin compared
with placebo had a RR of 0.89 (95% CI 0.79 to 1.01) for vascular
death and a RR of 0.74 (95% CI 0.68 to 0.80) for vascular events
in 15 trials.
Comparison 3: Dipyridamole versus other
antiplatelet drug
There was no evidence of a difference between dipyridamole and
aspirin in the avoidance of vascular death (RR 1.08, 95% CI 0.85
to 1.37) or the prevention of vascular events (RR 1.02, 95% CI0.88 to 1.18).These data originated from three trials, where ESPS-
2 contributed 98% of the information. One small trial compared
the combination of dipyridamole with aspirin versus sulfinpyra-
zone.
Comparison 5: Dipyridamole plus aspirin versus
aspirin
There was no evidence of an effect of the combination of dipyri-
damole plus aspirin compared with aspirin on vascular death; the
RR was 0.98 (95% CI 0.84 to 1.14). Based on data from 13 trials,
there was a significant reduction in vascular events; the RR was
0.87 (95% CI 0.79 to 0.96). The combination treatment had a RR of 1.08 (95% CI 0.75 to 1.54) for bleeding complications (all
major extracranial plus fatal extracranial bleeding complications).
D I S C U S S I O N
Inclusion of trials
The aim of this meta-analysis was to include all randomised long-
term secondary prevention trials on patients presenting with an
arterial vascular disease (excluding presumed embolism from the
heart). We included trials of patients presenting with a cardiac
disease, but excluded those that accepted patients after a major
intervention, for example coronary bypass grafting, because of
procedure-related side effects. In the trials of patients with cere-
bral ischaemia, it was not always clear whether a cardiac source
of embolism was used as an exclusion criterion (Caneschi 1985a /
Caneschi 1985b; ESPS-1 1990, Stoke 1969; Toulouse 1982a /
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Toulouse 1982b). Trials with haemodialysis patients were in-
cluded, since the cause of nephropathy in a large group of patients
is of atherosclerotic origin and all haemodialysis patients are prone
to develop atherosclerosis.
Quality of the trials
All included trials were randomised and controlled. Not all trials
published information about the method of concealment, moni-
toring of treatments and compliance, number of patients lost to
follow up and whether intention-to-treat analysis was possible.
However, these deficiencies were confined mainly to the smaller
trials. There was no significant heterogeneity.
Outcome events
The type of outcome events varied greatly between the included
RCTs. Some trialsdidnot evenhavethe primary intentionto inves-tigate vascular endpoints ( Atlanta 1967; Becker 1967; DAMAD
1989a /DAMAD 1989b; German Fistula 1992; Hess 1985a /Hess
1985b; Igloe 1970; Libretti 1986; Misra 1983; PISA 2001;
Schoop-I 1983a /Schoop-I 1983b; Sreedhara 1994a /Sreedhara
1994b/Sreedhara 1994c/Sreedhara 1994d; Wirecki 1967). There-
fore, we decided to reduce the number of outcome measures in
this meta analysis to those which were extractable from most of
the original publications or from the data collected by the An-
tithrombotic Trialists’ Collaboration: vascular death and vascular
events. As a measure for safety we used the combination of major
extracranial bleeding complication (according to the definition of
the original investigator) plus fatal extracranial bleeding compli-
cation, according to the Antithrombotic Trialists’ Collaboration.
Dose of dipyridamole
Different doses of dipyridamole were used, therefore subgroup
analyses were performed in which three dosage groups were cho-
sen. One trial compared dipyridamole in the presence of differ-
ent doses of aspirin in the treatment and control group (150 mg
versus 300 mg) (Caneschi 1985a ). However, in the Dutch TIA
trial no influence on the number of outcome events was observed
between such a difference in aspirin dose (Dutch TIA Trial 1991).
We present effect estimates for three groups of dipyridamole doses.
Such indirectcomparisonsof treatmenteffect donot provide a very
reliable assessment of the effects of different doses ( ATT 2002).
However, we were unable to identify any trials directly compar-
ing one dose of dipyridamole with another. The confidence in-
tervals of the effect estimates for the three different dipyridamole
dosage strata overlap considerably. So, there are no indications of
differential efficacy according to dipyridamole dose. It should be
noted that the largest trials with the largest effects used a mod-
ified release preparation (ESPS-2 1997a /ESPS-2 1997b/ESPS-2
1997c/ESPS-2 1997d; ESPRIT 2006). The modified release form
of dipyridamole is studied in these two clinical trials and only
one other small trial (PISA 2001). It is predictably bio-available
and inhibits platelet function ex vivo (FitzGerald 1987). A sep-
arate analysis was done post hoc according to formulation. The
modified release form showed a significant risk reduction for theprevention of vascular events (RR 0.83, 95% CI 0.76 to 0.91).
This effect was not found for the immediate release form in 4676
patients (RR 0.99 95% CI 0.86 to 1.14).
Presenting disease
The five different high-risk groups were analysed separately. More
than three-quarters of all information originated from patients
with cerebrovascular disease and about a sixth from patients with
ischaemic heart disease. There was a benefit of dipyridamole in the
absence or presence of another antiplatelet drug only in patients
presenting with cerebral ischaemia in the secondary prevention of
vascular events and not in the prevention of vascular death. Thequantity of data about patients with arterial peripheral vascular
disease, diabetes retinopathy or patients needing haemodialysis is
minute.
