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Adenosine-diphosphate (ADP) receptor antagonists for the
prevention of cardiovascular disease in type 2 diabetes
mellitus (Review)
Valentine N, Van de Laar FA, van Driel ML
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2012, Issue 11
http://www.thecochranelibrary.com
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 2.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 3.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 All-cause mortality, Outcome 1 Ticlopidine vs placebo. . . . . . . . . . . . .
Analysis 2.1. Comparison 2 Vascular mortality, Outcome 1 Ticlopidine vs placebo. . . . . . . . . . . . .
Analysis 3.1. Comparison 3 Stroke (fatal and non-fatal), Outcome 1 Ticlodipine vs placebo. . . . . . . . . .
Analysis 3.2. Comparison 3 Stroke (fatal and non-fatal), Outcome 2 Ticlodipine vs aspirin. . . . . . . . . .
Analysis 3.3. Comparison 3 Stroke (fatal and non-fatal), Outcome 3 Clopidogrel vs aspirin & dipyridamole. . . .
Analysis 3.4. Comparison 3 Stroke (fatal and non-fatal), Outcome 4 ADP receptor antagonists vs other antiplatelet drug.
Analysis 4.1. Comparison 4 Myocardial infarction (fatal and non-fatal), Outcome 1 Ticlopidine/Placebo. . . . .
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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[Intervention Review]
Adenosine-diphosphate (ADP) receptor antagonists for the
prevention of cardiovascular disease in type 2 diabetes
mellitus
Nyoli Valentine1 , Floris A Van de Laar2 , Mieke L van Driel3
1 Department
of General Practice, Bond University, Gold Coast, Australia. 2 Department of Primary and Community Care, 117 ELG,
Radboud University Nijmegen Medical Center, Nijmegen, Netherlands. 3 Discipline of General Practice, School of Medicine, The
University of Queensland, Brisbane, Australia
Contact address: Floris A Van de Laar, Department of Primary and Community Care, 117 ELG, Radboud University Nijmegen Medical
Center, PO Box 9101, Nijmegen, 6500 HB, Netherlands. f.vandelaar@elg.umcn.nl. f.vandelaar@cochraneprimarycare.org.
Editorial group: Cochrane Metabolic and Endocrine Disorders Group.
Publication status and date: New, published in Issue 11, 2012.
Review content assessed as up-to-date: 31 May 2011.
Citation: Valentine N, Van de Laar FA, van Driel ML. Adenosine-diphosphate (ADP) receptor antagonists for the prevention of
cardiovascular disease in type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2012, Issue 11. Art. No.: CD005449. DOI:
10.1002/14651858.CD005449.pub2.
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Background
Cardiovascular disease (CVD) is the most prevalent complication of type 2 diabetes with an estimated 65% of people with type 2
diabetes dying from a cause related to atherosclerosis. Adenosine-diphosphate (ADP) receptor antagonists like clopidogrel, ticlopidine,
prasugrel and ticagrelor impair platelet aggregation and fibrinogen-mediated platelet cross-linking and may be effective in preventing
CVD.
Objectives
To assess the effects of adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes
mellitus.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (issue 2, 2011), MEDLINE
(until April 2011) and EMBASE (until May 2011). We also performed a manual search, checking references of original articles and
pertinent reviews to identify additional studies.
Selection criteria
Randomised controlled trials comparing an ADP receptor antagonist with another antiplatelet agent or placebo for a minimum of 12
months in patients with diabetes. In particular, we looked for trials assessing clinical cardiovascular outcomes.
Data collection and analysis
Two review authors extracted data for studies which fulfilled the inclusion criteria, using standard data extraction templates. We sought
additional unpublished information and data from the principal investigators of all included studies.
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1
Main results
Eight studies with a total of 21,379 patients with diabetes were included. Three included studies investigated ticlopidine compared to
aspirin or placebo. Five included studies investigated clopidogrel compared to aspirin or a combination of aspirin and dipyridamole,
or compared clopidogrel in combination with aspirin to aspirin alone. All trials included patients with previous CVD except the
CHARISMA trial which included patients with multiple risk factors for coronary artery disease. Overall the risk of bias of the trials
was low. The mean duration of follow-up ranged from 365 days to 913 days.
Data for diabetes patients on all-cause mortality, vascular mortality and myocardial infarction were only available for one trial (355
patients). This trial compared ticlopidine to placebo and did not demonstrate any statistically significant differences for all-cause
mortality, vascular mortality or myocardial infarction. Diabetes outcome data for stroke were available in three trials (31% of total
diabetes participants). Overall pooling of two (statistically heterogeneous) studies showed no statistically significant reduction in the
combination of fatal and non-fatal stroke (359/3194 (11.2%) versus 356/3146 (11.3%), random effects odds ratio (OR) 0.81; 95%
confidence interval (CI) 0.44 to 1.49) for ADP receptor antagonists versus other antiplatelet drugs. There were no data available from
any of the trials on peripheral vascular disease, health-related quality of life, adverse events specifically for patients with diabetes, or
costs.
Authors’ conclusions
The available evidence for ADP receptor antagonists in patients with diabetes mellitus is limited and most trials do not report outcomes
for patients with diabetes separately. Therefore, recommendations for the use of ADP receptor antagonists for the prevention of CVD
in patients with diabetes are based on available evidence from trials including patients with and without diabetes. Trials with diabetes
patients and subgroup analyses of patients with diabetes in trials with combined populations are needed to provide a more robust
evidence base to guide clinical management in patients with diabetes.
PLAIN LANGUAGE SUMMARY
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in patients with type 2 diabetes
mellitus
Patients with type 2 diabetes have a much higher risk of strokes and heart attacks than the general population. Most strokes and
heart attacks are caused by blood clots. Adenosine-diphosphate (ADP) receptor antagonists are drugs which prevent the aggregation
(’clumping’) of platelets and consequently reduce the formation of blood clots. These medications are used to prevent cardiovascular
disease such as heart attacks and strokes in the general population. This review assessed if these medications would be useful in patients
with diabetes. We included eight trials with 21,379 patients and a mean duration of follow-up ranging from 365 to 913 days. Specific
data for patients with diabetes were only available in full for one of these trials and partial data were available for two trials. Analysis of
the available data demonstrated that adenosine-diphosphate receptor antagonists (such as clopidogrel, prasugrel, ticagrelor, ticlopidine)
were not more effective than other blood thinning drugs or placebo for death from any cause, death related to cardiovascular disease,
heart attacks or strokes. There was no available information on the effects of adenosine-diphosphate receptor antagonists on healthrelated quality of life, adverse effects specially for people with diabetes, or costs. The use of adenosine-diphosphate receptor antagonists
in patients with diabetes needs to be guided by the information available from trials which included patients with and without diabetes.
All future trials on adenosine-diphosphate receptor antagonists should include data which relate specifically to patients with diabetes
in order to inform evidence-based clinical guidelines.
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
2
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Adenosine-diphosphate (ADP) receptor antagonists (clopidogrel, ticlopidine, prasugrel, ticagrelor) for the prevention of cardiovascular disease in type 2 diabetes mellitus
Patient or population: patients with type 2 diabetes mellitus
Settings: out-patients
Intervention: ADP receptor antagonists
Comparison: Aspirin (/dipyramidole)/placebo
Outcomes
Illustrative comparative risks* (95% CI)
Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed risk
Corresponding risk
Control
ADP receptor antagonist
All-cause mortality
(ticlopidine vs placebo)
14.1%
17.4%
RR 1.29 (0.71 to 2.32)
335 (1)
moderate quality
Seea
Vascular mortality
(ticlopidine vs placebo)
11%
10.5%
RR 0.94 (0.47 to 1.88)
335 (1)
moderate quality
Seea
Myocardial infarction 11.7%
(fatal and non-fatal)
(ticlopidine vs placebo)
9.3%
RR 0.78 (0.39 to 1.57)
335 (1)
moderate quality
Seea
Stroke (fatal and non-fa- a. 0.14%
tal)
b. 0.11%
(a. ticlopidine vs aspirin)
(b. clopidogrel vs aspirin
& dipyramidole)
a. 0.9%
b. 0.12%
a. RR 0.56 (0.37 to 0.94) a. 597 (1)
b. RR 1.12 (0.95 - 1.32) b. 5770 (1)
a. moderate quality
b. moderate quality
a. Seea
b. Seeb
Health-related quality of See comment
life
See comment
Not estimable
See comment
See comment
Not investigated for diabetes sub-population
Adverse effects
See comment
Not estimable
See comment
See comment
Not investigated for diabetes sub-population
See comment
3
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Costs
See comment
See comment
Not estimable
See comment
See comment
Not investigated for diabetes sub-population
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
a
b
Only one study with small number of participants providing data
Unclear random sequence generation and high attrition rates
4
BACKGROUND
gation and fibrinogen-mediated platelet cross-linking (Goodwin
2011). The result is a 50% to 70% inhibition of platelet fibrinogen binding achieved after three to five days (Kam 2003).
Description of the condition
Diabetes mellitus is a metabolic disorder resulting from a defect in
insulin secretion, insulin action, or both. A consequence of this is
chronic hyperglycaemia (that is elevated levels of plasma glucose)
with disturbances of carbohydrate, fat and protein metabolism.
Long-term complications of diabetes mellitus include retinopathy, nephropathy and neuropathy. The risk of cardiovascular disease is increased. For a detailed overview of diabetes mellitus,
please see under ’Additional information’ in the information on
the Metabolic and Endocrine Disorders Group in The Cochrane
Library (see ’About’, ’Cochrane Review Groups (CRGs)’). For an
explanation of methodological terms, see the main glossary in The
Cochrane Library.
Diabetes, cardiovascular disease and the role of
platelets
The most prevalent complication of type 2 diabetes mellitus is
cardiovascular disease (CVD). It is estimated that 65% of patients
with type 2 diabetes die of a cause related to atherosclerosis (Gu
1998). Risk of mortality and morbidity due to myocardial infarction, stroke and peripheral arterial disease are two- to four-fold
increased compared with the general population. Once diagnosed
with having diabetes, overall survival is comparable to a patient
with a prior myocardial infarction (Haffner 1998).
Given the upcoming pandemic of patients with diabetes, world
wide prevalence is expected to increase from 2.8% in 2000 to
4.4% in 2030 (Wild 2004), cardiovascular disease will continue
to be responsible for a large proportion of global healthcare expenditures. This stresses the need for preventive measures. In the
development of a cardiovascular event, platelets play an important
role. Platelet adhesion and subsequent activation on dysfunctional
endothelium fuel the inflammatory process in the atherosclerotic
plaque. After disruption of the plaque, large aggregates of platelets
lead to vessel occlusion. In the patient with diabetes, anti-aggregatory mechanisms in the endothelium are impaired (Ceriello 2004).
Platelets are more susceptible to activation and aggregation (Kutti
1986) and antifibrinolytic activity is attenuated (Colwell 2003).
Adverse effects of the intervention
Gastrointestinal side effects and skin rashes are common. Neutropenia and thrombotic thrombocytopenic purpura are significant but rarely fatal adverse events. Recovery of platelet function is
delayed after discontinuation of the medication for approximately
three to seven days (Kam 2003). In terms of cost, ADP receptor
antagonists are considerably more expensive than aspirin.
How the intervention might work
There are clues that ADP receptor antagonists are superior to aspirin in preventing cardiovascular disease. In a Cochrane review,
clopidogrel and ticlopidine were slightly, but significantly, more
effective than aspirin in preventing serious vascular events in highrisk patients (previous clinical manifestations of cardiovascular disease) (Sudlow 2009). Other evidence was derived from an analysis
of the diabetic subgroup in the CAPRIE-study. In that trial, 15.6%
of patients with diabetes experienced a vascular endpoint versus
17.7% in the aspirin group (P = 0.042). In addition, patients in
the clopidogrel group had less bleeding events: 1.8% versus 2.8%
in the aspirin group (P = 0.031) (Bhatt 2002).
Why it is important to do this review
Despite the evidence for possible advantages, the role of ADP
receptor antagonists in the treatment of patients with diabetes
seems to be limited. A recent position statement by the American
Diabetes Association suggested the use of clopidogrel only in case
of allergy for aspirin or in combination therapy with aspirin for
one year after acute coronary syndrome (ADA 2011). The high
costs of ADP receptor antagonists seem to be the major reason
for the modest position these drugs have in treatment strategies.
Evidence from systematic reviews and meta-analyses is lacking for
ADP receptor antagonists in patients with diabetes. To value the
use of these agents in the treatment of patients with diabetes, a
well-designed systematic review is needed.
Description of the intervention
Adenosine-diphosphate (ADP) is a platelet activator that is released from red blood cells, activated platelets and damaged endothelial cells which induces platelet adhesion and aggregation
(Kam 2003). ADP receptor antagonists noncompetitively and irreversibly inhibit platelet ADP receptors preventing platelet activation. This prevents the activations of the glycoprotein IIb/IIIa receptor complex and prolongs bleeding time, impairs platelet aggre-
OBJECTIVES
To assess the effects of adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus.
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
5
METHODS
Criteria for considering studies for this review
Types of studies
We included all randomised controlled trials comparing an adenosine-diphosphate (ADP) receptor antagonist with another antiplatelet agent or placebo for a minimum of 12 months. Trials
with blinded trial participants and investigators were preferred,
however, single-blind and unblinded trials were considered. We
included studies published in any language.
Types of participants
Eligible patients were adults (18 years and older) with diabetes
mellitus. Trials which used the current standard criteria to establish
the diagnosis of diabetes at the time of the trial were preferred,
however, we accepted authors’ definitions (ADA 1997; ADA 1999;
WHO 1980; WHO 1985; WHO 1998).
Types of interventions
Intervention
Any orally administered ADP receptor antagonist given on a continuing basis.
Secondary outcomes
• Adverse effects, such as any major bleeding event, defined as
intracranial bleeding or bleeding requiring surgical intervention
or transfusion.
• Health-related quality of life, ideally measured with a
validated instrument.
• Costs.
Search methods for identification of studies
Electronic searches
The following sources were used from inception to specified time
for the identification of trials.
• The Cochrane Library (issue 2, 2011).
• MEDLINE (until April 2011).
• EMBASE (until May 2011).
We also searched databases of ongoing trials (
http://www.controlled-trials.com/ with links to several databases
and https://www.clinicaltrialsregister.eu/).
For detailed search strategies please see under Appendix 1.
No additional key words of relevance were detected during any
of the electronic or other searches. Thus, the electronic search
strategies were not modified. Studies published in any language
were included.
Searching other resources
Control
Placebo, another antiplatelet agent or no treatment.
We sought additional unpublished information and data from
the principal investigators of all included trials. We performed an
extensive manual search, checking references of original articles
and pertinent reviews to identify additional studies.
Types of outcome measures
Primary outcomes
Data collection and analysis
Mortality
Selection of studies
• All-cause mortality.
• Mortality related to cardiovascular events (death from
myocardial infarction, stroke, peripheral vascular disease, or
sudden death).
Two review authors (NV and MVD) independently scanned the
titles and abstracts from the original search. If inadequate information was provided in the abstract to determine eligibility, the
full text of the article was obtained. Any disagreement was resolved
through discussion between the reviewers. In studies which did
not report detailed subgroup data about patients with diabetes, we
contacted the principal investigators for additional information.
An adapted PRISMA (preferred reporting items for systematic
reviews and meta-analyses) flow-chart of study selection (Figure
1) (Liberati 2009) is attached.
Cardiovascular events
• Myocardial infarction (fatal and non-fatal).
• Stroke (fatal and non-fatal).
• Peripheral arterial disease.
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Figure 1. Study flow diagram.
