25 January 2010
This meta-analysis found aspirin did not statistically significantly reduce the risk of major CV events, CV mortality or all-cause mortality in people with diabetes and no pre-existing CV disease.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
The priority, evidence-based interventions which substantially reduce cardiovascular (CV) risk in people with diabetes mellitus are smoking cessation, blood pressure control, metformin, and cholesterol lowering with a statin. Aspirin should still be offered to patients with diabetes and evidence of CV disease i.e. for the secondary prevention of CV events. However, for primary prevention in patients with diabetes a more individualised approach would seem appropriate, as the presence of personal risk factors may change the risk:benefit profile. This meta-analysis adds to accumulating evidence that aspirin does not reduce future CV events in patients who do not have existing CV disease. Therefore, some patients with diabetes who don’t have CV disease may wish to slightly simplify their medicines regimen and no longer take aspirin. However, a small absolute benefit with aspirin for primary prevention remains a possibility, and for other patients with diabetes but no CV disease continuing their aspirin may be more appropriate.
What is the background to this?
Cardiovascular disease is the major cause of morbidity and mortality in patients with type 1 or 2 diabetes. There is good evidence that aspirin is effective for secondary prevention of CV events. However, it is less clear whether it prevents primary CV events in people who are at high risk of CV disease, such as those with type 2 diabetes.
NICE guidance on the management of type 2 diabetes advises that aspirin 75 mg daily should be offered to people:
- aged 50 years old or over with blood pressure below 145/90 mmHg.
- aged under 50 years old with significant CV risk factors (features of the metabolic syndrome, strong early family history of CV disease, smoking, hypertension, existing CV disease, microalbuminuria).
However, NICE have recently updated their website with the MHRA advice that (see below) “Aspirin is not licensed for the primary prevention of vascular events. If aspirin is used in primary prevention, the balance of benefits and risks should be considered for each individual, particularly the presence of risk factors for vascular disease (including conditions such as diabetes) and the risk of gastrointestinal bleeding.”
The NICE guideline development group acknowledged that there is little direct evidence to support the use of aspirin for the primary prevention of CV events in patients with type 2 diabetes. Recommendations are based largely on trials where a subgroup analysis of patients with type 2 diabetes was performed, and extrapolation from studies showing the benefits of aspirin in patients with type 2 diabetes and existing CV disease.
What does this study claim?
This meta-analysis of six randomised controlled trials (RCTs) comparing aspirin or no aspirin in people with diabetes and no pre-existing CV disease found aspirin did not statistically significantly reduce the risk of major CV events (relative risk [RR] 0.90; 95% confidence interval [CI] 0.81 to 1.00), CV mortality (RR 0.94; 95%CI 0.72 to 1.23), or all cause mortality (RR 0.93; 95%CI 0.82 to 1.05). Evidence relating to harms was inconsistent. However, there was no statistically significant increase in the risk of any bleeding or gastrointestinal bleeding with aspirin compared with placebo or no aspirin in this meta-analysis.
In the secondary prevention of CV events, the benefits of aspirin are clear. However, more data are questioning the role of aspirin in primary prevention, including in people with diabetes. Given the risk of major gastrointestinal or other extracranial bleeds associated with aspirin, the balance of benefits and harms in primary prevention may not be favourable.
The October edition of Drug Safety Update from the MHRA and CHM reminded prescribers that, in the UK, low-dose aspirin is licensed for prevention of thrombotic cerebrovascular or cardiovascular disease only in those who already have vascular disease — i.e. secondary prevention. Although aspirin is used in primary prevention, this is not a licensed indication.
A recent meta-analysis (ATT see related blog) found that, in the primary prevention of CV disease, the balance of benefits and risks with aspirin was unclear. While there appeared to be a small absolute reduction (around 0.06%) in some CV outcomes (e.g. non-fatal MI), there was also an increased absolute risk of major bleeds (around 0.03%). In a subgroup analysis of primary prevention patients with diabetes in this meta-analysis, aspirin did not significantly reduce the risk of serious vascular events (RR 0.88; 95%CI 0.67 to 1.15).
The POPADAD trial, which was conducted specifically in patients with diabetes (and was included in this recent meta-analysis) found aspirin was ineffective for the primary prevention of cardiovascular events. Fatal and non-fatal MIs, strokes and amputations occurred in 18.2% of patients taking aspirin, compared with 18.3% of those taking no aspirin (P=0.86). There were 43 deaths (6.7%) from coronary heart disease or stroke among people taking aspirin compared with 35 deaths (5.5%) in those not taking aspirin (P=0.36).
The POPADAD trial and this recent meta-analysis add to the weight of evidence that aspirin does not reduce future CV events in people with diabetes who don’t have existing CV disease. There remains a possibility that aspirin may show a small benefit for primary prevention in people with diabetes in larger, longer-term (i.e. better powered) studies. However, until more evidence is available, this new data supports treating people with diabetes with aspirin on an individual basis.
It is still important to manage CV risk factors in people with diabetes, for example, by encouraging smokers to stop smoking, controlling blood pressure, and/or adding a statin (usually commencing with simvastatin 40 mg/day); and aspirin should still be given for secondary prevention of CV disease in people with type 2 diabetes.
Study details –
Design, patients, intervention and comparison: Meta-analysis of six RCTs (n=10,117) comparing aspirin or no aspirin in people with diabetes and no pre-existing CV disease. Data on major CV events (death from CV causes, non-fatal MI, non-fatal stroke and all-cause mortality) were extracted and pooled with a random effect model.
Outcomes and results: When aspirin was compared with placebo there was no statistically significant reduction in the risk of major CV events (five studies, n=9,584, RR 0.90; 95%CI 0.81 to 1.00), CV mortality (four studies, n=8,557, RR 0.94; 95%CI 0.72 to 1.23), or all cause mortality (four studies, n=8,557, RR 0.93; 95%CI 0.82 to 1.05). Significant heterogeneity was found in the analysis for MI and stroke. Aspirin significantly reduced the risk of MI in men (RR 0.57; 95%CI 0.34 to 0.94) but not in women (RR 1.08; 95%CI 0.71 to 1.65). Evidence relating to harms was inconsistent.