A U T H O R S ’ C O N C L U S I O N S
Implications for practice
This review found that, for patients who presented with arterial
vascular disease, there was no evidence that dipyridamole, in the
presence or absence of another antiplatelet drug (chiefly aspirin)reduced the risk of vascular death, though it reduced the risk of
further vascular events. However, this benefit was found only in
patients presenting aftercerebral ischaemia.There was no evidence
that dipyridamole alone was more effective than aspirin alone. We
found no evidence to support the routine use of dipyridamole
alone as first line antiplatelet treatment in all patients at high risk
of vascular events. We found no evidence to justify routine use
of dipyridamole alone in preference to aspirin alone. The review
provides evidence that, among patients presenting with arterial
vascular disease, especially ischaemic stroke or TIA, the combina-
tion of dipyridamole plus aspirin is associated with a lower risk of
further vascular events than aspirin alone.
Implications for research
More trialsare neededin other high-riskgroups of patients,such as
those with arterial peripheral vascular disease, diabetic retinopathy
and patients undergoing haemodialysis to determine the role of
dipyridamole in secondary prevention. Also,trials with aspirinplus
extended release dipyridamole versus standard treatment (clopi-
dogrel, or clopidogrel plus aspirin - whichever is the gold stan-
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dard) might be warranted in patients with previous symptomatic
atherothrombosis of the coronary arteries.
A C K N O W L E D G E M E N T S We thank Hazel Fraser and Brenda Thomas for their help in the
search for trials, which could be included in this review. We also
thank Dr Colin Baigent and the Antiplatelet Trialists’ Collabora-
tion for providing us with the data used for the publication of the
second cycle.
R E F E R E N C E S
References to studies included in this review
ACCSG 1985 {published and unpublished data}The American-Canadian Co-operative Study Group.
Persantine aspirin trial in cerebral ischemia. Stroke 1983;14:
99–103.∗ The American-Canadian Co-operative Study Group.
Persantine aspirin trial in cerebral ischemia. Part II:
Endpoint results. Stroke 1985;16:406–15.
AICLA 1983a {published and unpublished data}
Bousser MG, Eschwege E, Haguenau M, Lefaucconnier
JM, Thibult N, Touboul D, et al.“AICLA” controlled trial
of aspirin and dipyridamole in the secondary prevention of
athero-thrombotic cerebral ischemia. Stroke 1983;14:5–14.
AICLA 1983b {published and unpublished data}
Bousser MG, Eschwege E, Haguenau M, Lefaucconnier JM, Thibult N, Touboul D, et al.“AICLA” controlled trial
of aspirin and dipyridamole in the secondary prevention of
athero-thrombotic cerebral ischemia. Stroke 1983;14:5–14.
Atlanta 1967 {published and unpublished data}
Sbar S, Schlant RC. Dipyridamole in the treatment of
angina pectoris. A double-blind evaluation. JAMA 1967;
201:865–7.
Becker 1967 {published and unpublished data}
Becker MC. Angina Pectoris: a double blind study with
dipyridamole. Journal of the Newark Beth Israel Hospital
1967;18:88–94.
Caneschi 1985a {published data only}
Caneschi S, Bonaventi C, Finzi F. Ischemic cerebrovasculardisease: treatment with various anti-platelet aggregation
drugs. Clinical follow-up of 80 patients (22-34 months).
Minverva Medica 1985;76:1933–43.
Caneschi 1985b {published data only}
Caneschi S, Bonaventi C, Finzi F. Ischemic cerebrovascular
disease: treatment with various anti-platelet aggregation
drugs. Clinical follow-up of 80 patients (22-34 months).
Minverva Medica 1985;76:1933–43.
Chairangsarit 2005 {published data only}
Chairangasarit P, Sithinamsuwan P, Niyasom S,
Udommongkol C, Nidhinandana S, Suwantamee J.Comparison between aspirin combined with dipyridamole
versus aspirin alone within 48 hours after ischemic stroke
event for prevention of recurrent stroke and improvement
of neurological function: a preliminary study. Journal of the
Medical Association of Thailand 2005;88 Suppl 3:148–54.
DAMAD 1989a {published and unpublished data}
The DAMAD Study Group. Effect of aspirin alone and
aspirin plus dipyridamole in early diabetic retinopathy. A
multicenter randomized controlled clinical trial. Diabetes
1989;38:491–8.
DAMAD 1989b {published and unpublished data}
The DAMAD Study Group. Effect of aspirin alone and
aspirin plus dipyridamole in early diabetic retinopathy. A multicenter randomized controlled clinical trial. Diabetes
1989;38:491–8.
ESPRIT 2006 {published data only}
De Schryver ELLM. Design of ESPRIT: an international
randomized trial for secondary prevention after non-
disabling cerebral ischaemia of arterial origin. European/
Australian Stroke Prevention in Reversible Ischaemia Trial
(ESPRIT) group. Cerebrovascular Diseases 2000;10(2):
147–50.∗ The ESPRIT Study Group. Aspirin plus dipyridamole
versus aspirin alone after cerebral ischaemia of arterial origin
(ESPRIT); randomised controlled trial. Lancet 2006;367:
1665–73.
ESPS-1 1990 {published and unpublished data}
ESPS Group. European Stroke Prevention Study. Stroke
1990;21:1122–30.
ESPS-2 1997a {published and unpublished data}
Diener HC, Cunha L, Forbes C, Sivenius J, Smets P,
Lowenthal A. European Stroke Prevention Study 2.
Dipyridamole and acetylsalicylic acid in the secondary
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prevention of stroke. Journal of Neurological Sciences 1996;
143:1–13.
The ESPS-2 Group. European Stroke Prevention Study 2.