Data extraction and management
For studies that fulfilled the inclusion criteria, we extracted relevant
population and intervention characteristics using standard data
extraction templates (for details see ’Characteristics of included
studies; Table 1; Appendix 2; Appendix 3; Appendix 4).
Assessment of risk of bias in included studies
Two authors (NV and MVD) assessed each trial independently.
Disagreements were resolved by consensus, or with consultation
of a third party.
We assessed risk of bias using The Cochrane Collaboration’s tool
(Higgins 2011). We used the following risk of bias criteria.
• Random sequence generation (selection bias).
• Allocation concealment (selection bias).
• Blinding (performance bias and detection bias).
• Incomplete outcome data (attrition bias).
• Selective reporting (reporting bias).
• Other bias.
We judged risk of bias criteria as ’low risk’, ’high risk’ or ’unclear risk’ and evaluated individual bias items as described in the
Cochrane Handbook for Systematic Reviews of Interventions (Higgins
2011). A ’Risk of bias’ figure (Figure 2) and a ’Risk of bias summary’ figure (Figure 3) are attached.
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
9
We assessed the impact of individual bias domains on study results
at endpoint and study levels.
Measures of treatment effect
Dichotomous data are expressed as odds ratios (OR) with 95%
confidence intervals (CI). We planned to calculate the risk difference (RD) and convert it into the number needed to treat to
benefit (NNTB) or the number needed to treat to harm (NNTH)
taking into account the time of follow-up if the overall estimate
of effect was statistically significant.
Unit of analysis issues
We planned to take into account the level at which randomisation
occurred, such as cross-over trials, cluster-randomised trials and
multiple observations for the same outcome. However, no such
trial designs were included in this review.
Dealing with missing data
We attempted to obtain relevant missing data from authors and
carefully performed evaluation of important numerical data such
as screened, randomised patients as well as intention-to-treat
(ITT), as-treated and per-protocol (PP) population. We investigated attrition rates, for example drop-outs, losses to follow-up
and withdrawals and critically appraised issues of missing data
and imputation methods (for example, last-observation-carriedforward (LOCF)).
Assessment of heterogeneity
As there was substantial clinical heterogeneity, study results were
only reported as meta-analytically pooled effect estimates for stroke
(fatal and non-fatal). We identified heterogeneity by visual inspection of the forest plots, by using a standard Chi2 test and a significance level of α = 0.1, in view of the low power of this test. We
specifically examined heterogeneity with the I2 statistic quantifying inconsistency across studies to assess the impact of heterogeneity on the meta-analysis (Higgins 2002; Higgins 2003), where an I
2 statistic of 75% and more indicates a considerable level of inconsistency (Higgins 2011). In the presence of considerable statistical
heterogeneity we used a random-effects model for pooling.
Data synthesis
We summarised data statistically if they were available, sufficiently
similar and of sufficient quality. We performed statistical analyses
according to the statistical guidelines referenced in the newest version of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
The table of comparisons was divided into all possible outcomes
(e.g. all-cause mortality, disease specific death). It was not possible
to subdivide into different dosages within the outcome subgroups
as these data were not available.
Subgroup analysis and investigation of heterogeneity
No further subgroup analyses were performed.
Sensitivity analysis
We planned to perform sensitivity analyses in order to explore the
influence of the following factors on the effect estimates.
• Restricting the analysis to published studies.
• Restricting the analysis taking account of risk of bias, as
specified above.
• Restricting the analysis to very long or large studies in order
to establish how much they dominated the results.
• Restricting the analysis to studies using the following filters:
diagnostic criteria, language of publication, source of funding
(industry versus other), country.
We planned to test the robustness of the results by repeating the
analysis using different measures of effect estimates (relative risk,
odds ratio etc.) and different statistical models (fixed-effect and
random-effects models).
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies; Characteristics of ongoing studies.
For details see Characteristics of included studies; Characteristics
of excluded studies and Characteristics of ongoing studies.
Assessment of reporting biases
If we had identified more than 10 RCTs, we planned to use funnel
plots to assess for the potential existence of small study bias. There
are a number of explanations for the asymmetry of a funnel plot
(Sterne 2001) and we planned to carefully interpret results (Lau
2006).
Results of the search
Our search identified a total of 3281 references. We excluded 2477
references because they were on a different topic, 42 were conducted on healthy volunteers or animals and 381 were not randomised controlled trials. A further 198 studies were excluded as
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
10
they used non-clinical outcomes, eight used intravenous medications and 91 used non-eligible populations, controls or interventions. The remaining 84 abstracts were reviewed for duplication
and 29 separate trials were identified. We obtained full text papers for these 29 trials. Of these, 20 were excluded (11 because
the follow-up was less than 12 months, five did not have eligible
controls, two did not collect information about diabetes status,
one was observational and one excluded patients on insulin). One
ongoing trial was identified (SPS3 2011) leaving eight included
studies. There were 35 references identified in the search referring
to these eight included studies. For details please see Figure 1.
classified with diabetes.
Excluded studies
The full text of 21 potential studies was reviewed and excluded
from this study. Further information is available in Characteristics
of excluded studies and Characteristics of ongoing studies.
Risk of bias in included studies
The risk of bias assessment is demonstrated in Figure 2 and Figure
3.
Included studies
We identified a total of eight completed randomised trials which
met the inclusion criteria (AAASPS 2003; CAPRIE 1996; CATS
1988; CHARISMA 2002; CURE 1998; Park 2010; PRoFESS
2008; TASS 1989). The oldest study was completed in 1988 (
CATS 1988) and the most recent study was completed in 2010
(Park 2010). A total of 21,379 patients with diabetes participated
in the eight studies. The mean duration of follow-up was 913 days
(range 365 days to 2373 days).
Three of the included studies investigated ticlopidine (AAASPS
2003; CATS 1988; TASS 1989). Ticlopidine was compared to aspirin in two trials: AAASPS 2003 which included African American participants with a recent history of stroke, and TASS 1989
which included patients with a neurological deficit. The third
study (CATS 1988) compared ticlopidine to placebo in patients
with a thromboembolic stroke.
Five included studies investigated clopidogrel. One study compared clopidogrel to aspirin in 3866 diabetes patients with ischaemic stroke, myocardial infarction or peripheral arterial disease
(CAPRIE 1996). The PRoFESS 2008 study compared clopidogrel to aspirin and dipyridamole in 20,332 patients with ischaemic
stroke, of which 5473 patients had diabetes. The remaining three
studies compared clopidogrel and aspirin to aspirin alone in a total
of 10,099 patients with diabetes; of whom 6555 patients had multiple risk factors for coronary artery disease (CHARISMA 2002),
2840 patients had unstable angina (CURE 1998) and 704 patients
had undergone insertion of drug eluding stents 12 months prior
(Park 2010).
All trials investigating clopidogrel used a dose of 75 mg daily and
all ticlopidine trials used a dose of 250 mg twice daily. The dose of
aspirin ranged from 75 mg daily to 650 mg twice daily. All trials
recorded all-cause mortality, vascular mortality, myocardial infarction and stroke except two (Park 2010; PRoFESS 2008). Only
three trials contributed to the main primary outcome as diabetes
data were not available for the other five trials. See Characteristics
of included studies for details of each trial.
The CAPRIE 1996 trial classified patients as having diabetes if
defined as such by the investigator. No other studies provided
information on how the diagnosis of diabetes was made for patients
Random sequence generation (selection bias)
All included studies used and reported an appropriate method of
randomisation, most commonly computer generated randomisation.
Allocation
Seven of the eight trials used and reported appropriate methods
of allocation concealment. Park 2010 was an open label trial with
study participants and investigators aware of the treatment assignments.
Blinding
All of the included trials were double-blinded, except for the Park
2010 trial in which patients were asked at every visit which medication they were taking. Outcomes were assessed as per standard
criteria; however, the assessors knew which medication patients
were taking and thus outcome assessment was not blinded either.
Incomplete outcome data
The number of participants lost to follow-up in the CHARISMA
trial was not reported (CHARISMA 2002). All other trials reported their loss to follow-up rate. There was a similar withdrawal
rate - approximately 20% - in three trials (AAASPS 2003; CAPRIE
1996; CHARISMA 2002). The withdrawal rate of Park 2010 was
not clearly reported, although it appeared to be over half of the
patients. The withdrawal rate in CURE 1998 was also very high
(approximately 45%).
Selective reporting
The five most recent trials have available published protocols or
registered trial documents. The oldest three trials (CAPRIE 1996;
CATS 1988; TASS 1989), do not have previously published protocols with outcomes and so risk of selective reporting is unknown.
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
11
Other potential sources of bias
All trials except Park 2010 received funding from the pharmaceutical companies who developed and sold adenosine-diphosphate
(ADP) receptor antagonists. The role of the pharmaceutical funding for the AAASPS 2003 trial was reported to be limited to supplying medications only.
Effects of interventions
See: Summary of findings for the main comparison
Unpublished data were sought from all trials, however, additional
unpublished information was only provided by the CATS trial.
The results presented are derived from data extracted from three
trials (CATS 1988; PRoFESS 2008; TASS 1989) including unpublished data provided for the CATS trial. No specific data on
patients with diabetes were available for any of the other trials. For
details see Appendix 3.
Primary outcomes
3194 (11.2%) versus 356/3146 (11.3%); OR 0.81 (95% CI 0.44
to 1.49)) for ADP receptor antagonists versus other antiplatelet
drugs (Analysis 3.4). In the study comparing ticlopidine with aspirin (TASS 1989) a reduction in fatal and non-fatal stroke was
demonstrated with the use of ticlopidine (25/291 (0.9%) versus
44/306 (0.14%) for aspirin; OR 0.56 (95% CI 0.33 to 0.94)
(Analysis 3.2). There was no significant reduction in fatal and nonfatal strokes in diabetes patients when clopidogrel was compared
to aspirin combined with dipyramidole (334/2840 (0.12%) versus
312/2903 (0.11%); OR 1.12 (95% CI 0.05 to 1.32)) (PRoFESS
2008; Analysis 3.3).
Peripheral vascular disease
No data were available from any of the trials on the reduction of
peripheral vascular disease.
Secondary outcomes
Published or unpublished data on safety and adverse events,
health-related quality of life specifically for patients with diabetes
and costs were not available for any of the trials.
Mortality
All-cause mortality and vascular mortality data were only available
for one trial (CATS 1988). This trial included 335 patients with
diabetes (1.5% of the total diabetes participants included in this
review). In this trial, when compared to placebo, ticlopidine was
noted to have no significant effect on all-cause mortality (30/172
(17.4%) versus 23/163 (14.1%); OR 1.29 (95% CI 0.71 to 2.32)
(Analysis 1.1) or vascular mortality (18/172 (10.5%) versus 18/
163 (11%); OR 0.94 (95% CI 0.47 to 1.88) (Analysis 2.1).
Cardiovascular events
Fatal and non-fatal myocardial infarction
Data for combined fatal and non-fatal myocardial infarction were
only available for one trial (CATS 1988). Ticlopidine was not
noted to have any statistically significant effect on reducing this
outcome when compared to placebo (16/172 (9.3%) versus 19/
163 (11.7%); OR 0.78 (95% CI 0.39 to 1.57) (Analysis 4.1).
Fatal and non-fatal stroke
Data for the outcome fatal or non-fatal stroke were available from
two trials (30% of the total diabetes participants), comparing ADP
receptor antagonists with other antiplatelet drugs (PRoFESS 2008;
TASS 1989). These two trials were statistically heterogeneous (I2
= 81%) and a random-effects model was used for pooling. Overall, in the pooled analysis there was no statistically significant reduction in the combination of fatal and non-fatal stroke ((359/
DISCUSSION
This systematic review summarises the available data from eight
eligible studies on the effect of adenosine-diphosphate (ADP) receptor antagonists on mortality and cardiovascular disease in patients with diabetes.
Summary of main results
Available data did not demonstrate a significant benefit of ADP
receptor antagonists over placebo or other antiplatelet drugs in
reducing all-cause mortality, vascular mortality, stroke or myocardial infarction. Ticlopidine was demonstrated to reduce combined
fatal and non-fatal strokes when compared to aspirin in one trial
(Analysis 3.2).
Overall completeness and applicability of
evidence
For most studies, data for patients with diabetes were incomplete.
Although eight trials comparing ADP receptor antagonists with
other antiplatelet drugs or placebo were eligible for inclusion,
only three provided data on patients with diabetes (CATS 1988;
PRoFESS 2008; TASS 1989) and only one CATS 1988 provided
data on more than one outcome for patients with diabetes. Authors of all eight trials were contacted, one author provided information (CATS 1988), the author of one study declined to provide
information (AAASPS 2003), one author did not have any further
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
12
data (PRoFESS 2008) and the authors of the five remaining studies did not respond to two requests (CAPRIE 1996; CHARISMA
2002; CURE 1998; Park 2010; TASS 1989).
All trials reported on safety and adverse outcomes for all included
patients; however, none of the trials reported on adverse outcomes
for patients with diabetes separately. For all patients, all four trials
comparing ADP receptor antagonists with aspirin noted slightly
lower bleeding rates for clopidogrel and ticlopidine compared to
aspirin or aspirin and dipyridamole in combination (AAASPS
2003; CAPRIE 1996; PRoFESS 2008; TASS 1989). However,
these trials used higher doses of aspirin than are commonly prescribed today. The trial comparing ticlopidine to placebo noted
one serious bleeding event in the placebo group compared with two
serious bleeding events in the ticlopidine group (CATS 1988). The
three trials which compared dual aspirin and clopidogrel therapy
to aspirin alone all noted increased bleeding risk with dual therapy (CHARISMA 2002; CURE 1998; Park 2010). A Cochrane
review comparing dual therapy of clopidogrel and aspirin to aspirin alone noted there would be an additional six major bleeds
per 1000 people treated (Squizzato 2011).
None of the included trials reviewed peripheral vascular disease as a
cardiovascular endpoint. No trial used standard diagnostic criteria
to diagnose diabetes and none of the trials separated patients into
type 1 or type 2 diabetes.
There are no trials specifically designed to look at the efficacy
and safety of ADP receptor antagonists for patients with type 2
diabetes. Patients with diabetes have different metabolism and
platelet function to patients without diabetes which predisposes
them to cardiovascular disease (Angiolillo 2009) and this may
change the efficacy and safety of ADP receptor antagonists.
The use of ADP receptor antagonists in diabetes patients is based
on evidence for their use from the analysis of patients with and
without diabetes. Many major guidelines now recommend the
use of clopidogrel in certain situations. For example, the National
Institute of Health and Clinical Excellence guidelines recommend
clopidogrel for 12 months in all patients with unstable angina or
non-ST elevated myocardial infarction with a six month mortality
risk of greater than 1.5% (NICE 2010), based on the CURE
trial findings. As a result, many patients with diabetes are being
prescribed ADP receptor antagonists and newer ADP receptor
antagonists are now compared to clopidogrel rather than to other
antiplatelet agents despite there being limited evidence for patients
with diabetes.
The intention of this review was to assess the use of ADP receptor
antagonists in primary and secondary prevention. However, all of
the trials except one (CHARISMA 2002) enrolled patients who
had previous cardiovascular or cerebrovascular events. ADP receptor antagonists in primary prevention of cardiovascular disease in
high risk vascular patients was investigated by the CHARISMA
trial, however, outcome data for patients with diabetes were unavailable from this trial.
Quality of the evidence
Overall the methodological quality of the eight included trials
was high. All of the trials except one (Park 2010) were doubleblind. The majority of the studies were funded by pharmaceutical
companies.
Most studies reported composite end points as well as individual outcome events. A specific analysis of diabetes patients of the
CAPRIE 1996 trial only reported a composite end point of vascular death, myocardial infarction, stroke and rehospitalisation for
bleeding or ischaemia (Bhatt 2002). From a clinical perspective,
reporting of composite endpoints is less useful as clinicians are
unable to provide relevant information to patients, for example,
the patient’s risk of death.
