|Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials
|De Berardis G, Sacco M, Strippoli GF, Pellegrini F, Graziano G, Tognoni G, Nicolucci A
This review concluded that a clear benefit of aspirin in the primary prevention of major cardiovascular events in people with diabetes was not proven. The pooled results should be viewed with caution; they were from studies with varied populations and aspirin regimens and might not represent the entire evidence base. Given the evidence presented, the conclusion seems to be appropriate.
To evaluate the benefits and disadvantages of low dose aspirin in people with diabetes and no cardiovascular disease.
MEDLINE (1966 to November 2008) and the Cochrane Central Register of Controlled Trials (CENTRAL, 2008) were searched for English-language studies; search terms were reported. Reference lists of identified studies and reviews were also searched.
Randomised controlled trials (RCTs) were eligible for inclusion if they had at least 500 participants, compared the use of aspirin for the primary prevention of heart disease with a placebo or no treatment, and had at least a subset of patients with diabetes. The primary outcomes were mortality (all-cause and cardiovascular), and non-fatal myocardial infarction (MI) or stroke. The participants in the studies varied, from healthy men or women, to patients with type 1 or type 2 diabetes, with or without cardiovascular risk factors; one study included a small proportion of patients with previous cardiovascular events. Aspirin dose ranged from 100mg every other day to 650mg every day and duration of therapy ranged from 3.6 to 10.1 years. The proportions of patients taking other interventions were not reported. Half the trials were conducted in the USA and the others were conducted in the UK, Italy, and Japan. Few other study details were reported.
Two authors independently screened the studies for inclusion; disagreements were resolved by discussion with a third reviewer.
Assessment of study quality
Two authors independently assessed study quality in terms of randomisation or allocation concealment, blinding, use of an intention-to-treat analysis, and completeness of follow-up. Disagreements were resolved by discussion with a third reviewer.
The incidence of cardiovascular events, mortality, and adverse events were extracted from each study and a relative risk (RR) and 95% confidence interval (CI) were calculated.
Two authors independently extracted data; disagreements were resolved by discussion with a third reviewer.
Methods of synthesis
Pooled RRs with 95% CIs were calculated using a random-effects model. Heterogeneity was assessed using the Cochran Q and I2 statistics. Variables identified as effect modifiers were gender, aspirin dose, duration of treatment, allocation concealment, and adherence. These were investigated in subgroup analyses. Sensitivity analyses were conducted to investigate the impact of individual studies on heterogeneity.
Results of the review
Six trials met the inclusion criteria (10,117 people with diabetes; range 533 to 3,711). Three of these adequately described randomisation or allocation concealment. Patients were blinded in four of the six trials. Outcome assessors were blind in all six trials. An intention-to-treat analysis was used in five trials. Completeness of follow-up was over 90% for the diabetic subsample in three trials and for the whole population in the other three trials.
The use of aspirin had no significant effect on major cardiovascular events (RR 0.90, 95% CI 0.81 to 1.00; five trials), MI (RR 0.86, 95% CI 0.61 to 1.21; six trials), stroke (RR 0.83, 95% CI 0.60 to 1.14; five trials), cardiovascular death (RR 0.94, 95% CI 0.72 to 1.23; four trials) or death from any cause (RR 0.93, 95% CI 0.82 to 1.05; four trials). The analyses for MI, stroke, and cardiovascular mortality showed moderate heterogeneity (I2>50%). There was no significant impact of aspirin on the incidence of adverse events. The subgroup analyses showed significant reduction in the risk of stroke with lower dose aspirin, in patients who had less than 90% compliance and in trials lasting more than five years. They also showed a reduction in the risk of MI in men, but not women. In the sensitivity analyses, the impact of excluding trials on the level of heterogeneity was reported (heterogeneity was reduced in each case), but the RRs were not.
A clear benefit of aspirin in the primary prevention of major cardiovascular events in people with diabetes was not proven.
The authors addressed a clear research question with well-defined inclusion criteria. Relevant sources were searched, but neither non-English-language studies nor unpublished data were sought, increasing the potential for language and publication bias. All stages of the review were conducted in duplicate, reducing the potential for error and bias. Appropriate criteria were used to assess study quality, some aspects of which were explored using subgroup analysis. From the few details of the included studies, it can be seen that they varied in terms of population and treatment regimens. Given this variability across studies, it is uncertain whether pooling the data was appropriate.
The methodology was generally good, but pooling of heterogeneous studies and the potential for missed studies mean the reliability of the results is uncertain. Given the evidence presented, the conclusions drawn by the authors seem to be appropriate.
Implications of the review for practice and research
Practice: The authors stated that there was no support for strong recommendations for the use of aspirin in the primary prevention of cardiovascular events in people with diabetes and decisions should be made on an individual basis.
Research: The authors stated that toxicity needed to be investigated and a better understanding of the pathophysiological mechanisms of the response of platelets to aspirin might help to identify those who would gain most from treatment.
De Berardis G, Sacco M, Strippoli GF, Pellegrini F, Graziano G, Tognoni G, Nicolucci A. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ 2009; 339:b4531
Other publications of related interest
Correction for De Berardis, et al., BMJ 339:b4531. BMJ 2010; 340:c374.
Subject indexing assigned by NLM
Aspirin /administration & dosage /adverse effects; Cardiovascular Agents /administration & dosage /adverse effects; Diabetic Angiopathies /prevention & control; Female; Humans; Male; Primary Prevention; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Risk Factors
Database entry date
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.