Efficacy and safety data. Journal of Neurological Sciences
1997;151 Suppl:S1–S77.
ESPS-2 1997b {published and unpublished data}Diener HC, Cunha L, Forbes C, Sivenius J, Smets P,
Lowenthal A. European Stroke Prevention Study 2.
Dipyridamole and acetylsalicylic acid in the secondary
prevention of stroke. Journal of Neurological Sciences 1996;
143:1–13.
ESPS-2 1997c {published and unpublished data}
Diener HC, Cunha L, Forbes C, Sivenius J, Smets P,
Lowenthal A. European Stroke Prevention Study 2.
Dipyridamole and acetylsalicylic acid in the secondary
prevention of stroke. Journal of Neurological Sciences 1996;
143:1–13.
ESPS-2 1997d {published and unpublished data}
Diener HC, Cunha L, Forbes C, Sivenius J, Smets P,
Lowenthal A. European Stroke Prevention Study 2.
Dipyridamole and acetylsalicylic acid in the secondary
prevention of stroke. Journal of Neurological Sciences 1996;
143:1–13.
Gent-AMI 1968 {published and unpublished data}
Gent AE, Brook CG, Foley TH, Miller TN. Dipyridamole:
a controlled trial of its effect in acute myocardial infarction.
BMJ 1968;4:366–8.
German Fistula 1992 {unpublished data only}
The profylaxis of thrombosis in new arteriovenous dialysis
shunts in the arm by low-dose acetylsalicylic acid and
dipyridamole. Unpublished work 1992.
Hess 1985a {published and unpublished data}Hess H, Mietaschk A, Deichsel G. Drug-induced inhibition
of platelet function delays progression of peripheral
occlusive arterial disease. A prospective double-blind
arteriographically controlled trial. Lancet 1985;1:415–9.
Hess 1985b {published and unpublished data}
Hess H, Mietaschk A, Deichsel G. Drug-induced inhibition
of platelet function delays progression of peripheral
occlusive arterial disease. A prospective double-blind
arteriographically controlled trial. Lancet 1985;1:415–9.
Igloe 1970 {published data only}
Igloe MC. Treatment of angina pectoris with dipyridamole:
a double-blind study. Journal of the American Geriatric
Society 1970;18:233–41.
Libretti 1986 {published and unpublished data}
Catalano M, Libretti A. Dipyridamole combined with
acetylsalicylic acid versus acetylsalicylic acid alone in the
treatment of peripheral vascular disease. International
Angiology 1984;3:321–2.∗ Libretti A, Catalano M. Treatment of claudication with
dipyridamole and aspirin. Monographs on Atherosclerosis
1986;14:207–9.
Mayo-B 1989 {published and unpublished data}
Chesebro JH. Antiplatelet therapy in coronary disease
progression reduced infarction and new lesion formation.
Circulation 1989;80 Suppl II:266.
Misra 1983 {published and unpublished data}
Misra NP, Bhargava RK, Manoria PC. Comparative trials
of sulphinpyrazone and aspirin + dipyridamole in acute
myocardial infarction. Current Therapeutic Research 1983;
34:558–66.
PARIS-I 1980a {published and unpublished data}
The Persantine-Aspirin Reinfarction Study (PARIS)
research group. The Persantine-Aspirin reinfarction study.
Circulation 1980;62:449–61.
PARIS-I 1980b {published and unpublished data}
The Persantine-Aspirin Reinfarction Study (PARIS)
research group. The Persantine-Aspirin reinfarction study.
Circulation 1980;62:449–61.
PARIS-II 1986 {published and unpublished data}
Klimt CR, Knatterud GL, Stamler J, Meier P. Persantine-
Aspirin Reinfarction Study. Part II. Secondary coronary prevention with persantine and aspirin. Journal of the
American College of Cardiology 1986;7:251–69.
PISA 2001 {published data only}
Picano E, on behalf of the PISA study group. Dipyridamole
in chronic stable angina pectoris; a randomized, double
blind, placebo-controlled, parallel group study. European
Heart Journal 2001;22:1785–93.
Prandoni 1991 {published and unpublished data}
Prandoni P, Milani L, Barbiero M, Cardaioli P, Sanson
A, Barbaresi F, et al.Treatment of unstable angina with
dipyridamole combined with low doses of aspirin. A
multicenter pilot double-blind controlled study. Minerva
Cardioangiologica 1991;39:267–73.
Rome 1986 {published data only}
Gentile R, Lagana B, Calcagni S, Sorgia MC, Baratta L.
Efficacy of platelet-inhibiting agents in the prevention of
reinfarction in smoker patients. Proceedings of X World
Congress of Cardiology, Washington, USA. 1986:302
(Abstract 1724).
Schoop-I 1983a {published and unpublished data}
Schoop W. Long-term results with conservative treatment
of occlusive arteriopathies. Internist 1984;25:429–33.∗ Schoop W, Levy H, Schoop B, Gaentzsch A.
Experimentelle und klinische Studien zu der sekundären
Prävention der peripheren Arteriosklerose. In: Bollinger
A, Rhyner K editor(s). Thrombozytenfunktionshemmer,
Wirkungsmechanismen, Dosierung und praktische Anwendung .
New York: Georg Thieme Verlag Stuttgart, 1983:49–58.
Schoop W, Levy R. Prevention of peripheral arterial
occlusive disease with antiaggregants. Thrombosis and
Haemostasis 1983;50:137.