Potential biases in the review process
It is possible that we have missed trials through the search strategy
despite three databases being searched and relevant review articles
being handsearched. Of the included trials, unpublished diabetesspecific data were provided by only one trial and this may have
introduced bias into the review.
Agreements and disagreements with other
studies or reviews
The largest meta-analysis of antiplatelet therapy versus control was done by the Antithrombotic Trialists Collaboration
(Antithrombotic Trialists’ Collaboration 2002). This meta-analysis reviewed all antiplatelet agents including aspirin and failed to
show a statistically significant reduction in risk of serious vascular
events in patients with diabetes.
There are two Cochrane reviews on ADP receptor antagonists
which differ from our review as they are not limited to patients with
diabetes. One review included all patients with previous clinical
manifestations of atherosclerosis of the cerebral, coronary or peripheral circulation and assessed the composite end point of stroke,
myocardial infarction or vascular death. This review noted that
ADP receptor antagonists modestly reduced the odds of a serious
vascular event when compared to aspirin. The result just reached
statistical significance (11.6% versus 12.5%, OR 0.92 (0.85 to
0.99)) and the authors concluded that ADP receptor antagonists
were at least as effective as aspirin, possibly more so (Sudlow 2009).
A different Cochrane review of clopidogrel and aspirin versus aspirin alone included all patients with known cardiovascular disease
or at high risk of atherothrombotic disease. The authors concluded
that in patients with acute non-ST coronary syndromes the benefits of clopidogrel plus aspirin outweighed the harms (Squizzato
2011).
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
13
AUTHORS’ CONCLUSIONS
Implications for practice
The role of adenosine diphosphate (ADP) receptor antagonists
in patients with diabetes is unclear. The use of ADP receptors
for prevention of cardiovascular disease in patients with diabetes
needs to be guided by evidence available from analysis done on
all patients, including those with and without diabetes. Current
available evidence analysed in previous Cochrane reviews suggests
ADP receptor antagonists were at least as effective as aspirin, possibly more so in preventing cardiovascular disease in secondary
prevention (Sudlow 2009) and that in acute non-ST coronary
syndromes the benefits of clopidogrel and aspirin outweighed the
harms (Squizzato 2011). Another factor to take into account is
the cost of ADP receptor antagonists which in many countries is
significantly higher than aspirin.
Implications for research
All future trials should separately report outcome data for patients
with diabetes to allow for development of clinical guidelines for
this specific patient population. Any previously conducted trial
should make diabetes specific data available for analysis regardless of outcomes. Improved identification and thorough analysis
of subgroups of diabetes patients in large primary and secondary
prevention trials would provide a more solid evidence base for recommendations for primary and secondary prevention in diabetes
patients.
ACKNOWLEDGEMENTS
The authors would like to thank Sarah Thorning for her assistance
with the search strategy and finding the full text for some of the
trials.
REFERENCES
References to studies included in this review
AAASPS 2003 {published data only (unpublished sought but not used)}
Gorelick PB, Leurgans S, Richardson J, Harris Y, Billingsley
M and the AAASPS Investigators. African American
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∗
Gorelick PB, Richardson D, Kelly M, Ruland S, Hung
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CATS 1988 {published and unpublished data}
Gent M, Blakely JA, Easton JD, Ellis DJ, Hachinski VC,
Harbison JW, et al.The Canadian American Ticlopidine
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∗
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Gent M, Ellis D. Canadian American ticlopidine study
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CAPRIE 1996 {published data only (unpublished sought but not used)}
Bhatt DL, Marso SP, Hirsch AT, Tingleb PA, Hacke W,
Topol EJ. Amplified benefit of clopidogrel versus aspirin in
patients with diabetes mellitus. The American Journal of
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∗
CAPRIE Steering Committee. A randomised, blinded,
trial of clopidogrel versus aspirin in patients at risk of
ischaemic events (CAPRIE). The Lancet 1996;348(9038):
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Creager MA. Results of the CAPRIE trial: efficacy and
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Harker LA, Boissel JP, Pilgrim AJ, Gent M. Comparative
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Hirsh J, Bhatt DL. Comparative benefits of clopidogrel and
aspirin in high-risk patient populations. Archives of Internal
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CHARISMA 2002 {published data only (unpublished sought but not
used)}
Bakhru MR, Bhatt DL. Interpreting the CHARISMA study.
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Bhatt DL, Flather MD, Hacke W, Berger PB, Black HR,
Boden WE, et al.Patients with prior myocardial infarction,
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CHARISMA trial. Journal of the American College of
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∗
Bhatt DL, Fox KAA, Hacke W, Berger PB, Black HR, for
the CHARISMA Investigators. Clopidogrel and aspirin
versus aspirin alone for the prevention of atherothrombotic
events. The New England Journal of Medicine 2006;354
(16):1706–17.
Bhatt DL, Topol EJ, on behalf of the CHARISMA
Executive Committee. Clopidogrel added to aspirin versus
aspirin alone in secondary prevention and high-risk primary
prevention: Rationale and design of the Clopidogrel for
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Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
14
High Atherothrombotic Risk and Ischemic Stabilization,
Management, and Avoidance (CHARISMA) trial. American
Heart Journal 2004;148(2):263–8.
Collet JP, Montalescot G, Steg PG, Steinhubl SR,
Fox KA, Hu TF, et al.Clinical outcomes according to
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CHARISMA trial. Archives of Cardiovascular Diseases 2009;
102(6-7):485–96.
Dasgupta A, Steinhubl SR, Bhatt DL, Berger PB, Shao
M, for the CHARISMA Investigators. Clinical outcomes
of patients with diabetic nephropathy randomized to
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analysis of the clopidogrel for high atherothrombotic risk
and ischaemic stabilization, management, and avoidance
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Gresele P, Migliacci R. The peripheral arterial disease
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Hankey GJ, Johnston SC, Easton JD, Hacke W, Mas JL,
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Wang TH, Bhatt DL, Fox KA, Steinhubl SR, Brennan DM,
Hacke W, et al.An analysis of mortality rates with dualantiplatelet therapy in the primary prevention population
of the CHARISMA trial. European Heart Journal 2007;28
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CURE 1998 {published data only (unpublished sought but not used)}
Fox KA, Mehta SR, Peters R, Zhao F, Lakkis N, Gersh BJ,
et al.Benefits and risks of the combination of clopidogrel
and aspirin in patients undergoing surgical revascularization
for non-ST-elevation acute coronary syndrome: the
Clopidogrel in Unstable angina to prevent Recurrent
ischemic Events (CURE) Trial. Circulation 2004;110(10):
1202–8.
Hirsh J, Bhatt DL. Comparative benefits of clopidogrel and
aspirin in high-risk patient populations: Lessons from the
CAPRIE and CURE studies. Archives of Internal Medicine
2004;164(19):2106–10.
Peters RJ, Mehta SR, Fox KA, Zhao F, Lewis BS, Kopecky
SL, et al.Effects of aspirin dose when used alone or in
combination with clopidogrel in patients with acute
coronary syndromes: observations from the Clopidogrel
in Unstable angina to prevent Recurrent Events (CURE)
study. Circulation 2003;108(12):1682–7.
∗
The Clopidogrel in Unstable Angina to Prevent Recurrent
Events Trial Investigators. Effects of clopidogrel in addition
to aspirin in patients with acute coronary syndromes
without ST-segment elevation. The New England Journal of
Medicine 2001;345(7):494–502.
Park 2010 {published data only (unpublished sought but not used)}
Park SJ, Park DW, Kim YH. Duration of dual antiplatelet
therapy after implantation of drug-eluding stents. The New
England Journal of Medicine 2010;362(15):1374–82.
PRoFESS 2008 {published data only (unpublished sought but not
used)}
Bath PM, Cotton D, Martin RH, Palesch Y, Yusuf S, Sacco
R, et al.Effect of combined aspirin and extended-release
dipyridamole versus clopidogrel on functional outcome
and recurrence in acute, mild ischemic stroke: PRoFESS
subgroup analysis. Stroke 2010;41(4):732–8.
Diener HC. The PRoFESS trial: future impact on secondary
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7(9):1085–91.
Diener HS, Sacco R, Yusuf S, for the Steering Committee
and PRoFESS Study Group. Rationale, design and
baseline data of a randomized, double-blind, controlled
trial comparing two antithrombotic regimens (a fixed-dose
combination of extended-release dipyridamole plus ASA
with clopidogrel) and telmisartan versus placebo in patients
with strokes: the Prevention Regimen for Effectively
Avoiding Second Strokes Trial (PRoFESS). Cerebrovascular
Diseases 2007;23(5-6):368–80.
∗
Sacco RL, Diener HC, Yusuf S, Cotton D, Ounpuu S, for
the PRoFESS Study Group. Aspirin and extended-release
dipyridamole versus clopidogrel for recurrent stroke. The
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TASS 1989 {published data only (unpublished sought but not used)}
Bellavance A. Efficacy of ticlopidine and aspirin for
prevention of reversible cerebrovascular ischemic events.
The ticlopidine aspirin stroke study. Stroke 1993;24(10):
1452–7.
Grutta JC, Norris JW, Kamin B and the TASS Baseline and
Angiographic Data Subgroup. Prevention of stroke with
ticlopidine: Who benefits most?. Neurology 1992;42(1):
111–5.
Harbison JW. Ticlopidine versus aspirin for the prevention
of recurrent stroke. Analysis of patients with minor stroke
from the ticlopidine aspirin stroke study. Stroke 1992;23
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∗
Hass WK, Easton J, Adams HP, Pryse-Phillips W, Molony
BA, for the Ticlopidine Aspirin Stroke Study Group. A
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aspirin for the prevention of stroke in high-risk patients.
The New England Journal of Medicine 1989;321(8):501–7.
Pryse-Phillips WAU, for the TASS Group. Ticlopidine
aspirin stroke study: outcome by vascular distribution of
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Ticlopidine Aspirin Stroke Study Group. Ticlopidine versus
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the ticlopidine aspirin stroke study. Journal of Stroke and
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Weisberg LA. The efficacy and safety of ticlopidine and
aspirin in non-whites: analysis of a patient subgroup from
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References to studies excluded from this review
Balsano 1990 {published data only}
∗
Balsano F, Rizzon P, Violi F, Scrutinio D, Cimminiello
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
15
C, Aguglia F, et al.Antiplatelet treatment with ticlopidine
in unstable angina. A controlled multicenter clinical trial.
Circulation 1990;82(1):17–26.
CHANCE 2010 {published data only}
∗
Wang Y, Johnston SC, for the CHANCE investigators.
Rationale and design of a randomized, double-blind trial
comparing the effects of a 3-month clopidogrel-aspirin
regimen versus aspirin alone for the treatment of high-risk
patients with acute nondisabling cerebrovascular event.
American Heart Journal 2010;160(3):380–6.
CLARITY 2005 {published data only}
∗
Sabatine MS, Cannon CP, Gibson CM, López-Sendón
JL, Montalescot G, Theroux P, et al.Effect of clopidogrel
pretreatment before percutaneous coronary intervention in
patients with ST-elevation myocardial infarction treated
with fibrinolytics: the PCI-CLARITY study. JAMA 2005;
294(10):1224–32.
COMMIT 2005 {published data only}
Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, et
al.Addition of clopidogrel to aspirin in 45,852 patients with
acute myocardial infarction: randomised placebo-controlled
trial. The Lancet 2005;366(9497):1607–21.
CREDO 2002 {published data only}
Steinhubl SR, Berger PB, Mann JT III, Fry ET, DeLago A,
Wilmer C, et al.Early and sustained dual oral antiplatelet
therapy following percutaneous coronary intervention:
a randomized controlled trial. JAMA 2002;288(19):
2411–20.
Cun 2002 {published data only}
Cun VG, Temuzhan A, Pekdemur H, Toka M, Tartanoglu
O. The effects of ticlopidine in acute myocardial infarction
as an adjunctive treatment to aspirin in an intermediate
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Harrington 2009 {published data only}
Harrington RA, Stone GW, McNulty S, White HD, Lincoff
AM, Gibson CM, et al.Platelet inhibition with cangrelor
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JUMBO TIMI 2005 {published data only}
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of prasugrel (CS-747, LY640315), a novel thienopyridine
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ticlopidine with aspirin for the prevention of ischaemic
cerebral stroke. Acta Pharmacologica Sinica 1999;20(5):476.
Machraoui 2001 {published data only}
Machraoui A, Germing A, Lindstaedt M, von Dryander S,
Bojara W, Lawo T, et al.Efficacy and safety of ticlopidine
monotherapy versus ticlopidine and aspirin after coronary
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MATCH 2004 {published data only}
Diener HC, Bogousslavsky J, Brass LM, Cimminiello C,
Csiba L, Kaste M, et al.Aspirin and clopidogrel compared
with clopidogrel alone after recent ischaemic stroke or
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Mueller 2003 {published data only}
Mueller C, Roskamm H, Neumann FJ, Hunziker P,
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PLATO 2006 {published data only}
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patients with acute coronary syndromes. The New England
Journal of Medicine 2009;361(11):1045–57.
STAMI 2001 {published data only}
Scrutinio D, Cimminiello C, Marubini E, Pitzalis MV,
Di Biase M, Rizzon P. Ticlopidine versus aspirin after
myocardial infarction (STAMI) trial. Journal of American
College of Cardiology 2001;37(5):1259–65.
STIMS 1990 {published data only}
Janzon L, Berggvist D, Boberg J, Boberg M, Eriksson I,
Lindgarde F, et al.Prevention of myocardial infarction and
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ticlopidine. Results from STIMS, the Swedish Ticlopidine
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TISS 1997 {published data only}
Bergamasco B, Benna P, Carolei A, Rasura M, Rudelli
G, Fieschi C. A randomized trial comparing ticlopidine
hydrochloride with ibuprofen for the prevention of stroke
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and open 24 month follow up study. Japanese Journal of
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TOPALS 2003 {published data only}
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S, Nakajima M. Ticlopidine alone versus ticlopidine plus
aspirin for preventing recurrent stroke (the Tokai Panaldine
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
16
Aspirin Long-term Study (TOPALS)). Internal Medicine
2003;42(9):793–9.
TRITON-TIMI 38 2008 {published data only}
Wivott SD, Braunwald E, McCabe CH, Montalescot G,
Ruzyllo W, Gottlieb S, et al.Prasugrel versus clopidogrel in
patients with acute coronary syndromes. The New England
Journal of Medicine 2007;357(20):2001–15.
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SPS3 2011 {published data only}
Benavente OR, White CL, Pearce L, Pergola P, Roldan A,
Benavente MF, and the SPS3 Investigators. The secondary
prevention of small subcortical strokes (SPS3) study.
International Journal of Stroke April 2011;6(2):164–75.
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American Diabetes Association. Report of the Expert
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ADA 1999
American Diabetes Association. The Expert Committee on
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Goodwin MM, Desilets AR, Willett KC. Thienopyridines
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Gu K, Cowie CC, Harris MI. Mortality in adults with
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Haffner 1998
Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso
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557–60.
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American Diabetes Association. Standards of medical care
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for Systematic Reviews of Interventions Version 5.1.0
[updated March 2011]. The Cochrane Collaboration,
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Angiolillo 2009
Angiolillo DJ, Suryadevara S. Aspirin and clopidogrel:
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Kam, CA, Nethery, CM. The thienopyridine derivatives
(platelet adenosine diphosphate receptor antagonists),
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28–35.
