Belch J, MacCuish A, Campbell I, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008;337:a1840
This trial found aspirin was ineffective for the primary prevention of cardiovascular (CV) events in patients with diabetes and asymptomatic peripheral arterial disease (a risk factor for CV disease).
Data indicates that the priority, evidence-based interventions which substantially reduce 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 for the secondary prevention of CV events. For primary prevention in patients with diabetes mellitus, clinicians and patients should weigh this new evidence in their discussions. Some patients, perhaps especially those taking a large number of medicines, may wish to slightly simplify their medicines regimen and no longer take aspirin for primary prevention. However, studies with sufficient power are required to confirm these findings – a small absolute benefit may remain a possibility.
The publication of this study has highlighted that evidence is accumulating that aspirin does not reduce future CV events in any group of patients who do not have existing CV disease.
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, the 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 randomised controlled trial [RCT] in people with diabetes and asymptomatic peripheral arterial disease found no significant difference between aspirin and placebo in terms of the primary composite endpoints of CV events and CV mortality. Fatal and non-fatal myocardial infarctions [MI], 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). Similar results were obtained in the antioxidant groups. Serious adverse GI events were not increased in the group taking aspirin.
The authors conclude that the trial does not support the use of aspirin or antioxidants for primary prevention of CV events and mortality in patients with diabetes. They note that clinically important benefits are unlikely from the results of this study, although it is possible that small effects may be shown with larger trials continued over a longer time.
How does this relate to other studies?
Previously, a meta-analysis showed that, although aspirin may be beneficial in some high-risk patients, the benefits in patients with type 1 or type 2 diabetes are limited. Overall, among high-risk people with or without diabetes (195 RCTs, n=135,640) antiplatelet therapy (mainly aspirin) significantly reduced serious vascular events (non-fatal MI, non-fatal stroke, or vascular death) by about a quarter. However, antiplatelet treatment (9 RCTs, n=4,961) did not significantly reduce serious vascular events among high-risk patients with diabetes, compared with controls.
Similarly, a Cochrane Review concluded that aspirin cannot be recommended for primary prevention in patients with elevated blood pressure because the magnitude of benefit is negated by a harm of similar magnitude. Based on one large trial (the HOT study), aspirin taken for 5 years reduced MI (absolute risk reduction [ARR] 0.5%, number needed to treat [NNT] 200 for 5 years). However it increased major haemorrhage (absolute risk increase [ARI] 0.7%, number needed to harm [NNH] 154), and did not reduce all cause mortality or CV mortality.
It should be noted that recruitment to this trial was slower than anticipated and the number of events was less than expected. This potentially reduces the power of the trial to detect a benefit if one truly existed, although if there was a large benefit from aspirin in this population then it is likely that this study would have been able to detect it. In addition, the patients in this study had a mean age of 60 years, and it is not clear what the balance of risks and benefits would be in an older population at higher risk of both CV and GI events.
This study raises questions over the level of CV risk at which the benefits of aspirin use outweigh the risks. As stated in an accompanying editorial, the results suggest that risk assessment alone cannot predict which patients will benefit from aspirin. The only predictor of a clinical response to aspirin appears to be a history of a major coronary or cerebral ischaemic attack. The editorial points out that this is in contrast to evidence that statins and antihypertensive drugs have benefits in patients at all levels at risk, including those with and without CV disease.
It is still important to manage CV risk factors in people with diabetes mellitus, for example, by encouraging smokers to stop smoking, controlling blood pressure, and/or adding a statin (usually commencing with simvastatin 40 mg/day). Aspirin should still be given for secondary prevention of CV disease in people with type 2 diabetes. However, for primary prevention in type 2 diabetes, consideration on an individualised basis following an assessment of the benefits and risks may be more appropriate.
Design: Multicentre, randomised, double-blind placebo-controlled trial, using a factorial 2x2design in 16 hospital centres in Scotland supported by 188 primary care groups
Patients: 1,276 adults aged 40 years or more with type 1 or type 2 diabetes and asymptomatic peripheral arterial disease (ankle brachial pressure index of 0.99 or less) but no symptomatic CV disease
Intervention: Aspirin 100mg daily plus antioxidant (n=320) vs. aspirin plus placebo (n=318) vs. antioxidant plus placebo (n=320) vs. two placebos (n=318)
Comparison: To determine whether aspirin and antioxidant therapy, alone or in combination, are more effective than placebo in reducing the development of CV events in people with diabetes and asymptomatic peripheral arterial disease (a risk factor for CV disease)
Outcome measures: Two hierarchical composite primary end points:
- death from coronary heart disease or stroke, non-fatal MI or stroke, or amputation above the ankle for critical limb ischaemia
- death from coronary heart disease or stroke
Results: Median length of follow up was 6.7 years. There was no evidence of an interaction between aspirin and the antioxidant so patients in the two aspirin groups were compared to those in the two no aspirin groups and similarly for the antioxidant groups. Overall, there was no significant difference between the groups. 116 of 638 primary events occurred in the aspirin groups compared with 117 of 638 in the no aspirin groups (18.2% v 18.3%; hazard ratio [HR] 0.98, 95% confidence interval [CI] 0.76 to 1.26). 43 deaths from coronary heart disease or stroke occurred in the aspirin groups compared with 35 in the no aspirin groups (6.7% vs. 5.5%; HR 1.23, 95% CI 0.79 to 1.93). Among the antioxidant groups 117 of 640 primary events occurred compared with 116 of 636 in the no antioxidant groups (18.3% vs. 18.2%; HR 1.03, 95% CI 0.79 to 1.33). Forty two deaths from coronary heart disease or stroke occurred in the antioxidant groups compared with 36 in the no antioxidant groups (6.6% vs. 5.7%; HR 1.21, 95% CI 0.78 to 1.89). No significant difference was seen in the rate of gastrointestinal bleeding in either the aspirin or the antioxidant groups.
Sponsorship: UK Medical Research Council grant. All researchers were independent of the funder