Schoop-I 1983b {published and unpublished data}
Schoop W, Levy H, Schoop B, Gaentzsch A. Experimentelle
und klinische Studien zu der sekundären Prävention der
peripheren Arteriosklerose. In: Bollinger A, Rhyner K editor
(s). Thrombozytenfunktionshemmer, Wirkungsmechanismen,
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Dosierung und praktische Anwendung . New York: Georg
Thieme Verlag Stuttgart, 1983:49–58.
Sreedhara 1994a {published and unpublished data}
Sreedhara R, Himmelfarb J, Lazarus JM, Hakim RM. Anti-
platelet therapy in graft thrombosis: results of a prospective,
randomized, double-blind study. Kidney International 1994;
45:1477–83.
Sreedhara 1994b {published and unpublished data}
Sreedhara R, Himmelfarb J, Lazarus JM, Hakim RM. Anti-
platelet therapy in graft thrombosis: results of a prospective,
randomized, double-blind study. Kidney International 1994;
45:1477–83.
Sreedhara 1994c {published and unpublished data}
Sreedhara R, Himmelfarb J, Lazarus JM, Hakim RM. Anti-
platelet therapy in graft thrombosis: results of a prospective,
randomized, double-blind study. Kidney International 1994;
45:1477–83.
Sreedhara 1994d {published and unpublished data}
Sreedhara R, Himmelfarb J, Lazarus JM, Hakim RM. Anti-
platelet therapy in graft thrombosis: results of a prospective,randomized, double-blind study. Kidney International 1994;
45:1477–83.
Stoke 1969 {published and unpublished data}
Acheson J, Danta G, Hutchinson EC. Controlled trial of
dipyridamole in cerebral vascular disease. BMJ 1969;i:
614–5.
Toulouse 1982a {published and unpublished data}
Guiraud-Chaumeil B, Rascol A, David J, Boneu B, Clanet
M, Bierme R. Prévention des récidives des accidents
vasculaires cérébraux ischémiques par les anti-agrégants
plaquettaires. Résultats d’un essai thérapeutique controlé de
3 ans. Revue Neurologique (Paris) 1982;138:367–85.
Toulouse 1982b {published and unpublished data}
Guiraud-Chaumeil B, Rascol A, David J, Boneu B, Clanet
M, Bierme R. Prévention des récidives des accidents
vasculaires cérébraux ischémiques par les anti-agrégants
plaquettaires. Résultats d’un essai thérapeutique controlé de
3 ans. Revue Neurologique (Paris) 1982;138:367–85.
VA Co-op 1986 {published and unpublished data}
Colwell JA, Bingham SF, Abraira C, Anderson JW,
Comstock JP, Kwaan HC, et al.Veterans Administration
Cooperative Study on antiplatelet agents in diabetic patients
after amputation for gangrene: II. Effects of aspirin and
dipyridamole on atherosclerotic vascular disease rates.
Diabetes Care 1986;9:140–8.
White 1995 {published and unpublished data}
White HD, French JK, Hamer AW, Brown MA, WilliamsBF, Ormiston JA, et al.Frequent reocclusion of patent
infarct-related arteries between 4 weeks and 1 year: effects
of antiplatelet therapy. Journal of the American College of
Cardiology 1995;25:218–23.
Wirecki 1967 {published and unpublished data}
Wirecki M. Treatment of angina pectoris with dipyridamole:
a long-term double blind study. Journal of Chronic Diseases
1967;20:139–45.
Additional references
Algra 1996
Algra A, van Gijn J. Aspirin at any dose above 30 mg offers
only modest protection after cerebral ischaemia. Journal of
Neurology Neurosurgery and Psychiatry 1996;60:197–99.
Algra 1999a
Algra A, Koudstaal PJ, van Gijn J. Secondary prevention
after cerebral ischaemia of presumed arterial origin:
is aspirin still the touchstone?. Journal of Neurology
Neurosurgery and Psychiatry 1999;66:557–9.
Algra 1999b
Algra A, van Gijn J. Cumulative meta-analysis of aspirin
efficacy after cerebral ischaemia of arterial origin. Journal of
Neurology Neurosurgery and Psychiatry 1999;66:255.
APT I 1994
Antiplatelet Trialists’ Collaboration. Collaborative overview
of randomised trials of antiplatelet therapy - 1: Prevention
of death, myocardial infarction, and stroke by prolonged
antiplatelet therapy in various categories of patients. BMJ 1994;308:81–106.
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;324:71–86.
Deeks 2005
Deeks JJ, Higgins JPT, Altman DG. Analysing and
presenting results. Cochrane Handbook of Systematic
Review of Interventions 4.2.5 [Updated May 2005]; Section
8.8. In: Higgins JPT, Green S editor(s). The Cochrane
Library, Issue 3, 2005 . Chichester, UK: John Wiley & Sons
Ltd, 2005.Dutch TIA Trial 1991
The Dutch TIA Trial Study Group. A comparison of two
doses of aspirin (30 mg vs 283 mg a day) in patients after
a transient ischemic attack or minor ischemic stroke. New
England Journal of Medicine 1991;325:1261–6.
FitzGerald 1987
FitzGerald GA. Modern drug therapy: dipyridamole. New
England Journal of Medicine 1987;316:1247–57.
Kaye 1990
Kaye J. A trial to evaluate the relative roles of dipyridamole
and aspirin in the prevention of deep vein thrombosis
in stroke patients. Boehringer Ingelheim Internal Report
1990.
UK-TIA Trial 1991
UK-TIA Study Group. The United Kingdom transient
ischaemic attack (UK-TIA) aspirin trial: final results.
Journal of Neurology Neurosurgery and Psychiatry 1991;54:
1044–54.