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Bhatt 2002
Bhatt DL, Marso SP, Hirsch AT, Ringleb PA, Hacke W,
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Ceriello A, Motz E. Is oxidative stress the pathogenic
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guidance.nice.org.uk/CG94/NICEGuidance/pdf/English
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Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
17
Squizzato 2011
Squizzato A, Keller T, Romualdi E, Middeldorp
S. Clopidogrel plus aspirin versus aspirin alone for
preventing cardiovascular disease. Cochrane Database
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14651858.CD005158.pub3]
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Sudlow CLM, Mason G, Maurice JB, Wedderburn CJ,
Hankey GJ. Thienopyridine derivatives versus aspirin
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prevalence of diabetes: estimates for the year 2000 and
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∗
Indicates the major publication for the study
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
18
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
AAASPS 2003
Methods
RANDOMISED CONTROLLED CLINICAL TRIAL, RANDOMISATION RATIO: 1:1, EQUIVALENCE DESIGN
Participants
INCLUSION CRITERIA:
African American
29 to 85 years of age
Non-cardioembolic cerebral infarct
Cerebral infarct 7 to 90 days prior
CT or MRI consistent with occurrence of entry cerebral infarct (shows entry infarct, old
infarct, or no infarct)
Measurable neurological deficit that correlates with onset of entry cerebral infarct
Able to follow an outpatient treatment program
EXCLUSION CRITERIA:
Transient ischaemic attack
Subarachnoid haemorrhage
Cardiac embolism
Iatrogenic stroke
Postoperative stroke within 30 days of operation
Carotid endarterectomy as preventive treatment of entry cerebral infarct
Mean arterial blood pressure > 130 mm Hg on 3 consecutive days
Modified Barthel Index < 10
History of dementia or neurodegenerative disease
Severe comorbid condition such as cancer that would limit survival during 2-year followup period
Concurrent enrolment in another clinical trial
Sensitivity or allergy to aspirin or ticlopidine
Women of childbearing potential
Peptic ulcer disease, active bleeding diathesis, lower gastrointestinal bleeding, platelet or
other haematologic abnormality clinically active in the past year
Haematuria
Positive stool guaiac
Prolonged prothrombin time or partial thromboplastin time
Blood urea nitrogen > 40 mg %,
Serum creatinine > 2.0 mg %
Thrombocytopenia or neutropenia as defined by the lower limit of normal for the platelet
count or white blood cell count
≥ 2 times the upper range of normal on liver function tests
PARTICIPANTS:
Total participants: 1809 (Aspirin: 907, Ticlodipine: 902)
Diabetes participants: 738 (Aspirin: 379, Ticlodipine: 359)
Total participants withdrawn or prematurely discontinuing study medication: 454 (Aspirin: 215, Ticlodipine: 239)
Total participants lost to follow-up: 68 (Aspirin: 31, Ticlodipine: 37)
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
19
AAASPS 2003
(Continued)
Interventions
INTERVENTION: Ticlopidine 250 mg twice daily and placebo
CONTROL: Aspirin 325 mg twice daily and placebo
NUMBER OF STUDY CENTRES: 62
COUNTRY/ LOCATION: United States of America
SETTING: Hospital and community
Outcomes
OUTCOMES (as documented in the published protocol):
Composite endpoint of myocardial infarction, recurrent stroke and vascular death
All cause mortality patients with diabetes: unknown
All cause mortality all patients: Aspirin: 40, Ticlopidine: 45
Vascular mortality patients with diabetes: unknown
Vascular mortality all patients: Aspirin:18, Ticlopidine: 18
Myocardial infarction patients with diabetes (fatal): unknown
Myocardial infarction patients with diabetes (non-fatal): unknown
Myocardial infarction all patients (fatal): Aspirin: 0, Ticlopidine: 1
Myocardial infarction all patients (non-fatal): Aspirin: 8, Ticlopidine: 8
Stroke patients with diabetes (fatal): unknown
Stroke patients with diabetes (non-fatal): unknown
Stroke all patients (fatal): Aspirin: 2, Ticlopidine: 4
Stroke all patients (non-fatal): Aspirin: 84, Ticlopidine: 102
Serious adverse event patients with diabetes: unknown
Serious adverse event all patients: Aspirin: 262, Ticlopidine: 270
Study details
RUN-IN PERIOD: None
STUDY TERMINATED BEFORE REGULAR END: Yes - at 6.5 years
Publication details
LANGUAGE OF PUBLICATION: English
COMMERCIAL FUNDING
PUBLICATION STATUS: PEER REVIEW JOURNAL
Stated aim of study
“the primary hypothesis of this ... trial ... is that ticlopidine hydrochloride is more effective than aspirin in preventing the composite endpoints of recurrent stroke, myocardial
infarction, and vascular death among middle-aged and elderly African Americans with
non-cardioembolic ischemic stroke”
Notes
Supported by the National Institute of Neurological Disorders and Stroke. Medications
and placebos were supplied by Roche Laboratories and Bayer
Abbreviations: CT: computed tomography; MRI: magnetic resonance imaging
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
“Randomisation algorithm developed by
chief study statistician”
Allocation concealment (selection bias)
“Local site personnel call the Automated
Phone Registration System for AAASPS
Low risk
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
20
AAASPS 2003
(Continued)
operated by the Moffitt Cancer Research
Institute of the University of South Florida
... for allocation”
Blinding (performance bias and detection Low risk
bias)
All outcomes
“all study personnel were masked (blinded)
from treatment assignment with the exception of 1 study statistician who developed
the randomization algorithm”
“placebo tablets had identical physical
properties”
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk
276 participants withdrew in the Ticlopidine group and 246 in the Aspirin group.
Analysis was done on intention-to-treat basis
Selective reporting (reporting bias)
Low risk
Outcomes reported as stated in the published protocol
Other bias
Low risk
“Roche Laboratories and Bayer had no role
beyond supplying study medications and
placebos.”
CAPRIE 1996
Methods
RANDOMISED CONTROLLED CLINICAL TRIAL, RANDOMISATION RATIO: 1:1, EQUIVALENCE DESIGN
Participants
INCLUSION CRITERIA:
Ischaemic stroke: (including retinal and lacunar infarction) ≥ 1 week and ≤ 6 months
and neurological signs persisting ≥ 1 week from stroke onset and CT or MRI ruling out
haemorrhage or non-relevant disease
MI: Onset ≤ 35 days before randomisation and two of:
Characteristic ischaemic pain for ≥ 20 min
Elevation of CK, CK-MB, LDH, or AST to 2 times upper limit of laboratory normal
with no other explanation
Development of new ≥ 40 Q waves in at least two adjacent ECG leads or new dominant
R wave in V1 (R ≥ 1 mm > S in V1)
Atherosclerotic peripheral arterial disease: Intermittent claudication (WHO: leg pain on
walking, disappearing in < 10 min on standing) of presumed atherosclerotic origin; and
ankle/arm systolic BP ratio ≤ 0·85 in either leg at rest (two assessments on separate days)
; or history of intermittent claudication with previous leg amputation, reconstructive
surgery, or angioplasty with no persisting complications from intervention
EXCLUSION CRITERIA:
Age < 21 years
Severe cerebral deficit likely to lead to patient being bedridden or demented
Carotid endarterectomy after qualifying stroke
Qualifying stroke induced by carotid endarterectomy or angiography
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
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21
CAPRIE 1996
(Continued)
Patient unlikely to be discharged alive after qualifying event
Severe comorbidity likely to limit patient’s life expectancy to less than 3 years
Uncontrolled hypertension
Scheduled for major surgery
Contraindications to study drugs
Severe renal or hepatic insufficiency
Haemostatic disorder or systemic bleeding
History of haemostatic disorder or systemic bleeding
History of thrombocytopenia or neutropenia
History of drug-induced haematologic or hepatic abnormalities
Known to have abnormal WBC, differential, or platelet count
Anticipated requirement for long-term anticoagulants, non-study antiplatelet drugs or
NSAIDs affecting platelet function
History of aspirin sensitivity
Women of childbearing age not using reliable contraception
Currently receiving investigation drug
Previously entered in other clopidogrel studies
Geographic or other factors making study participation impractical
CO-MEDICATIONS:
Antiplatelet or anticoagulation drugs were discontinued before randomisation. Patients
with anticipated need for long term anticoagulation or NSAIDs were excluded. Concomitant medications were recorded
PARTICIPANTS:
Total participants: 19,185 (Aspirin: 9546, Clopidogrel: 9553) [86 did not receive medication, Aspirin 40, Clopidogrel 46]
Diabetes participants: 3866 (Aspirin: 20% of total group, Clopidogrel: 20% of total
group)
Total participants withdrawn or prematurely discontinuing study medication: 4059 (Aspirin: 21.1%, Clopidogrel: 21.3%)
Total participants lost to follow-up: 42 (Aspirin: 20, Clopidogrel: 22)
Interventions
INTERVENTION: Clopidogrel 75 mg daily and placebo
CONTROL: Aspirin 325 mg daily and placebo
NUMBER OF STUDY CENTRES: 384 centres
COUNTRY/ LOCATION: 16 countries
SETTING: Hospital and community
Outcomes
OUTCOMES (as stated in the publication):
Non-fatal Ischaemic Stroke: acute neurological event with focal signs for ≥ 24 hrs; if new
location without evidence of intracranial haemorrhage; if worsening of previous event,
must have lasted > 1 week, or more than 24 hrs if accompanied by appropriate CT or
MRI findings
Non-fatal MI: same as inclusion criteria
Non-fatal primary intracranial haemorrhage: Intracerebral haemorrhage (including intracranial and subarachnoid), and subdural haematoma documented by appropriate neuroimaging investigations
Non-fatal leg amputation: Only if above the ankle and not done for trauma or cancer.
Fatal events: Ischaemic stroke (within 28 days of onset of symptoms/signs), MI (within
28 days of onset of symptoms signs), haemorrhage, other vascular causes (deaths that
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
22
CAPRIE 1996
(Continued)
were not clearly non-vascular and did not meet other criteria) or non-vascular causes
All cause mortality patients with diabetes: unknown
All cause mortality all patients: Aspirin: 571, Clopidogrel: 560
Vascular mortality patients with diabetes: unknown
Vascular mortality all patients: Aspirin: 378, Clopidogrel: 350
Myocardial infarction patients with diabetes (fatal): unknown
Myocardial infarction patients with diabetes (non-fatal): unknown
Myocardial infarction all patients (fatal): Aspirin: 75, Clopidogrel: 53
Myocardial infarction all patients (non-fatal): Aspirin: 301, Clopidogrel: 255
Stroke patients with diabetes (fatal): unknown
Stroke patients with diabetes (non-fatal): unknown
Stroke all patients (fatal): Aspirin: 42, Clopidogrel: 37
Stroke all patients (non-fatal): Aspirin: 504, Clopidogrel: 472
Serious adverse event patients with diabetes: unknown
Serious adverse event all patients: Aspirin: 409, Clopidogrel: 360
Study details
RUN-IN PERIOD: No
STUDY TERMINATED BEFORE REGULAR END: No (recruitment completed
early but follow-up remained at one year post recruitment completion)
Publication details
LANGUAGE OF PUBLICATION: English
COMMERCIAL FUNDING
PUBLICATION STATUS: PEER REVIEW JOURNAL
Stated aim of study
“to assess the potential benefit of clopidogrel, compared with aspirin, in reducing the
risk of ischaemic stroke, myocardial infarction, or vascular death in patients with recent
ischaemic stroke, recent myocardial infarction or peripheral arterial disease”
Notes
This study was funded by Sanofi and Bristol-Myers Squibb
Abbreviations: AST aspartate aminotransferase; BP: blood pressure; CK: creatine kinase; CK-MB: creatine kinase myocardial band; CT: computed tomography; ECG: electrocardiogram; LDH: lactate dehydrogenase; MI: myocardial infarction; MRI: magnetic
resonance imaging; WBC: white blood cells; WHO: World Health Organisation
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
“The Independent Statistical Centre provided computer-generated .... with random
allocation”
Allocation concealment (selection bias)
Low risk
“The Independent Statistical Centre provided computer-generated .... with random
allocation”
Blinding (performance bias and detection Low risk
bias)
All outcomes
“These [Medication] supplies were in the
form of blister packs containing either
75 mg tablets of clopidogrel plus aspirin
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
23
CAPRIE 1996
(Continued)
placebo tablets or 325 mg aspirin tablets
plus clopidogrel placebo tablets, such blister packs being indistinguishable from one
another ”
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk
“19,185 patients ... were randomised”; “46
patients in clopidogrel group and 40 in aspirin group never took any study drug”;
“42 patients lost to follow-up ... included
in the analysis”
“4059 patients discontinued study drug
early...., 21.3% in clopidogrel and 21.1%
in the aspirin group. Reasons for stopping
study drug early were similar in the two
groups”
Comment: equal loss in both groups, included in analysis.
