Dipiridamol Para La Prevención de Eventos Vasculares Accidente Cerebrovascular y Otros

8/12/2019 Dipiridamol Para La Prevención de Eventos Vasculares Accidente Cerebrovascular y Otros

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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.

http://www.thecochranelibrary.com/http://www.thecochranelibrary.com/


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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


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


presenting disease, Outcome 1 vascular death. . . . . . . . . . . . . . . . . . . . . . . . 50


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.


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.

1Dipyridamole for preventing stroke and other vascular events in patients with vascular disease (Review)


mailto:[email protected]:[email protected]


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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-




9/67

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,




143:1–13.

ESPS-2 1997c {published and unpublished data}





143:1–13.

ESPS-2 1997d {published and unpublished data}





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}




45:1477–83.

Sreedhara 1994c {published and unpublished data}




45:1477–83.

Sreedhara 1994d {published and unpublished data}


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


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


Concealment: unclear

Blinding: double

Intention-to-treat analysis not defined

Participants France

604 patients


Cerebral or retinal atherothrombotic ischaemic event in preceding year

CT or LP not required

Comparability of groups: no major differences


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


Allocation concealment? Unclear B - Unclear

AICLA 1983b

Methods As AICLA[a]

Participants


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



Atlanta 1967



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






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Becker 1967


Concealment: code labelled containers

Blinding: double

Intention-to-treat analysis possible

Participants Israel

27 patients


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


Monitoring: monthly

Compliance: no stop of drug

Control: placebo

Monitoring: idem


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



Caneschi 1985a



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


Monitoring: not described





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Caneschi 1985a (Continued)


Monitoring: idem

Compliance: idem

Outcomes TIA, RIND, PRIND, stroke, death from any cause (also data on intra/extracranial and fatal intracranial


Notes Ex crit: none

Follow up: 22 to 34 months, number of patients lost not described

Risk of bias



Caneschi 1985b

Methods As Caneschi[a]

Participants


Monitoring: idem

Compliance: idem


Monitoring: idem

Compliance: idem

Outcomes

Notes

Risk of bias



Chairangsarit 2005



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


Interventions Rx: dipyridamole 225mg/day + aspirin 300mg/day



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



DAMAD 1989a



Blinding: double

Intention-to-treat analysis

Participants France and United Kingdom

475 patients


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


Monitoring: four month intervals, inhibition platelet aggregation or tablet count

Compliance: 74% to 84%


Monitoring: idem





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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



DAMAD 1989b

Methods As DAMAD[a]

Participants


Monitoring: idem


Control: placebo

Monitoring: idem


Outcomes

Notes

Risk of bias



ESPRIT 2006


Concealment: computer generated randomised codesBlinding: open label, outcome assessment blind

Intention-to-treat analysis and explanatory analysis

Participants Europe, Australia, Asia, USA

2739 patients


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


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


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



ESPS-1 1990



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



Monitoring: not defined


Control: placeboMonitoring: idem


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



ESPS-2 1997a


Concealment: randomisation by a central computer, corresponding number treatment packages

Blinding: doubleIntention-to-treat analysis and explanatory analysis

Participants 13 European countries

6602 patients


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


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


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






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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



Monitoring: idem


Outcomes

Notes

Risk of bias



ESPS-2 1997c


Participants

Interventions Rx: dipyridamole 400 mg/day (retard)

Monitoring: idem. Compliance: 71% to 79%


Monitoring: idem


Outcomes

Notes

Risk of bias






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ESPS-2 1997d


Participants

Interventions Rx: dipyridamole 400 mg/day (retard) + aspirin 50 mg/day

Monitoring: idem


Control: placebo

Monitoring: idem


Outcomes

Notes

Risk of bias



Gent-AMI 1968


Concealment: numbers issued by pharmacist

Blinding: double


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



Monitoring: serum dipyridamole levels


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



German Fistula 1992



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



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



Hess 1985a



Blinding: double


Participants Germany

240 patients





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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


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



Hess 1985b

Methods As Hess 1995[a]

Participants


Monitoring: idem


Control: placebo

Monitoring: idem


Outcomes

Notes Follow up: idem, 17 patients withdrawn in treated group, 11 patients in control group

Risk of bias






26/67

Igloe 1970


Concealment: code-labelled tablets, individual numbers

Blinding: double


Participants USA

56 patients


Angina pectoris, mean requiring of > 2 nitroglycerin tablets/day

ECG in all

Comparability of groups: no major differences in sex, age and cardiac disease




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



Libretti 1986



Blinding: not described


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





27/67

Libretti 1986 (Continued)


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



Mayo-B 1989



Blinding: double


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




Control: placebo



Outcomes Myocardial infarction and angiographic progression of coronary artery disease


Follow up: 60 months, number of lost patients not described

Risk of bias





28/67

Mayo-B 1989 (Continued)


Misra 1983



Blinding: double


Participants India

50 patients

Mean age: no data; 84% male

Acute myocardial infarction

ECG in all





Control: sulphinpyrazone 800 mg/day

Monitoring: idem

Compliance: idem

Outcomes Platelet adhesiveness and plasma fibrinolytic activity


Follow up: 6 weeks, number of patients lost not described

Risk of bias



PARIS-I 1980a


Concealment: by co-ordinating center

Blinding: double


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





29/67

PARIS-I 1980a (Continued)


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



PARIS-I 1980b

Methods As PARIS-1[a]

Participants


Monitoring: idem

Compliance: 70.3%

Control: placebo

Monitoring: idem

Compliance: 74.2%

Outcomes

Notes

Risk of bias






30/67

PARIS-II 1986


Concealment: by co-ordinating center, treatment allocation envelope

Blinding: double


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



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



PISA 2001



Blinding: double


Participants Italy and United Kingdom

400 patients


Chronic stable angina pectoris more than or equal to 3 months and positive treadmill exercise test





31/67

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


Allocation concealment?

Documents

Dipiridamol Para La Prevención de Eventos Vasculares Accidente Cerebrovascular y Otros