Warlow 1992
Warlow C. Secondary prevention of stroke. Lancet 1992;
339:724–7.
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References to other published versions of this review
De Schryver 2006
De Schryver ELLM, Algra A, van Gijn J. Dipyridamole for
preventing stroke and other vascular events in patients with
vascular disease. Cochrane Database of Systematic Reviews
2006, Issue 2. [Art. No.: CD001820. DOI: 10.1002/14651858.CD001820]
∗ Indicates the major publication for the study
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C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
ACCSG 1985
Methods Randomised trial
Concealment: encoded shelf cartons
Blinding: double
Intention-to-treat-analysis
Participants USA and Canada
890 patients
Mean age 63 years; 67% male
Carotid territory TIAs
Time since TIA < 3 months
CT or LP not required
Comparability of groups: differences in risk factors of stroke and history of diabetes and aortic valvular
disease
Interventions Rx: dipyridamole 300 mg/day + aspirin 1300 mg/day
Monitoring: three month intervals and urine drug levels
Compliance: drug stopped in 197 patients
Control: placebo + aspirin 1300 mg/day
Monitoring: idem
Compliance: drug stopped in 185 patients
Outcomes Stroke, retinal infarction, death from any cause (also data on vascular death and intra/extracranial/fatal
bleeding complications)
Notes Ex crit: ill-defined or non-lateralized symptoms only, severe neurological deficits, serious concurrent
illnesses, anticoagulation, possible cardiac source for emboli, history of peptic ulcer, bleeding or clotting
disorder
Follow up: median 25 months, 19 patients lost in treated group, 18 in control group
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
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AICLA 1983a
Methods Randomised trial
Concealment: unclear
Blinding: double
Intention-to-treat analysis not defined
Participants France
604 patients
Mean age 63 years; 70% male
Cerebral or retinal atherothrombotic ischaemic event in preceding year
CT or LP not required
Comparability of groups: no major differences
Interventions Rx: dipyridamole 225 mg/day + aspirin 990 mg/day
Monitoring: four month intervals and urine salicylate measurements
Compliance: 87%
Control: aspirin 990 mg/day
Monitoring: idem
Compliance: 90%
Outcomes Fatal and non-fatal cerebral infarction, myocardial infarction, death form any cause (also data on vascular
death and intra/extracranial bleeding complications)
Notes Ex crit: female < age 50, non-atherosclerotic or embolic causes, contraindication to aspirin, use of an-
tiplatelet drugs for other disease, referral for arterial surgery
Follow up: 36 months, withdrawal after event or non-compliance, 2 patients lost in treated group, 4 in
control group
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
AICLA 1983b
Methods As AICLA[a]
Participants
Interventions Rx: dipyridamole 225 mg/day + aspirin 990 mg/day
Monitoring: idemCompliance: 87%
Control: placebo
Monitoring: idem
Compliance: 91%
Outcomes
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AICLA 1983b (Continued)
Notes 2 patients lost in treated group, 2 in control group
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Atlanta 1967
Methods Randomised trial
Concealment: unclear
Blinding: double
Intention-to-treat analysis not performed
Participants USA
60 patients
Mean age and sex: not described for all patients
Frequent attacks of angina pectoris
Comparability of groups: incomplete data
Interventions Rx: dipyridamole 150 mg/day
Monitoring: monthly
Compliance: not described
Control: placebo
Monitoring: idem
Compliance: idem
Outcomes Frequencyof attacks ofangina pectoris, numberof nitroglycerintabletstakendaily(alsodata onmyocardial
infarction, vascular death and death from any cause)
Notes Excrit:diastolic bloodpressure> 120 mmHg,bloodureanitrogenlevel> 35mg/100ml,uncontrolledcon-
gestive heart failure, uncontrolled diabetes mellitus, myocardial infarction within the previous 3 months
Follow up: 6 months planned, mean and lost patients not described, exclusion after myocardial infarction
or discontinuation of drug
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
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Becker 1967
Methods Randomised trial
Concealment: code labelled containers
Blinding: double
Intention-to-treat analysis possible
Participants Israel
27 patients
Mean age 63 years; 70% male
Angina pectoris > 14 attacks per month during 2 months
ECG at start and end of study
Comparability of groups: not enough data, more severe angina in treatment group
Interventions Rx: dipyridamole 225 mg/day
Monitoring: monthly
Compliance: no stop of drug
Control: placebo
Monitoring: idem
Compliance: drug stopped in 3 patients
Outcomes Number of attacks per day, number of nitroglycerin tablets
Notes Ex crit: none?