Selective reporting (reporting bias)
Unclear risk
Registration of trial or prior protocol publication unavailable. Outcomes stated in
publication document reported
Other bias
High risk
“This study was funded by Sanofi and Bristol-Myers Squibb”
CATS 1988
Methods
RANDOMISED CONTROLLED CLINICAL TRIAL, RANDOMISATION RATIO: 1:1, EQUIVALENCE DESIGN
Participants
INCLUSION CRITERIA:
Thromboemoblic stroke 1 week to 4 months prior to entry into study
Diagnosis based on clinical assessment and history
Neurological deficit had to be persistent at time of entry into study
CT scan excluded haemorrhagic stroke or other intracerebral pathology
EXCLUSION CRITERIA:
Cardioembolic strokes (defined as two of AF, sick sinus syndrome, seizure at onset,
involvement in more than one vascular territory)
Bedridden or dementia
Life-limiting illness
Contraindications to ticlopidine (hepatic or renal insufficiency, haemostatic disorder,
thrombocytopenia, history of drug-induced haematologic abnormalities)
Significant laboratory test abnormalities
Carotid endarterectomy prior to randomisation
Stroke due to carotid endarterectomy
Long term anticoagulation or antiplatelet therapy required
History of drug or alcohol abuse
Inclusion in another trial
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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CATS 1988
(Continued)
PARTICIPANTS:
Total participants: 1053 (Ticlodipine: 525, Placebo: 528)
Diabetes participants: 335 (Ticlodipine: 172, Placebo: 163)
Total participants withdrawn or prematurely discontinuing study medication: 402
(Ticlodipine: 238, Placebo: 164)
Total participants lost to follow-up: 4 (Ticlodipine: 3, Placebo: 1)
Interventions
INTERVENTION: Ticlopidine 250 mg twice daily
CONTROL: Placebo
NUMBER OF STUDY CENTRES: 25
COUNTRY/ LOCATION: USA and Canada
SETTING: Hospital inpatient
Outcomes
OUTCOMES (as reported in published protocol):
Non-fatal stroke:
Diagnosis based on clinical assessment and history
Duration of > 24 hours if in new location or > 1 week if worsening of previous deficit
unless accompanied by new CT finding
CT scan excluded haemorrhagic stroke or other intracerebral pathology
Non-fatal myocardial infarction:
At least two of:
a) typical symptoms of pain
b) compatible ECG changes or positive pyrophosphate radionuclide scan
c) appropriate serum enzyme changes (peak value > twice upper limit of normal)
Vascular death:
New cerebral infarction
Myocardial infarction
Sudden death
Congestive heart failure
All cause mortality patients with diabetes: 30 ticlopidine, 23 placebo
All cause mortality all patients: 66 ticlopidine, 65 placebo
Vascular mortality patients with diabetes with diabetes: 18 ticlopidine, 18 placebo
Vascular mortality all patients: 35 ticlopidine, 43 placebo
Myocardial infarction patients with diabetes (fatal): 13 ticlopidine, 10 placebo
Myocardial infarction patients with diabetes (non-fatal): 3 ticlopidine, 9 placebo
Myocardial infarction all patients (fatal): 21 ticlopidine, 22 placebo
Myocardial infarction all patients (non-fatal): 11 ticlopidine, 15 placebo
Stroke patients with diabetes (fatal): 6 ticlopidine, 9 placebo
Stroke patients with diabetes (non-fatal): 28 ticlopidine, 32 placebo
Stroke all patients (fatal): 14 ticlopidine, 17 placebo
Stroke all patients (non-fatal): 67 ticlopidine, 86 placebo
Serious adverse event patients with diabetes: unknown
Serious adverse event all patients: 43 ticlopidine, 15 placebo
Study details
RUN-IN PERIOD: No
STUDY TERMINATED BEFORE REGULAR END: No
Publication details
LANGUAGE OF PUBLICATION: English
COMMERCIAL FUNDING
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
25
CATS 1988
(Continued)
PUBLICATION STATUS: PEER REVIEW JOURNAL
Stated aim of study
“to assess the effect of ticlopidine (250 mg twice daily) in reducing the rate of subsequent
occurrence of stroke, myocardial infarction, or vascular death in patients who have had
a recent thromboembolic stroke”
Notes
This study was funded by Syntax Research (USA) Inc and Sanofi, France
Abbreviations: AF: atrial fibrillation; CT: computed tomography; ECG: electrocardiogram
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
Prescribed randomisation arrangement
generated separately for each clinical centre, 528 patients randomised to placebo,
525 to ticlopidine
Allocation concealment (selection bias)
Low risk
Only the safety committee knew the randomisation code for a particular centre
Blinding (performance bias and detection Low risk
bias)
All outcomes
Ticlopidine was supplied.... in plastic containers .... placebo tablets were identical in
packaging and appearance
Incomplete outcome data (attrition bias)
All outcomes
Low risk
4 patients lost to follow-up, 3 in ticlopidine
group, 1 in placebo group
Selective reporting (reporting bias)
Unclear risk
Registration of trial or prior protocol publication unavailable. Outcomes stated in
publication document reported
Other bias
High risk
Funded by pharmaceutical company
CHARISMA 2002
Methods
RANDOMISED CONTROLLED CLINICAL TRIAL, RANDOMISATION RATIO: 1:1, EQUIVALENCE DESIGN
Participants
INCLUSION CRITERIA:
High risk primary prevention: 2 major risk factors or 3 minor risk factors or 1 major
and 2 minor risk factors
Major risk factors:
Diabetes mellitus (on drug therapy)
Diabetic neuropathy
ABI < 0.9
Asymptomatic carotid stenosis ≥ 70%
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
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CHARISMA 2002
(Continued)
Carotid plaque evidence by intima-media thickness
Minor risk factors:
Systolic BP ≥ 150 mm Hg despite therapy for 3 months
Primary hypercholesterolaemia
Current smoker > 15 cigarettes per day
Male ≥ 65 years, female ≥ 70 years
Coronary artery disease: 1 of:
Stable angina with document multivessel coronary disease
History of multivessel CABG
History of multivessel PCI
Previous MI
Cerebrovascular disease: previous ischaemic stroke or TIA
Peripheral arterial disease: intermittent claudication with ABI ≤ 0.85 or intermittent
claudication with previous intervention
EXCLUSION CRITERIA:
Chronic oral antithrombotic medications (warfarin, high dose aspirin, NSAIDs)
Requiring prolonged clopidogrel therapy
CO-MEDICATIONS:
Concurrent oral antithrombotic therapy not permitted. Other standard therapy at the
discretion of clinicians
PARTICIPANTS:
Total participants: 15,603 (Clopidogrel: 7802, Placebo: 7801)
Diabetes participants: 6556 (Clopidogrel: 3304, Placebo: 3252)
Total participants withdrawn or prematurely discontinuing study medication: Clopidogrel: 20.4%, Placebo: 18.2%
Total participants lost to follow-up: unknown
Interventions
INTERVENTION: Clopidogrel 75 mg daily and aspirin 75 mg to 162 mg daily
CONTROL: Placebo and aspirin 75 mg to 162 mg daily
NUMBER OF STUDY CENTRES: 768
COUNTRY/ LOCATION: 32 countries
SETTING: Hospital
Outcomes
OUTCOMES (as stated in the published protocol):
Primary outcome: first occurrence of cardiovascular death, MI (according to American
College of Cardiology definition) or stroke (acute onset of focal neurological symptoms
or signs lasting more than 24 hours, with CT or MRI to exclude other causes)
All cause mortality patients with diabetes: unknown
All cause mortality all patients: Clopidogrel: 371, Placebo: 374
Vascular mortality patients with diabetes: unknown
Vascular mortality all patients: Clopidogrel: 238, Placebo: 229
Myocardial infarction patients with diabetes (fatal): unknown
Myocardial infarction patients with diabetes (non-fatal): unknown
Myocardial infarction all patients (fatal): unknown
Myocardial infarction all patients (non-fatal): Clopidogrel: 146, Placebo: 155
Stroke patients with diabetes (fatal): unknown
Stroke patients with diabetes (non-fatal): unknown
Stroke all patients (fatal): unknown
Stroke all patients (non-fatal): Clopidogrel: 150, Placebo: 189
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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CHARISMA 2002
(Continued)
Serious adverse event patients with diabetes: unknown
Serious adverse event all patients (only bleeding recorded): Clopidogrel: 130, Placebo:
104
Study details
RUN-IN PERIOD: No
STUDY TERMINATED BEFORE REGULAR END: No
Publication details
LANGUAGE OF PUBLICATION: English
COMMERCIAL & NON-COMMERCIAL FUNDING
PUBLICATION STATUS: PEER REVIEW JOURNAL
Stated aim of study
To test if “clopidogrel in combination with aspirin would be an improvement over aspirin
alone across the spectrum of high risk patients with atherothrombosis”
Notes
Sponsored and funded by Sanofi-Aventis and Bristol-Myers Squibb and the National
Institutes of Health
Abbreviations: ABI: ankle brachial index; CABG: coronary artery bypass grafting; CT:
computed tomography; MI: myocardial infarction; MRI: magnetic resonance imaging;
NSAIDs: non-steriodal anti-inflammatory drugs; PCI: percutaneous coronary intervention; TIA: transient ischaemic attack
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
“pre-established randomisation scheme,
stratified according to site”
Allocation concealment (selection bias)
“Study drug assignment was performed
centrally by an interactive voice-response
system”
Low risk
Blinding (performance bias and detection Low risk
bias)
All outcomes
“Matching placebo drug”
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk
Withdrawal rate 20% for clopidogrel
group, 18.2% for placebo group. Number
of patients lost to follow-up unknown
Selective reporting (reporting bias)
Low risk
Outcomes reported as stated
Other bias
High risk
Pharmaceutical funding from Sanofi-Aventis and Bristol-Myers Squibb
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
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28
CURE 1998
Methods
RANDOMISED CONTROLLED CLINICAL TRIAL, RANDOMISATION RATIO: 1:1, EQUIVALENCE DESIGN
Participants
INCLUSION CRITERIA:
Admitted to hospital with:
Symptoms suggestive of ACS without ST segment elevation > 1 mm
Within 24 hours of onset of chest pain/symptoms
Either ECG changes compatible with new ischaemia or elevated cardiac enzymes or
troponin I or T at least twice upper limit of normal
EXCLUSION CRITERIA:
Contraindications to antiplatelet/antithrombotic therapy
High risk of bleeding
Class IV heart failure
Ongoing long term need for anticoagulants
PTCA/stent or CABG within 3 months prior to randomisation
CO-MEDICATIONS:
Aspirin (75 mg to 325 mg) started at randomisation or continued if already taking
PARTICIPANTS:
Total participants: 12,562 (Clopidogrel: 6259, Placebo: 6303)
Diabetes participants: 2840 (Clopidogrel: 1405, Placebo: 1435)
Total participants withdrawn or prematurely discontinuing study medication: Clopidogrel: 21.1%, Placebo: 18.8%
Total participants lost to follow-up: 13 (Clopidogrel: 6, Placebo: 7)
Interventions
INTERVENTION: 300 mg loading dose of clopidogrel then 75 mg per day and aspirin
75 mg to 325 mg daily
CONTROL: Placebo and aspirin 75 mg to 325 mg daily
NUMBER OF STUDY CENTRES: 482
COUNTRY/ LOCATION: 28 countries
SETTING: Hospital
Outcomes
OUTCOMES (as stated in the published protocol):
1.
The composite of cardiovascular death, non-fatal myocardial infarction or stroke
2.
The composite of cardiovascular death, non-fatal myocardial infarction, stroke or
refractory ischaemia
Death from cardiovascular cause: death for which there was no clearly documented nonvascular cause
Myocardial infarction: presence of at least two of: ischaemic chest pain, elevation of
cardiac markers or enzymes to at least twice upper limit of normal within 48 hours after
percutaneous coronary intervention (or to a level 20% higher than the previous value
if the level had already been elevated because of an early myocardial infarction), ECG
changes compatible with infarction
Stroke: result of intracranial haemorrhage, ischaemia or uncertain cause
Refractory ischaemia in hospital: recurrent chest pain lasting more than five minutes with
new ischaemic ECG changes while the patient was receiving optimal medical therapy
(two anti-anginal agents, including V nitrate unless contraindicated) leading to additional
intervention by midnight of the next calendar day
Refractory ischaemia on discharge: rehospitalisation lasting at least 24 hours for unstable
angina with ischaemic ECG changes
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
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29
CURE 1998
(Continued)
Severe ischaemia: Ischaemia similar to refractory ischaemia for which no urgent intervention was performed
All cause mortality patients with diabetes: unknown
All cause mortality all patients: Clopidogrel: 359, Placebo: 390
Vascular mortality patients with diabetes: unknown
Vascular mortality all patients: Clopidogrel: 318, Placebo: 345
Myocardial infarction patients with diabetes (fatal): unknown
Myocardial infarction patients with diabetes (non-fatal): unknown
Myocardial infarction all patients (fatal and non-fatal): Clopidogrel: 324, Placebo 419
Stroke patients with diabetes (fatal): unknown
Stroke patients with diabetes (non-fatal): unknown
Stroke all patients (fatal and non-fatal): Clopidogrel: 75, Placebo: 87
Serious adverse event patients with diabetes: unknown
Serious adverse event all patients (only bleeding recorded): Clopidogrel: 231, Placebo:
169
Study details
RUN-IN PERIOD: No
STUDY TERMINATED BEFORE REGULAR END: No - study initially designed
for 9000 patients, however, increased to 12,500 due to lower event rates than expected
Publication details
LANGUAGE OF PUBLICATION: English
COMMERCIAL FUNDING
PUBLICATION STATUS: PEER REVIEW JOURNAL
Stated aim of study
“To compare the efficacy and safety of the early and long-term use of clopidogrel plus
aspirin with those of aspirin alone in patients with acute coronary syndromes and no
ST-segment elevation”
Notes
Supported by Sanofi-Synthelabo and Bristol-Myers Squibb
Abbreviations: ACS: acute coronary syndrome; ECG: electrocardiogram; PTCA: percutaneous transluminal coronary angioplasty; CABG: coronary artery bypass grafting
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
“Randomised to either clopidogrel or
placebo by telephone call to central computerised randomisation service”
“Permuted block randomisation .... is used”
Allocation concealment (selection bias)
Low risk
“Telephone call to central computerised
randomisation service”
Blinding (performance bias and detection Low risk
bias)
All outcomes
“Blinded study drug... matching placebo”
“A central committee of clinicians who are
blinded to treatment allocation will adjudicate ... outcomes”
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
30
CURE 1998
(Continued)
Incomplete outcome data (attrition bias)
All outcomes
High risk
“Vital status was ascertained for 12,549 of
the 12,562 patients who underwent randomization (99.9 percent), with 6 patients
in the clopidogrel group and 7 in the
placebo group lost to follow-up”
“46.2% of patients in clopidogrel group
discontinued study medication ... as compared with 45.4% in the placebo group”
Selective reporting (reporting bias)
Low risk
Outcome data reported as stated in published protocol
Other bias
High risk
Funded by pharmaceutical company
Park 2010
Methods
RANDOMISED CONTROLLED CLINICAL TRIAL, RANDOMISATION RATIO: 1:1, EQUIVALENCE DESIGN
Participants
INCLUSION CRITERIA:
Undergone implantation of drug eluting stents at least 12 months before enrolment
Receiving dual antiplatelet therapy at time of enrolment
EXCLUSION CRITERIA:
Major adverse cardiovascular event (myocardial infarction, stroke, repeat revascularisation) since implantation
Major bleeding since implantation
Contraindications to the use of antiplatelet drugs
Requirement of long term clopidogrel
Non-cardiac coexisting condition with anticipated life expectancy of less than one year
Participitation in another trial
CO-MEDICATIONS:
Usual care as per treating physician
PARTICIPANTS:
Total participants: 2701 (Clopidogrel and aspirin: 1357, Aspirin only: 1344)
Diabetes participants: 704 (Clopidogrel and aspirin: 340, Aspirin: 364)
Total participants withdrawn or prematurely discontinuing study medication: 2061
(Clopidogrel and aspirin: 1030, Aspirin: 1031)
Total participants lost to follow-up: unknown
Interventions
INTERVENTION: Clopidogrel 75 mg daily and aspirin 100 mg to 200 mg daily
CONTROL: Aspirin 100 mg to 200 mg per day
NUMBER OF STUDY CENTRES: 22
COUNTRY/ LOCATION: South Korea
SETTING: Inpatient and community
TREATMENT BEFORE STUDY: Dual antiplatelet therapy
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
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31
Park 2010
(Continued)
Outcomes
OUTCOMES (as stated in registered trial documents):
Myocardial infarction
Death from cardiac causes
Death from any cause
Composite of myocardial infarction, stoke, death from cardiac causes
Major bleeding
All cause mortality patients with diabetes: unknown
All cause mortality all patients: Aspirin and clopidogrel: 20, Aspirin only 13
Vascular mortality patients with diabetes: unknown
Vascular mortality all patients: unknown
Myocardial infarction patients with diabetes (fatal and non-fatal): unknown
Myocardial infarction all patients (fatal and non-fatal): Aspirin and clopidogrel: 10,
Aspirin only: 7 [specific numbers for fatal and non-fatal unknown]
Stroke patients with diabetes (fatal and non-fatal): unknown
Stroke all patients (fatal and non-fatal): Aspirin and clopidogrel: 9, Aspirin only: 4
[specific numbers for fatal and non-fatal unknown]
Major bleeding patients with diabetes: unknown
Major bleeding all patients: Aspirin and clopidogrel: 3, Aspirin only: 1
Study details
RUN-IN PERIOD: No
STUDY TERMINATED BEFORE REGULAR END: No
Publication details
LANGUAGE OF PUBLICATION: English
COMMERCIAL FUNDING: No
NON-COMMERCIAL FUNDING: Unknown
PUBLICATION STATUS: PEER REVIEW JOURNAL
Stated aim of study
“evaluated the effect of the use of dual antiplatelet therapy for more than 12 months
on long-term clinical outcomes in patients who had undergone initial PCI with the
placement of a drug-eluting stent”
Notes
“There was no industry involvement in the design, conduct, financial support, or analysis”
Abbrevations: PCI: percutaneous coronary intervention
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
“assignments were made according to a preestablished, computer-generated randomization scheme, with stratification on the
basis of site and type of ... drug eluting
stent”
Allocation concealment (selection bias)
“the trial was open label study..... subjects
and the investigators were aware of the
treatment assignments”
High risk
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
32
Park 2010
(Continued)
Blinding (performance bias and detection High risk
bias)
All outcomes
Participants and investigators were not
blinded
Incomplete outcome data (attrition bias)
All outcomes
High risk
More than half of the patients discontinued
study medication by the end of the study
Selective reporting (reporting bias)
Low risk
Outcomes reported as stated
Other bias
Low risk
“no industry involvement in the design,
conduct, financial support, or analysis”
PRoFESS 2008
Methods
RANDOMISED CONTROLLED CLINICAL TRIAL, RANDOMISATION RATIO: 1:1, EQUIVALENCE DESIGN
FACTORIAL RCT: 2 x 2 factorial design comparing aspirin and dipyridamole with
clopidogrel and telmisartan with placebo
Participants
INCLUSION CRITERIA:
1. Patients ≥ 55 years AND ischaemic stroke within 90 days before randomisation
After enrolment of 6000 patients the protocol was amended to broaden the inclusion
criteria as follows:
2. Patients 50to 54 years AND ischaemic stroke within 120 days AND two additional
risk factors (diabetes mellitus, hypertension, smoker at time of qualifying stroke, obesity
(body mass index > 30), previous vascular disease (stroke, MI or peripheral arterial disease)
, end-organ damage (retinopathy, left ventricular hypertrophy or microalbuminuria) or
hyperlipidaemia
3. Patients ≥ 55 years AND ischaemic stroke within 120 days AND two additional risk
factors
EXCLUSION CRITERIA:
1. Patients unable to give informed consent
2. Patients presenting with a primary haemorrhagic stroke (intracerebral haemorrhage
or subarachnoid haemorrhage)
3. Patients who are unable to take by mouth all required study medication
4. Known brain tumour
5. Pre-stroke history of dementia requiring institutional care
6. A modified Rankin scale score > 4 at baseline
7. The patient is unlikely to be released from hospital following the qualifying stroke, or
the presence of a severe disability after the qualifying stroke likely to lead to the patient
being bedridden or demented, or a non-vascular disease or condition which makes it
unlikely that the patient will survive to the end of the trial
8. Patients whose qualifying stroke had been induced by a surgical or cardiovascular
procedure such as carotid endarterectomy, angiogram or cardiac surgery
9. Patients with known hypersensitivity to dipyridamole, clopidogrel, aspirin or telmisartan
10. Uncontrolled hypertension which equals or exceeds either a sitting systolic BP greater
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
33
PRoFESS 2008
(Continued)
than 180 mm Hg, or a sitting diastolic BP greater than 110 mm Hg (all hypertensive
patients are treated appropriately, and ‘goal’ BPs are much lower than 180/110)
11. Seated systolic BP ≤ 120 mm Hg for patients who are still hospitalised following
the qualifying stroke
12. Patients currently being treated with an angiotensin II receptor blocker who are
unable or unwilling to discontinue treatment with this type of drug
13. Patients with required or planned continued treatment with antithrombotics or
anticoagulants including heparin or warfarin, or non-study platelet inhibitors
14. Known severe renal insufficiency defined as renal artery stenosis or creatinine clearance < 0.6 ml/s or serum creatinine > 265 µmol/L (> 3.0 mg/dL)
15. Known severe hepatic dysfunction as defined by the following laboratory parameters:
SGPT (ALT) or SGOT (AST) > 4 times upper limit of normal, or total bilirubin > 20
µmol/L
16. Hyperkalaemia, defined as potassium > 5.5 mmol/L
17. Uncorrected volume depletion or sodium depletion
18. Known current active peptic ulcer disease
19. Patients with the syndrome of asthma, rhinitis and nasal polyps (all three present)
20. Known severe coronary artery disease including unstable angina pectoris or an MI
within the previous 3 months
21. Patients considered unreliable by the investigator concerning the requirements for
follow-up during the study and/or compliance with study drug administration
22. Known presence of or history of a haemostatic disorder or systemic bleeding
23. History of thrombocytopenia (i.e. less than 100 × 109/L for platelets) or neutropenia
(1.2 × 109/L for neutrophils)
24. Women who are breast-feeding, pregnant or of childbearing potential who do not
use a medically acceptable form of contraception
25. Patients who have been exposed to an investigational drug or device within the last
30 days, or are currently participating in such a trial
26. Patients scheduled for major surgery, carotid endarterectomy or carotid angioplasty
should not enter the study; such patients may enter the trial 4 weeks after such procedures,
if they still meet all other entry criteria
PARTICIPANTS:
Total participants: 20,332 (Clopidogrel: 10,151, Aspirin/dipyridamole: 10,181)
Diabetes participants: 5743 (Clopidogrel: 2840, Aspirin/dipyridamole: 2903)
Total participants withdrawn or prematurely discontinuing study medication: Clopidogrel: 2290, Aspirin/dipyridamole: 2961)
Total participants lost to follow-up: 250 (Clopidogrel: 125, Aspirin/dipyridamole: 125)
Interventions
INTERVENTION: Clopidogrel 75 mg daily and placebo
CONTROL: Aspirin/dipyridamole 25 mg/200 mg twice daily and placebo
For the first 8 months, 2027 patients in the clopidogrel group were receiving aspirin and
clopidogrel however the MATCH trial demonstrated increased bleeding with aspirin and
clopidogrel so the protocol was changed to clopidogrel only.
NUMBER OF STUDY CENTRES: 695
COUNTRY/ LOCATION: 35 countries
SETTING: Hospital and community
Outcomes
OUTCOMES (as stated in the published protocol):
Primary outcome event:
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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PRoFESS 2008
(Continued)
Stroke (non-fatal or fatal) either ischaemic or haemorrhagic or of uncertain cause
Secondary outcome events:
Vascular events either stroke or MI or vascular death
All cause mortality patients with diabetes: unknown
All cause mortality all patients: Clopidogrel: 756, Aspirin/dipyridamole: 739
Vascular mortality patients with diabetes: unknown
Vascular mortality all patients: unknown
Myocardial infarction patients with diabetes (fatal and non-fatal): unknown
Myocardial infarction all patients (fatal and non-fatal): Clopidogrel: 197, Aspirin/dipyridamole: 178 [specific numbers for fatal and non-fatal unknown]
Stroke patients with diabetes (fatal and non-fatal): Clopidogrel: 334, Aspirin/dipyridamole: 312 [specific numbers for fatal and non-fatal unknown]
Stroke all patients (fatal and non-fatal): Clopidogrel: 862, Aspirin/dipyridamole: 879
[specific numbers for fatal and non-fatal unknown]
Serious adverse event patients with diabetes: unknown
Serious adverse event all patients (only bleeding recorded): Clopidogrel: 365, Aspirin/
dipyridamole: 419
Study details
RUN-IN PERIOD: No
STUDY TERMINATED BEFORE REGULAR END: No
Publication details
LANGUAGE OF PUBLICATION: English
COMMERCIAL FUNDING
PUBLICATION STATUS: PEER REVIEW JOURNAL
Stated aim of study
“to compare the relative efficacy and safety of aspirin plus extended-release dipyridamole
with that of clopidogrel among patients who had a recent ischemic stroke”
Notes
Supported by Boehringer Ingelheim (which manufactures Aggrenox [a combination of
extended-release dipyridamole and aspirin] and Micardis [telmisartan])
Abbreviations: BP: blood pressure; MI: myocardial infarction; SGOT (AST): Serum
glutamic oxaloacetic transaminase / aspartate transaminase;.SGPT (ALT): Serum glutamic pyruvate transaminase / alanine transaminase
Risk of bias
Bias
Authors’ judgement
Support for judgement
Random sequence generation (selection Low risk
bias)
“The randomization to telmisartanwas
stratified based on whether or not individuals were receiving ACE inhibitors, although
the analysis will be based on both strata
combined. Patients were randomized using
a central telephone randomization system.
” (from protocol of PRoFESS)
Allocation concealment (selection bias)
“Patients were randomized using a central
telephone randomization system”
Low risk
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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PRoFESS 2008
(Continued)
Blinding (performance bias and detection Low risk
bias)
All outcomes
“the medication was ‘double dummy’ ... so
that all patients received identically appearing medication kits”
Incomplete outcome data (attrition bias)
All outcomes
Low risk
175 patients lost in both groups
Selective reporting (reporting bias)
Low risk
Outcomes reported as stated
Other bias
High risk
“the ASA active and placebo component of
the clopidogrel arm was discontinued following the presentation of the MATCH results and removed from subsequent treatment kits”
Funded by Boehringer Ingelheim
TASS 1989
Methods
RANDOMISED CONTROLLED CLINICAL TRIAL, RANDOMISATION RATIO: 1:1, EQUIVALENCE DESIGN
Participants
INCLUSION CRITERIA:
One of the following within the past 3 months:
Transient Ischaemic attack: focal ischaemic cerebrovascular event lasting < 24 hours
followed by complete recovery
Amaurosis fugax: unilateral ischaemic retinal episode lasting < 24 hours
Reversible ischaemic neurologic deficit: focal ischaemic cerebrovascular event lasting >
24 hours and < 3 weeks followed by complete recovery
Minor stroke: focal ischaemic cerebrovascular event results in minimal permanent neurologic deficit and at least 80% recovery of function within three weeks
EXCLUSION CRITERIA:
Carotid artery surgery within last three months
Moderate to major stroke within last three months
Women with child bearing potential
Cardiogenic embolism
Haematological disorders
History of peptic ulcer disease or gastrointestinal bleeding
Life-threatening diseases such as cancer
Hypersensitivity or intolerance to aspirin
Need for continued use of aspirin or anticoagulants
CONCURRENT MEDICATIONS: Anticoagulants and antiplatelets prohibited
PARTICIPANTS:
Total participants: 3069 (Ticlodipine: 1529, Aspirin: 1540) [12 participants later judged
ineligible]
Diabetes participants: 597 (Ticlodipine: 291, Aspirin: 306)
Total participants withdrawn or prematurely discontinuing study medication: 1216
(Ticlopidine: 655, Aspirin: 561)
Total participants lost to follow-up: 84 (Ticlodipine: 46, Aspirin: 38)
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
36
TASS 1989
(Continued)
Interventions
INTERVENTION: Ticlopidine 250 mg twice daily
CONTROL: Aspirin 650 mg twice daily
NUMBER OF STUDY CENTRES: 56
COUNTRY/ LOCATION: United States and Canada
SETTING: Hospital and community
Outcomes
OUTCOMES (as stated in the published report):
Stroke: Demonstration of brain infarction at autopsy or rapid onset of focal cerebral
dysfunction > 24 hours associated with typical findings on neurologic examination,
laboratory studies and radiologic tests
Death from all causes
All cause mortality patients with diabetes: unknown
All cause mortality all patients: Ticlopidine: 175, Aspirin: 196
Vascular mortality patients with diabetes: unknown
Vascular mortality all patients: Ticlopidine: 120, Aspirin: 116
Myocardial infarction patients with diabetes (fatal): unknown
Myocardial infarction patients with diabetes (non-fatal): unknown
Myocardial infarction all patients (fatal): Ticlopidine: 21, Aspirin: 14
Myocardial infarction all patients (non-fatal): unknown
Stroke patients with diabetes (fatal and non-fatal): Ticlopidine: 25, Aspirin: 44 [specific
numbers for fatal and non-fatal unknown]
Stroke all patients (fatal): Ticlopidine: 16, Aspirin: 23
Stroke all patients (non-fatal): Ticlopidine: 156, Aspirin:189
Serious adverse event patients with diabetes: unknown
Serious adverse event (bleeding only) all patients: Ticlopidine: 137, Aspirin: 152
Study details
RUN-IN PERIOD: No
STUDY TERMINATED BEFORE REGULAR END: No
Publication details
LANGUAGE OF PUBLICATION: English
COMMERCIAL FUNDING
PUBLICATION STATUS: PEER REVIEW JOURNAL
Stated aim of study
“to test the usefulness of ticlopidine in preventing stroke or death in patients at high
risk, we undertook a randomized trial comparing ticlopidine and aspirin”
Notes
“supported by Syntex Research, Palo Alto, Calif.”
Risk of bias
Bias
Authors’ judgement
Random sequence generation (selection Low risk
bias)
Support for judgement
“randomization within each center stratified on ... history of ischemic cardiovascular disease, the occurrence of a moderate or
major stroke more than three months before entry, and the patient’s sex” “Maryland
Medical Research Institute ... randomly as-
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
37
TASS 1989
(Continued)
signed eligible patients”
Allocation concealment (selection bias)
Low risk
“only the Maryland Medical Research Institute and an independent, external safety
committee had access to the randomized
code”
Blinding (performance bias and detection Low risk
bias)
All outcomes
“medications were suppIied in identical
capsules and containers”
“Blinded adjudicators ... classified alI endpoint events using standardized criteria
drawn up
before the study”
Incomplete outcome data (attrition bias)
All outcomes
Low risk
“intention to treat analyses were performed”
less than 3% loss to follow-up
Selective reporting (reporting bias)
Unclear risk
Published protocol or registered trial document not available
Other bias
High risk
Pharmaceutical funded
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Balsano 1990
Follow-up only 6 months
CHANCE 2010
Follow-up only 3 months
CLARITY 2005
Follow-up only 30 days
COMMIT 2005
Follow-up only 30 days
CREDO 2002
Placebo group received clopidogrel for 30 days after PCI
Cun 2002
Follow-up only 6 months
Harrington 2009
Follow-up only 30 days
Ishikawa 1997
Observational trial
JUMBO TIMI 2005
Follow-up only 30 days
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
38
(Continued)
Li 1999
Diabetes information not collected
Machraoui 2001
Follow-up only 3 months
MATCH 2004
ADP-receptor inhibitor was not compared with alternative treatment or placebo
Mueller 2003
Intervention for only 4 weeks
PLATO 2006
ADP-receptor inhibitor is not compared with alternative treatment or placebo
STAMI 2001
Follow-up only 3 months
STIMS 1990
Diabetes patients on insulin excluded
TISS 1997
Follow-up only 30 days
Tohgi 1987
Diabetes information not collected
TOPALS 2003
ADP-receptor inhibitor was not compared with alternative treatment or placebo
TRITON-TIMI 38 2008
ADP-receptor inhibitor was not compared with alternative treatment or placebo
Characteristics of ongoing studies [ordered by study ID]
SPS3 2011
Trial name or title
Secondary Prevention of Small Subcortical Strokes (SPS3)
Methods
Randomised controlled trial
Participants
3000 patients with small subcortical strokes within the last 6 months
Interventions
Clopidogrel and aspirin or aspirin and placebo
Intensive or usual blood pressure treatment
Outcomes
Recurrent stroke, rate of cognitive decline and major vascular events
Starting date
February 2003
Contact information
SPS3 Coordinating Centre
UBC Department of Medicine | Division of Neurology
S169-2211 Wesbrook Mall, Vancouver, BC, V6T 2B5
Phone: 604-822-1789
Notes
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
39
DATA AND ANALYSES
Comparison 1. All-cause mortality
Outcome or subgroup title
1 Ticlopidine vs placebo
No. of
studies
No. of
participants
1
Statistical method
Odds Ratio (M-H, Fixed, 95% CI)
Effect size
Subtotals only
Comparison 2. Vascular mortality
Outcome or subgroup title
1 Ticlopidine vs placebo
No. of
studies
No. of
participants
1
Statistical method
Odds Ratio (M-H, Fixed, 95% CI)
Effect size
Subtotals only
Comparison 3. Stroke (fatal and non-fatal)
Outcome or subgroup title
1 Ticlodipine vs placebo
2 Ticlodipine vs aspirin
3 Clopidogrel vs aspirin &
dipyridamole
4 ADP receptor antagonists vs
other antiplatelet drug
No. of
studies
No. of
participants
1
1
1
2
6340
Statistical method
Effect size
Odds Ratio (M-H, Fixed, 95% CI)
Odds Ratio (M-H, Fixed, 95% CI)
Odds Ratio (M-H, Fixed, 95% CI)
Subtotals only
Subtotals only
Subtotals only
Odds Ratio (M-H, Random, 95% CI)
0.81 [0.44, 1.49]
Comparison 4. Myocardial infarction (fatal and non-fatal)
Outcome or subgroup title
1 Ticlopidine/Placebo
No. of
studies
1
No. of
participants
Statistical method
Odds Ratio (M-H, Fixed, 95% CI)
Effect size
Subtotals only
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
40
Analysis 1.1. Comparison 1 All-cause mortality, Outcome 1 Ticlopidine vs placebo.