Follow up: mean 5 months, no lost patients
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
Caneschi 1985a
Methods Randomised trial
Concealment: unclear
Blinding: not described
Intention-to-treat analysis not described
Participants Italy
50 patients
Mean age cannot be extracted; 72% male
Cerebral ischaemia Time since stroke not described
CT, doppler and angiography in all
Comparability of groups: no data
Interventions Rx: dipyridamole 225 mg/day + aspirin 150 mg/day
Monitoring: not described
Compliance: not described
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Caneschi 1985a (Continued)
Control: aspirin 300 mg/day
Monitoring: idem
Compliance: idem
Outcomes TIA, RIND, PRIND, stroke, death from any cause (also data on intra/extracranial and fatal intracranial
bleeding complications)
Notes Ex crit: none
Follow up: 22 to 34 months, number of patients lost not described
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Caneschi 1985b
Methods As Caneschi[a]
Participants
Interventions Rx: dipyridamole 225 mg/day
Monitoring: idem
Compliance: idem
Control: aspirin 300 mg/day
Monitoring: idem
Compliance: idem
Outcomes
Notes
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Chairangsarit 2005
Methods Randomised trial
Concealment: unclear
Blinding: open label, discrete data
Intention-to-treat analysis not described
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Chairangsarit 2005 (Continued)
Participants Thailand
38 patients
Mean age 64 years; 53% male Acute ischaemic stroke within 48 hours, > 34 years old, ischaemia confirmed with CT or MRI
Comparability of groups: no major differences
Interventions Rx: dipyridamole 225mg/day + aspirin 300mg/day
Monitoring: not described
Compliance: not described
Control: aspirin 300mg/day
Monitoring: idem
Compliance: idem
Monitoring: idem
Outcomes TIA, ischaemic stroke, vascular death
Notes Ex crit: atrial fibrillation or cardio-embolus, valvular heart disease, dyspepsia, bleeding tendency, organ
bleeding < 1 year, previous antiplatelet or anticoagulant use, severe co-morbidity
Follow up: 6 months, 7 patients lost
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
DAMAD 1989a
Methods Randomised trial
Concealment: unclear
Blinding: double
Intention-to-treat analysis
Participants France and United Kingdom
475 patients
Mean age 47 years; 64% male
Early diabetic retinopathy in patients with diabetes mellitus type I or II between ages 17 and 67 years
Good quality fluorescein angiograms in all
Start of one month placebo for all patients
Comparability of groups: comparable for medical parameters tested
Interventions Rx: dipyridamole 225 mg/day + aspirin 990 mg/day
Monitoring: four month intervals, inhibition platelet aggregation or tablet count
Compliance: 74% to 84%
Control: aspirin 990 mg/day
Monitoring: idem
Compliance: 73% to 82%
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DAMAD 1989a (Continued)
Outcomes Change in number of micro aneurysms (also data on death from any cause, vascular death and myocardial
infarction)
Notes Ex crit: other intercurrent disease or hypertension > 105 mmHg, contraindication to aspirin, macular
oedema, proliferative lesions, previous photocoagulation or other eye disease
Follow up: 36 months, 33 patients lost
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
DAMAD 1989b
Methods As DAMAD[a]
Participants
Interventions Rx: dipyridamole 225 mg/day + aspirin 990 mg/day
Monitoring: idem
Compliance: 74% to 84%
Control: placebo
Monitoring: idem
Compliance: 76% to 89%
Outcomes
Notes
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
ESPRIT 2006
Methods Randomised trial
Concealment: computer generated randomised codesBlinding: open label, outcome assessment blind
Intention-to-treat analysis and explanatory analysis
Participants Europe, Australia, Asia, USA
2739 patients
Mean age 63 years; 66% male
Patients with (transient) cerebral or retinal ischaemia of presumed arterial origin within 6 months of the
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ESPRIT 2006 (Continued)
last event Rankin < 4
CT or MRI in all except for amaurosis fugax, ECG in all, carotid duplex optional
Comparability of groups: no major differences
Interventions Rx: dipyridamole 400mg/day (retard) + aspirin 30 to 325/day
Monitoring: interview
Compliance: 34% dropped out
Control: aspirin 30 to 325mg/day
Monitoring: idem
Compliance: 13% dropped out
Outcomes Ischaemic stroke, myocardial infarction, major bleeding complication, vascular death
Notes Ex crit: cardiac embolism, planning of carotid endarterectomy or endovascular treatment, coagulation
disorder, contraindication for treatment medication, limited life expectancy
Follow up: mean 42 months,106 patients lost (part of the trial), 11 incomplete follow up
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
ESPS-1 1990
Methods Randomised trial
Concealment: unclear
Blinding: doubleIntention-to-treat analysis and explanatory analysis
Participants Belgium, Denmark, Ireland, Finland, The Netherlands, United Kingdom
2500 patients.
Mean age: 64 years; 58% male
Atherothrombotic TIA, RIND or stroke in preceding 3 months
X-thorax, ECG in all. CT, EEG, angiography optional
Comparability of groups: no major differences
Interventions Rx: dipyridamole 225 mg/day + aspirin 990 mg/day
Monitoring: not defined
Compliance: 34% dropped out
Control: placeboMonitoring: idem
Compliance: 30% dropped out
Outcomes Stroke or death from any cause (also data on vascular death)
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ESPS-1 1990 (Continued)
Notes Ex crit: anticoagulant or antithrombotic drug before randomisation, life-threatening associated disease,
allergy to treatment drug
Follow up: 24 months planned, 7 patients lost
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
ESPS-2 1997a
Methods Randomised trial
Concealment: randomisation by a central computer, corresponding number treatment packages
Blinding: doubleIntention-to-treat analysis and explanatory analysis
Participants 13 European countries
6602 patients
Mean age 67 years; 58% male
Ischaemic cerebrovascular event within preceding 3 months
Blood pressure and ECG in all. CT or MRI not compulsory
Comparability of groups: no major differences in risk factors and demographics
Interventions Rx: dipyridamole
400 mg/day (retard)
Monitoring: plasma salicylic acid and dipyridamole concentrations in 15%, patient questioning and tablet
countCompliance: 71% to 79%
Control: placebo
Monitoring: idem
Compliance: 78% to 81%
Outcomes Stroke, death from any cause, TIA, myocardial infarction, other vascular events (pulmonary embolism,
deep venous thrombosis, peripheral arterial occlusion, venous retinal thrombosis) (also data on severe
bleeding complications)
Notes Excrit:recenthistory ofpepticulcer orgastrointestinalbleeding,intoleranceto study medication, bleeding
disturbance, use of aspirin or anticoagulants, life-threatening condition
Follow up 24 months, 42 patients lost
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
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ESPS-2 1997b
Methods As ESPS-2[a]
Participants
Interventions Rx: dipyridamole 400 mg/day (retard) + aspirin 50 mg/day
Monitoring: idem
Compliance: 71% to 80%
Control: aspirin 50 mg/day
Monitoring: idem
Compliance: 78% to 82%
Outcomes
Notes
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
ESPS-2 1997c
Methods As ESPS-2[a]
Participants
Interventions Rx: dipyridamole 400 mg/day (retard)
Monitoring: idem. Compliance: 71% to 79%
Control: aspirin 50 mg/day
Monitoring: idem
Compliance: 78% to 82%
Outcomes
Notes
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
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ESPS-2 1997d
Methods As ESPS-2[a]
Participants
Interventions Rx: dipyridamole 400 mg/day (retard) + aspirin 50 mg/day
Monitoring: idem
Compliance: 71% to 80%
Control: placebo
Monitoring: idem
Compliance: 78% to 81%
Outcomes
Notes
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
Gent-AMI 1968
Methods Randomised trial
Concealment: numbers issued by pharmacist
Blinding: double
Intention-to-treat analysis not defined
Participants United Kingdom
120 patients
Age between 30 and 89 years; 85% male
Myocardial infarction in preceding 2 weeks
ECG and serum transaminase levels in all
Comparability of groups: no data
Interventions Rx: dipyridamole 400 mg/day
Monitoring: serum dipyridamole levels
Compliance: not described
Control: placebo
Monitoring: idem
Compliance: idem
Outcomes Lengthof timespentin bed,myocardialreinfarction, systemicand pulmonary emboli, leg veinthrombosis
(also data on death from any cause)
Notes Ex crit: liver disease, use of anticoagulants, malignant hypertension, bleeding diathesis
Follow up: 4 weeks, 4 patients lost
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Gent-AMI 1968 (Continued)
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
German Fistula 1992
Methods Randomised trial
Concealment: unclear
Blinding: double
Intention-to-treat analysis and explanatory analysis
Participants Germany
903 patientsMean age: 56 years; 57% male
Preterminal and terminal renal insufficiency requiring dialysis, a subcutaneous AV-shunt in the arm
Comparability of groups: comparable for age, sex, weight and risk factors
Interventions Rx: dipyridamole 400 mg/day + aspirin 50 mg/day
Monitoring: not described
Compliance: stopped in 50%
Control: placebo
Monitoring: idem
Compliance: stopped in 50%
Outcomes Occlusion of AV-shunt, functional duration of shunt (also data on death from any cause)
Notes Ex crit: not described
Follow up: 6 to 18 months, no data of lost patients
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Hess 1985a
Methods Randomised trial
Concealment: unclear
Blinding: double
Intention-to-treat analysis not performed
Participants Germany
240 patients
Mean age: 62 years; 80% male
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Hess 1985a (Continued)
Occlusive arteriosclerosis of the lower extremities
Arteriography in all
Comparability of groups: comparable for age and risk factors
Interventions Rx. dipyridamole 225 mg/day + aspirin 990 mg/day
Monitoring: 3 month intervals and urine salicylate and dipyridamole levels
Compliance: poor in 5 patients
Control: aspirin 990 mg/day + placebo
Monitoring: idem
Compliance: poor in 3 patients
Outcomes (Semi)qualitative evaluation of arteriograms: occlusion, arteriosclerotic changes (also data on death from
any cause, vascular death, myocardial infarction and stroke)
Notes Ex crit: arteritis, malignant hypertension, thyrotoxicosis, malignant neoplasm, age > 75 years, vascular
surgery, severe hepatic or renal disease, active gastroduodenal ulcer in preceding 2 yearsFollow up: 24 months, withdrawal after death, poor compliance, intolerance to drug and various con-
comitant illnesses; 17 patients withdrawn in treated group, 13 patients in control group
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Hess 1985b
Methods As Hess 1995[a]
Participants
Interventions Rx: dipyridamole 225 mg/day + aspirin 990 mg/day
Monitoring: idem
Compliance: poor in 5 patients
Control: placebo
Monitoring: idem
Compliance: poor in 6 patients
Outcomes
Notes Follow up: idem, 17 patients withdrawn in treated group, 11 patients in control group
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
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Igloe 1970
Methods Randomised trial
Concealment: code-labelled tablets, individual numbers
Blinding: double
Intention-to-treat analysis not performed
Participants USA
56 patients
Mean age: 62 years; 67% male
Angina pectoris, mean requiring of > 2 nitroglycerin tablets/day
ECG in all
Comparability of groups: no major differences in sex, age and cardiac disease
Interventions Rx: dipyridamole 200 mg/day
Monitoring: not described
Compliance: not described
Control: placeboMonitoring: idem
Compliance: idem
Outcomes Number of angina attacks per day, number of nitroglycerin tablets required per day, number of blocks
walked per day
Notes Ex crit: follow up less than 2 months; 3 treated patients and 5 control patients excluded
Follow up: mean 21 weeks for treated group and 19 weeks for control group