Review:
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus
Comparison: 1 All-cause mortality
Outcome: 1 Ticlopidine vs placebo
Study or subgroup
Ticlopidine
Placebo
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
30/172
23/163
1.29 [ 0.71, 2.32 ]
0
0
0.0 [ 0.0, 0.0 ]
CATS 1988
Subtotal (95% CI)
Total events: 30 (Ticlopidine), 23 (Placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
Test for subgroup differences: Not applicable
0.01
0.1
1
Favours Ticlopidine
10
100
Favours Placebo
Analysis 2.1. Comparison 2 Vascular mortality, Outcome 1 Ticlopidine vs placebo.
Review:
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus
Comparison: 2 Vascular mortality
Outcome: 1 Ticlopidine vs placebo
Study or subgroup
Ticlopidine
Placebo
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
18/172
18/163
0.94 [ 0.47, 1.88 ]
0
0
0.0 [ 0.0, 0.0 ]
CATS 1988
Subtotal (95% CI)
Total events: 18 (Ticlopidine), 18 (Placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
Test for subgroup differences: Not applicable
0.01
0.1
Favours Ticlopidine
1
10
100
Favours Placebo
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
41
Analysis 3.1. Comparison 3 Stroke (fatal and non-fatal), Outcome 1 Ticlodipine vs placebo.
Review:
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus
Comparison: 3 Stroke (fatal and non-fatal)
Outcome: 1 Ticlodipine vs placebo
Study or subgroup
Ticlodipine
Placebo
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
34/172
41/163
0.73 [ 0.44, 1.23 ]
0
0
0.0 [ 0.0, 0.0 ]
CATS 1988
Subtotal (95% CI)
Total events: 34 (Ticlodipine), 41 (Placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
Test for subgroup differences: Not applicable
0.2
0.5
1
Favours Ticlopidine
2
5
Favours Placebo
Analysis 3.2. Comparison 3 Stroke (fatal and non-fatal), Outcome 2 Ticlodipine vs aspirin.
Review:
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus
Comparison: 3 Stroke (fatal and non-fatal)
Outcome: 2 Ticlodipine vs aspirin
Study or subgroup
Ticlopidine
Aspirin
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
25/291
44/306
0.56 [ 0.33, 0.94 ]
0
0
0.0 [ 0.0, 0.0 ]
TASS 1989
Subtotal (95% CI)
Total events: 25 (Ticlopidine), 44 (Aspirin)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
Test for subgroup differences: Not applicable
0.05
0.2
Favours ticlodipine
1
5
20
Favours aspirin
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
42
Analysis 3.3. Comparison 3 Stroke (fatal and non-fatal), Outcome 3 Clopidogrel vs aspirin & dipyridamole.
Review:
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus
Comparison: 3 Stroke (fatal and non-fatal)
Outcome: 3 Clopidogrel vs aspirin % dipyridamole
Study or subgroup
PRoFESS 2008
Clopidogrel
Aspirin/dipyridamole
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
334/2840
312/2930
1.12 [ 0.95, 1.32 ]
0
0
0.0 [ 0.0, 0.0 ]
Subtotal (95% CI)
Total events: 334 (Clopidogrel), 312 (Aspirin/dipyridamole)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
Test for subgroup differences: Not applicable
0.1 0.2
0.5
Favours Clopidogrel
1
2
5
10
Favours Aspirin/dipyridam
Analysis 3.4. Comparison 3 Stroke (fatal and non-fatal), Outcome 4 ADP receptor antagonists vs other
antiplatelet drug.
Review:
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus
Comparison: 3 Stroke (fatal and non-fatal)
Outcome: 4 ADP receptor antagonists vs other antiplatelet drug
Study or subgroup
PRoFESS 2008
TASS 1989
Total (95% CI)
ADP
receptor
antagonists
Other
antiplatelet
drugs
n/N
n/N
334/2903
312/2840
57.9 %
1.05 [ 0.89, 1.24 ]
25/291
44/306
42.1 %
0.56 [ 0.33, 0.94 ]
3194
3146
100.0 %
0.81 [ 0.44, 1.49 ]
Odds Ratio
MH,Random,95%
CI
Weight
Odds Ratio
MH,Random,95%
CI
Total events: 359 (ADP receptor antagonists), 356 (Other antiplatelet drugs)
Heterogeneity: Tau2 = 0.16; Chi2 = 5.18, df = 1 (P = 0.02); I2 =81%
Test for overall effect: Z = 0.69 (P = 0.49)
Test for subgroup differences: Not applicable
0.5
0.7
Favours ADP
1
1.5
2
Favours control
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
43
Analysis 4.1. Comparison 4 Myocardial infarction (fatal and non-fatal), Outcome 1 Ticlopidine/Placebo.
Review:
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus
Comparison: 4 Myocardial infarction (fatal and non-fatal)
Outcome: 1 Ticlopidine/Placebo
Study or subgroup
Ticlopidine
Placebo
Odds Ratio
Odds Ratio
n/N
n/N
M-H,Fixed,95% CI
M-H,Fixed,95% CI
16/172
19/163
0.78 [ 0.39, 1.57 ]
0
0
0.0 [ 0.0, 0.0 ]
CATS 1988
Subtotal (95% CI)
Total events: 16 (Ticlopidine), 19 (Placebo)
Heterogeneity: not applicable
Test for overall effect: Z = 0.0 (P < 0.00001)
Test for subgroup differences: Not applicable
0.01
0.1
Favours Ticlopidine
1
10
100
Favours Placebo
ADDITIONAL TABLES
Table 1. Overview of study populations
Characteristic
Study ID
Intervention [n] screened
(s) and control(s)
[n]
randomised
[n] ITT
[n] finishing [%] of ranstudy
domised participants
finishing
study
AAASPS
I(d): Ticlopi- Idine 250 mg
bd (diabetes
patients)
C(d): Aspirin
325 mg bd
(diabetes patients)
I(t)
I(d): 359
C(d): 379
I(t): 902
C(t): 907
I(d): 359
C(d): 379
I(t): 902
C(t): 907
I(d): C(d): I(t): 626
C(t): 661
I(d): C(d): I(t): 69.4
C(t): 72.9
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
44
Table 1. Overview of study populations
(Continued)
: Ticlopidine
250 mg bd (all
patients)
C(t): Aspirin
325 mg bd (all
patients)
CAPRIE
I(d): Clopido- grel 75 mg
daily (diabetes
patients)
C(d): Aspirin
325 mg daily
(diabetes patients)
I(t):
Clopidogrel 75 mg
daily (all patients)
C(t): Aspirin
325 mg daily
(all patients)
I(d): 20%
C(d): 20%
I(t): 9599
C(t): 9586
I(d):
20%
(1920)
C(d):
20%
(1917)
I(t): 9599
C(t): 9586
I(d): C(d): I(t): 9577
C(t): 9566
I(d): C(d): I(t): 99.8
C(t): 99.8
CATS
I(d): Ticlopi- dine 250 mg
bd (diabetes
patients)
C(d): Placebo
(diabetes patients)
I(t)
: Ticlopidine
250 mg bd (all
patients)
C(t): Placebo
(all patients)
I(d): 172
C(d): 163
I(t): 525
C(t): 528
I(d): 172
C(d): 163
I(t): 519
C(t): 515
I(d): C(d): I(t): 287
C(t): 364
I(d): C(d): I(t): 54.7
C(t): 68.9
CHARISMA
I(d): Clopido- grel
75
mg daily and
aspirin 75 to
162 mg daily
(diabetes patients)
C(d): Aspirin
75 to 162 mg
daily (diabetes
patients)
I(t): Clopido-
I(d): 3304
C(d): 3252
I(t): 7802
C(t): 7801
I(d): 3304
C(d): 3252
I(t): 7802
C(t): 7801
I(d): C(d): I(t): 79.6%
C(t): 81.8%
I(d): C(d): I(t): 79.6
C(t): 81.8
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
45
Table 1. Overview of study populations
(Continued)
grel
75
mg daily and
aspirin 75 to
162 mg daily
(all patients)
C(t): Aspirin
75 to 162 mg
daily (all patients)
CURE
I(d): Clopido- grel
75
mg daily and
aspirin 75 to
300 mg daily
(diabetes patients)
C(d): Aspirin
75 to 300 mg
daily (diabetes
patients)
I(t): Clopidogrel
75
mg daily and
aspirin 75 to
300 mg daily
(all patients)
C(t): Aspirin
75 to 300 mg
daily (all patients)
I(d): 1405
C(d): 1435
I(t): 6259
C(t): 6303
I(d): 1405
C(d): 1435
I(t): 6259
C(t): 6303
I(d): C(d): I(t): 78.9%
C(t): 81.2%
I(d): C(d): I(t): 78.9
C(t): 81.2
Park
I(d): Clopido- grel
75
mg daily and
aspirin 100 to
200 mg daily
(diabetes patients)
C(d): Aspirin
100 to 200 mg
daily (diabetes
patients)
I(t): Clopidogrel
75
mg daily and
aspirin 100 to
200 mg daily
(all patients)
I(d): 340
C(d): 364
I(t): 1357
C(t): 1344
-
I(d): C(d): I(t): 327
C(t): 313
-
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
46
Table 1. Overview of study populations
(Continued)
C(t): Aspirin
100 to 200 mg
daily (all patients)
PRoFESS
I(d): Clopido- grel 75 mg
daily (diabetes
patients)
C(d): Aspirin/
dipyridamole
25
mg/200
mg bd (diabetes patients)
I(t):
Clopidogrel 75 mg
daily (all patients)
C(t): Aspirin/
dipyridamole
25
mg/
200 mg bd (all
patients)
I(d): 2840
C(d): 2903
I(t): 10.151
C(t): 10.181
I(d): 2840
C(d): 2903
I(t): 10.151
C(t): 10.181
I(d): C(d): I(t): 7736
C(t): 7095
I(d): C(d): I(t): 76.2
C(t): 69.7
TASS
I(d): Ticlopi- dine 250 mg
bd (diabetes
patients)
C(d): Aspirin
650 mg bd
(diabetes patients)
I(t)
: Ticlopidine
250 mg bd (all
patients)
C(t): Aspirin
650 mg bd (all
patients)
I(d): 291
C(d): 306
I(t): 1529
C(t): 1540
I(d): C(d): I(t): 1529
C(t): 1540
I(d): C(d): I(t): 828
C(t): 941
I(d): C(d): I(t): 54.2
C(t): 61.1
Total
All interventions
(diabetes patients)
8711
(and CAPRIE
participants)
All controls
(diabetes patients)
8802
(and CAPRIE
participants)
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
47
Table 1. Overview of study populations
(Continued)
All interventions (all patients)
38,124
All controls
(all patients)
38,190
All interventions and controls
(diabetes patients)
21,379
All interventions and controls (all patients)
76,314
“-” denotes not reported
Abbreviations:
bd: twice daily; C: control; C(d): intervention (diabetes patients); C(t): intervention (all patients); I: intervention; I(d): intervention
(diabetes patients); I(t): intervention (all patients); ITT: intention-to-treat
APPENDICES
Appendix 1. Search strategies
Search terms and databases
Unless otherwise stated, search terms are free text terms.
Abbreviations:
’$’: stands for any character; ’?’: substitutes one or no character; adj: adjacent (i.e. number of words within range of search term); exp:
exploded MeSH; MeSH: medical subject heading (MEDLINE medical index term); pt: publication type; sh: MeSH; tw: text word
The Cochrane Library
#1 MeSH descriptor Diabetes mellitus, type 2 explode all trees
#2 (obes* in All Text near/6 diabet* in All Text)
#3 (MODY in All Text or NIDDM in All Text or TDM2 in All Text or TD2 in All Text)
#4 ( (non in All Text and insulin* in All Text and depend* in All Text) or (noninsulin* in All Text and depend* in All Text) or (non
in All Text and insulindepend* in All Text) or noninsulindepend* in All Text)
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
48
(Continued)
#5 (typ? in All Text and (2 in All Text near/6 diabet* in All Text) )
#6 (typ? in All Text and (II in All Text near/6 diabet* in All Text) )
#7 (non in All Text and (keto* in All Text near/6 diabet* in All Text) )
#8 (nonketo* in All Text near/6 diabet* in All Text)
#9 (adult* in All Text near/6 diabet* in All Text)
#10 (matur* in All Text near/6 diabet* in All Text)
#11 (late in All Text near/6 diabet* in All Text)
#12 (slow in All Text near/6 diabet* in All Text)
#13 (stabl* in All Text near/6 diabet* in All Text)
#14 (insulin* in All Text and (defic* in All Text near/6 diabet* in All Text) )
#15 (plurimetabolic in All Text and syndrom* in All Text)
#16 (pluri in All Text and metabolic in All Text and syndrom* in All Text)
#17 (typ?2 in All Text near/3 diabet* in All Text)
#18 (keto in All Text and (resist* in All Text near/3 diabet* in All Text) )
#19 (non in All Text and (keto* in All Text near/3 diabet* in All Text) )
#20 (nonketo* in All Text near/3 diabet* in All Text)
#21 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or
#20)
#22 MeSH descriptor Ticlopidine explode all trees
#23 (ticlopidin* in All Text or clopidogrel in All Text or prasugrel in All Text or ticagrelor in All Text)
#24 (ticlodone in All Text or ticlodix in All Text or ticlid in All Text)
#25 (#22 or #23 or #24)
#26 (#21 and #25)
Medline
1 exp Diabetes Mellitus, Type 2/
2 exp Insulin Resistance/
3 exp Glucose Intolerance/
4 exp Metabolic Syndrome X/
5 (impaired glucos$ toleranc$ or glucos$ intoleranc$ or insulin resistan$).tw,ot.
6 (obes$ adj3 diabet$).tw,ot.
7 (MODY or NIDDM or T2DM or T2D).tw,ot.
8 (non insulin$ depend$ or noninsulin$ depend$ or noninsulin?depend$ or non insulin?depend$).tw,ot.
9 ((typ? 2 or typ? II or typ?2 or typ?II) adj3 diabet$).tw,ot.
10 ((keto?resist$ or non?keto$) adj6 diabet$).tw,ot.
11 (((late or adult$ or matur$ or slow or stabl$) adj3 onset) and diabet$).tw,ot.
12 metabolic syndrom*.tw,ot.
13 or/1-12
14 exp Diabetes Insipidus/
15 diabet$ insipidus.tw,ot.
16 14 or 15
17 13 not 16
18 exp Ticlopidine/
19 (ticlopidin* or clopidogrel or prasugrel).tw,ot.
20 (ADP adj3 receptor antagonist*).tw,ot.
21 (ticlodone or ticlodix or ticlid).tw,ot.
22 or/18-21
23 17 and 22
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
49
(Continued)
24 randomized controlled trial.pt.
25 controlled clinical trial.pt.
26 randomi?ed.ab.
27 placebo.ab.
28 drug therapy.fs.
29 randomly.ab.
30 trial.ab.
31 groups.ab.
32 or/24-31
33 Meta-analysis.pt.
34 exp Technology Assessment, Biomedical/
35 exp Meta-analysis/
36 exp Meta-analysis as topic/
37 hta.tw,ot.
38 (health technology adj6 assessment$).tw,ot.
39 (meta analy$ or metaanaly$ or meta?analy$).tw,ot.
40 ((review$ or search$) adj10 (literature$ or medical database$ or medline or pubmed or embase or cochrane or cinahl or psycinfo
or psyclit or healthstar or biosis or current content$ or systemat$)).tw,ot.
41 or/33-40
42 32 or 41
43 (comment or editorial or historical-article).pt.
44 42 not 43
45 23 and 44
Embase
1 exp Diabetes Mellitus, Type 2/
2 exp Insulin Resistance/
3 (MODY or NIDDM or T2D or T2DM).tw,ot.
4 ((typ? 2 or typ? II or typ?II or typ?2) adj3 diabet*).tw,ot.
5 (obes* adj3 diabet*).tw,ot.
6 (non insulin* depend* or non insulin?depend* or noninsulin* depend* or noninsulin?depend*).tw,ot.
7 ((keto?resist* or non?keto*) adj3 diabet*).tw,ot.
8 ((adult* or matur* or late or slow or stabl*) adj3 diabet*).tw,ot.
9 (insulin* defic* adj3 relativ*).tw,ot.
10 (insulin* resistanc* or impaired glucos* toleranc* or glucos* intoleranc*).tw,ot.
11 or/1-10
12 exp Diabetes Insipidus/
13 diabet* insipidus.tw,ot.
14 12 or 13
15 11 not 14
16 exp ticlopidine/
17 exp clopidogrel/
18 exp prasugrel/
19 exp ticagrelor/
20 (ADP adj3 receptor antagonist*).tw,ot.
21 (ticlopidin* or clopidogrel or prasugrel or ticagrelor).tw,ot.
22 (ticlodone or ticlodix or ticlid).tw,ot.
23 or/16-22
24 15 and 23
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
50
(Continued)
25 exp Randomized Controlled Trial/
26 exp Controlled Clinical Trial/
27 exp Clinical Trial/
28 exp Comparative Study/
29 exp Drug comparison/
30 exp Randomization/
31 exp Crossover procedure/
32 exp Double blind procedure/
33 exp Single blind procedure/
34 exp Placebo/
35 exp Prospective Study/
36 ((clinical or control$ or comparativ$ or placebo$ or prospectiv$ or randomi?ed) adj3 (trial$ or stud$)).ab,ti.
37 (random$ adj6 (allocat$ or assign$ or basis or order$)).ab,ti.
38 ((singl$ or doubl$ or trebl$ or tripl$) adj6 (blind$ or mask$)).ab,ti.
39 (cross over or crossover).ab,ti.
40 or/25-39
41 exp meta analysis/
42 (metaanaly$ or meta analy$ or meta?analy$).ab,ti,ot.
43 ((review$ or search$) adj10 (literature$ or medical database$ or medline or pubmed or embase or cochrane or cinahl or psycinfo
or psyclit or healthstar or biosis or current content$ or systematic$)).ab,ti,ot.
44 exp Literature/
45 exp Biomedical Technology Assessment/
46 hta.tw,ot.
47 (health technology adj6 assessment$).tw,ot.
48 or/41-47
49 40 or 48
50 (comment or editorial or historical-article).pt.
51 49 not 50
52 24 and 51
53 review.pt.
54 52 not 53
Appendix 2. Baseline characteristics
Study ID
Characteristic
AAASPS
IntervenI: Ticlopition(s) and dine 250 mg
control(s)
bd
C: Aspirin
325 mg bd
CAPRIE
CATS
CURE
Park
PRoFESS
TASS
I: Clopidogrel 75 mg
daily and aspirin 75 to
300
mg
daily
C: Aspirin
75 to 300
I: Clopidogrel 75 mg
daily and aspirin 100 to
200
mg
daily
C
(d): Aspirin
I: Clopidogrel 75 mg
daily
C: Aspirin /
dipyridamole
25 mg / 200
I: Ticlopidine 250 mg
bd
C: Aspirin
650 mg bd
CHARISMA
I: Clopidogrel 75 mg
daily
C:
Aspirin 325
mg daily
I: Ticlopidine 250 mg
bd
C: Placebo
I: Clopidogrel 75 mg
daily and aspirin 75 to
162
mg
daily
C: Aspirin
75 to 162
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
51
(Continued)
mg daily
ParticiPatients
Patients
Patients
pating pop- with cere- with vascu- with
ulation
bral infarcts lar disease
thromboembolic
strokes
16 countries USA,
Canada
mg daily
HighPatients
risk vascular with acute
patients
coronary
syndrome
100 to 200 mg bd
mg daily
Patients
with
drug eluding
stents
Patients
with
ischaemic
strokes
Patients
with
ischaemic
neurological
events
Country
USA
Setting
HospiHospiHospital in- Hospital
tal and com- tal and com- patients
munity
munity
Hospital
InHospiHospipatients and tal and com- tal and comcommunity munity
munity
Sex
[female%]
I: 54.5
C: 52.4
I: 30.0
C: 30.6
I: 40
C: 37
I: 29.7
C: 29.8
I: 38.7
C: 38.3
Age [mean I: 60.9 (10. I: 62.5 (11. I: 66
years (SD)] 7)
1)
C: 65
C: 61.6 (10. C: 62.5 (11.
4)
1)
Median
I: 64.0
C: 64.0
I: 64.2 (11. I: 62 (9.8)
I: 66.2 (8.5) I: 62.7 (9.4)
3)
C: 61.9 (9. C: 66.1 (8. C: 63.2 (9.
C: 64.2 (11. 9)
6)
3)
3)
I: 36.0
C: 35.9
I: 36
C: 35
-
-
-
-
-
-
BMI [mean I: 29.9 (7.1) kg/m2 (SD) C: 30.0 (6.
]
8)
-
-
-
-
I: 26.8 (5.0) C: 26.8 (5.
0)
Caucasian
I: 73%
C: 71%
White
I: 80.4%
C: 79.9%
-
-
White / Eu- White
ropean
I: 80%
I: 57.3%
C: 81%
C: 57.7%
HbA1c
[mean
(SD)]
-
I: 28
C: 28
32 countries 28 countries South Korea 35 countries USA,
Canada
-
%
Ethnic
groups [%]
I: African American
C: African
American
Duration of I: 710 days
follow-up
C: 716 days
(mean)
I: 1.91 years I: 17 months Median
I: 12 months
C:
1.91 C:
19 I: 28 months C:
12
years
months
C:
28 months
months
I:
19.2 I: 2.5 years
months
C: 2.5 years
C:
19.2
months
I: 778 days
C: 858 days
Footnotes
“-” denotes not reported
Abbreviations:
bd: twice daily; BMI: body mass index; C: control; C(d): intervention (diabetes patients); C(t): intervention (all patients); HbA1c:
glycosylated haemoglobin A1c; I: intervention; I(d): intervention (diabetes patients); I(t): intervention (all patients); SD: standard
deviation
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
52
Appendix 3. Study outcomes
Study ID
Characteristic
AAASPS
CAPRIE
CATS
CURE
Park
PRoFESS
TASS
CHARISMA
IntervenI: Ticlopition(s) and dine 250 mg
control(s)
bd
C: Aspirin
325 mg bd
I: Clopidogrel 75 mg
daily
C:
Aspirin 325
mg daily
I: Ticlopidine 250 mg
bd
C: Placebo
I: Clopidogrel 75 mg
daily and aspirin 75 to
162
mg
daily
C: Aspirin
75 to 162
mg daily
I: Clopidogrel 75 mg
daily and aspirin 75 to
300
mg
daily
C: Aspirin
75 to 300
mg daily
I: Clopidogrel 75 mg
daily and aspirin 100 to
200
mg
daily
C
(d): Aspirin
100 to 200
mg daily
I: Clopidogrel 75 mg
daily
C: Aspirin /
dipyridamole
25 mg / 200
mg bd
I: Ticlopidine 250 mg
bd
C: Aspirin
650 mg bd
All-cause
mortality
I(d): C(d): I(t): 45
C(t): 40
I(d): C(d): I(t): 560
C(t): 571
I(d): 30
C(d): 23
I(t): 66
C(t): 65
I(d): C(d): I(t): 371
C(t): 374
I(d): C(d): I(t): 359
C(t): 390
I(d): C(d): I(t): 20
C(t): 13
I(d): C(d): I(t): 756
C(t): 739
I(d): C(d): I(t): 175
C(t): 196
Vascular
mortality
I(d): C(d): I(t): 18
C(t): 18
I(d): C(d): I(t): 350
C(t): 378
I(d): 18
C(d): 18
I(t): 35
C(t): 43
I(d): C(d): I(t): 238
C(t): 229
I(d): C(d): I(t): 318
C(t): 345
-
-
I(d): C(d): I(t): 120
C(t): 116
Myocardial infarction (fatal)
I(d): C(d): I(t): 1
C(t): 0
I(d): C(d): I(t): 53
C(t): 75
I(d): 13
C(d): 10
I(t): 21
C(t): 22
-
-
-
-
I(d): C(d): I(t): 21
C(t): 14
Myocardial infarction (nonfatal)
I(d): C(d): I(t): 8
C(t): 8
I(d): C(d): I(t): 255
C(t): 301
I(d): 3
C(d): 9
I(t): 11
C(t): 15
I(d): C(d): I(t): 146
C(t): 155
-
-
-
-
Myocardial infarction (fatal and nonfatal)
I(d): C(d): I(t): 9
C(t): 8
I(d): C(d): I(t): 308
C(t): 376
I(d): 16
C(d): 19
I(t): 32
C(t): 37
-
I(d): C(d): I(t): 324
C(t): 419
I(d): C(d): I(t): 10
C(t): 7
I(d): C(d): I(t): 197
C(t): 178
-
I(d): C(d): I(t): 37
C(t): 42
I(d): 6
C(d): 9
I(t): 14
C(t): 17
-
-
-
-
I(d): C(d): I(t): 16
C(t): 23
Stroke (fa- I(d): tal)
C(d): I(t): 4
C(t): 2
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
53
(Continued)
I(d): C(d): I(t): 102
C(t): 84
I(d): C(d): I(t): 472
C(t): 504
I(d): 28
C(d): 32
I(t): 67
C(t): 86
I(d): C(d): I(t): 150
C(t): 189
-
-
-
I(d): C(d): I(t): 156
C(t): 189
Stroke (fa- I(d): tal and non- C(d): fatal)
I(t): 106
C(t): 86
I(d): C(d): I(t): 509
C(t): 546
I(d): 34
C(d): 41
I(t): 81
C(t): 103
-
I(d): C(d): I(t): 75
C(t): 87
I(d): C(d): I(t): 9
C(t): 4
I(d): 334
C(d): 312
I(t): 862
C(t): 879
I(d): 25
C(d): 44
I(t): 172
C(t): 212
Stroke
(non-fatal)
Footnotes
“-” denotes not reported
Abbreviations:
bd: twice daily; C: control; C(d): intervention (diabetes patients); C(t): intervention (all patients); I: intervention; I(d): intervention
(diabetes patients); I(t): intervention (all patients)
Appendix 4. Adverse events
Study ID
Characteristic
AAASPS
CAPRIE
CATS
CURE
Park
PRoFESS
TASS
CHARISMA
IntervenI: Ticlopition(s) and dine 250 mg
control(s)
bd
C: Aspirin
325 mg bd
I: Clopidogrel 75 mg
daily
C:
Aspirin 325
mg daily
I: Ticlopidine 250 mg
bd
C: Placebo
I: Clopidogrel 75 mg
daily and aspirin 75 to
162
mg
daily
C: Aspirin
75 to 162
mg daily
I: Clopidogrel 75 mg
daily and aspirin 75 to
300
mg
daily
C: Aspirin
75 to 300
mg daily
I: Clopidogrel 75 mg
daily and aspirin 100 to
200
mg
daily
C
(d): Aspirin
100 to 200
mg daily
I: Clopidogrel 75 mg
daily
C: Aspirin /
dipyridamole
25 mg / 200
mg bd
I: Ticlopidine 250 mg
bd
C: Aspirin
650 mg bd
Serious adverse events
(including
bleeding)
I(d): C(d): I(t): 270
C(t): 262
I(d): C(d): I(t): 360
C(t): 409
I(d): C(d): I(t): 43
C(t): 15
-
-
-
I(d): C(d): I(t): 373
C(t): 426
-
Serious
bleeding
I(d): C(d): I(t): 10
C(t): 19
I(d): C(d): I(t): 77
C(t): 109
I(d): C(d): I(t): 2
C(t): 1
I(d): C(d): I(t): 130
C(t): 104
I(d): C(d): I(t): 231
C(t): 169
I(d): C(d): I(t): 3
C(t): 1
I(d): C(d): I(t): 116
C(t): 128
I(d): C(d): I(t): 137
C(t): 152
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
54
(Continued)
Footnotes
“-” denotes not reported
Abbreviations:
bd: twice daily; C: control; C(d): intervention (diabetes patients); C(t): intervention (all patients); I: intervention; I(d): intervention
(diabetes patients); I(t): intervention (all patients)
HISTORY
Protocol first published: Issue 3, 2005
Review first published: Issue 11, 2012
Date
Event
Description
24 May 2005
New citation required and conclusions have changed
Substantive amendment
CONTRIBUTIONS OF AUTHORS
Nyoli Valentine: Searching for trials, abstract assessment for eligibility, quality assessment of trials, data extraction, data entry, data
analysis and review development.
Floris van de Laar: Protocol development and review development.
Mieke van Driel: Searching for trials, abstract assessment for eligibility, quality assessment of trials, data extraction, data entry, data
analysis and review development.
DECLARATIONS OF INTEREST
No declarations are known for Nyoli Valentine, Floris van de Laar or Mieke van Driel.
SOURCES OF SUPPORT
Internal sources
• Radboud University Nijmegen Medical Centre, Netherlands.
Support for FvdL
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
55
External sources
• General Practice Education & Training, Australia.
Funding support for NV
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
At the time of protocol publication, it was anticipated there would be more data on patients with diabetes available for this review. Due
to the limited data available, we were not able to undertake various statistical analyses. The protocol stated that data would be extracted
on outcomes including peripheral artery disease, health-related quality of life and costs; however, these were not available. Similarly,
data were not available on potential patient covariates such as compliance and glycaemic control.
The protocol also intended for an analysis to be done on patients with type 2 diabetes only. None of the included trials separated
patients into type 1 and type 2 diabetes so analysis was done on all types of diabetes mellitus.
The search strategy published in the protocol was changed as it was found to be too narrow. The actual search strategy used (Appendix
1) did not include a subheading ’diabetes’ as all of the trials on ADP receptor antagonists were conducted on patients both with and
without diabetes.
The authors undertaking this review were different to the authors of the protocol due to other commitments. The title of the review has
been expanded to include additional oral ADP receptor antagonists which have become available since the publication of the protocol.
INDEX TERMS
Medical Subject Headings (MeSH)
Aspirin [therapeutic use]; Cardiovascular Diseases [∗ prevention & control]; Diabetes Mellitus, Type 2 [∗ complications]; Dipyridamole
[therapeutic use]; Drug Therapy, Combination [methods]; Platelet Aggregation Inhibitors [∗ therapeutic use]; Purinergic P2Y Receptor
Antagonists [∗ therapeutic use]; Randomized Controlled Trials as Topic; Ticlopidine [analogs & derivatives; therapeutic use]
MeSH check words
Humans
Adenosine-diphosphate (ADP) receptor antagonists for the prevention of cardiovascular disease in type 2 diabetes mellitus (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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