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
Libretti 1986
Methods Randomised trial
Concealment: unclear
Blinding: not described
Intention-to-treat analysis not defined
Participants Italy
54 patients
Age: between 40 and 74 years; 100% male. Arterial peripheral vascular disease of the lower limbs, stage 2
Symptom free interval on the treadmill, ankle-arm index, oscillographic index for four limbs and venous
occlusion plethysmography on the legs in all
Comparability of groups: no data
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Libretti 1986 (Continued)
Interventions Rx: dipyridamole 225 mg/day + aspirin 600 mg/day
Monitoring: after six months
Compliance: 5 patients dropped outControl: aspirin 600 mg/day
Monitoring: idem
Compliance: 8 patients dropped out
Outcomes Symptom free interval on the treadmill, venous occlusion plethysmography of the lower limbs
Notes Excrit:concomitantcoronaryheartdisease,cerebrovasculardisease,diabetes, gastrointestinaldisturbances
Follow up: 6 months
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Mayo-B 1989
Methods Randomised trial
Concealment: unclear
Blinding: double
Intention-to-treat analysis not defined
Participants USA
370 patients
Mean age and sex: no data
Low risk (mean ejection fraction 59%) medically treated coronary artery disease
Angiogram in all
Comparability of groups: well matched for baseline criteria
Interventions Rx: dipyridamole 225 mg/day + aspirin 975 mg/day
Monitoring: not described
Compliance: not described
Control: placebo
Monitoring: not described
Compliance: not described
Outcomes Myocardial infarction and angiographic progression of coronary artery disease
Notes Ex crit: not described
Follow up: 60 months, number of lost patients not described
Risk of bias
Item Authors’ judgement Description
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Mayo-B 1989 (Continued)
Allocation concealment? Unclear B - Unclear
Misra 1983
Methods Randomised trial
Concealment: unclear
Blinding: double
Intention-to-treat analysis not defined
Participants India
50 patients
Mean age: no data; 84% male
Acute myocardial infarction
ECG in all
Comparability of groups: no data
Interventions Rx: dipyridamole 300 mg/day + aspirin 1050 mg/day
Monitoring: not described
Compliance: not described
Control: sulphinpyrazone 800 mg/day
Monitoring: idem
Compliance: idem
Outcomes Platelet adhesiveness and plasma fibrinolytic activity
Notes Ex crit: not described
Follow up: 6 weeks, number of patients lost not described
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
PARIS-I 1980a
Methods Randomised trial
Concealment: by co-ordinating center
Blinding: double
Intention-to-treat analysis
Participants USA and United Kingdom
2026 patients
Age: between 30 and 74 years; 87% male
Recovering from proved myocardial infarction, randomisation within 8 weeks to 60 months
ECG changes and enzyme elevations in all
Comparability of groups: no major differences
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PARIS-I 1980a (Continued)
Interventions Rx: dipyridamole 225 mg/day + aspirin 975 mg/day
Monitoring: 4-month intervals, urine drug levels
Compliance: 70.3%Control: aspirin 975 mg/day + placebo
Monitoring: idem
Compliance: 71.7%
Outcomes Death from any cause, non-fatal cardiovascular events, stroke, pulmonary embolism and cardiovascular
surgery (also data on vascular death and myocardial infarction)
Notes Ex crit: other life-limiting diseases, any condition precluding use of trial drug
Follow up: mean 41 months, 2 patients lost in treated group, 4 patients lost in control group
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
PARIS-I 1980b
Methods As PARIS-1[a]
Participants
Interventions Rx: dipyridamole 225 mg/day + aspirin 975 mg/day
Monitoring: idem
Compliance: 70.3%
Control: placebo
Monitoring: idem
Compliance: 74.2%
Outcomes
Notes
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
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PARIS-II 1986
Methods Randomised trial
Concealment: by co-ordinating center, treatment allocation envelope
Blinding: double
Intention-to-treat analysis
Participants USA and United Kingdom
3128 patients
Age: 30 to 74 years; 84% male
Myocardial infarction with no or slight limitation of physical activity, randomisation within 4 weeks to 4
months
ECG changes and enzyme elevations in all
Comparability of groups: no major differences
Interventions Rx: dipyridamole 225 mg/day + aspirin 990 mg/day
Monitoring: 4 month intervals, pill count and urine drug levels
Compliance: 69.8%
Control: placebo
Monitoring: idem
Compliance: 74.3%
Outcomes Death from any cause, coronary mortality and coronary incidence (non-fatal myocardial infarction or
coronary death), other non-fatal cardiovascular events (also data on vascular death and stroke)
Notes Ex crit: previous cardiac or coronary surgery, life-limiting diseases, need of platelet affecting drug, history
of upper gastrointestinal bleeding, anticoagulant therapy, postural hypotension, systolic blood pressure >
200 mmHg, diastolic blood pressure > 115 mmHg
Follow up: mean 23.4 months, 6 patients lost in treated group, 2 patients in control group
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Yes A - Adequate
PISA 2001
Methods Randomised trial
Concealment: unclear
Blinding: double
Intention-to-treat analysis
Participants Italy and United Kingdom
400 patients
Mean age: 62 years; 81% male
Chronic stable angina pectoris more than or equal to 3 months and positive treadmill exercise test
Comparability of groups: no major differences
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PISA 2001 (Continued)
Interventions Rx: dipyridamole 400 mg/day (retard)
Monitoring: at week 2, 8, 24, 26, 28
Compliance: 68%Control: placebo
Monitoring: idem
Compliance: 80%
Outcomes Change from baseline in duration of treadmill exercise
Notes Ex crit: pacemaker, diastolic blood pressure < 95 mmHg, unable exercise testing
Follow up: 28 weeks, 1 patient lost in both groups
Risk of bias
Item Authors’ judgement Description
Allocation concealment?
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