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Aspirin: Should It Be Used for Primary Prevention in Diabetics?

Oct 28, 2008

A new study has found no evidence that aspirin or antioxidants are of any benefit in the primary prevention of cardiovascular events in diabetic patients with asymptomatic peripheral arterial disease (PAD)

Dr Jill Belch (University of Dundee, Scotland) reported the findings from the Prevention and Progression of Arterial Disease and Diabetes (POPADAD) trial online October 16, 2008, in BMJ.

The findings indicate that certain guidelines advocating the use of aspirin in patients with diabetes but without cardiovascular disease should be revised. "In our therapeutic greed to try to reduce risk further, we have been extrapolating aspirin data to primary prevention, and actually the data for primary prevention with aspirin are weak, and they are particularly weak in the diabetes population," she comments. She also stresses that aspirin is not without risks: "One of the commonest drug-related causes of admission to the hospital is aspirin."

An accompanying editorial, by Dr William R Hiatt (University of Colorado Denver School of Medicine), agrees wholeheartedly with these conclusions. "A total of seven well-controlled trials now show that aspirin has no benefit for primary prevention of cardiovascular events, even in people at higher risk. Although aspirin is cheap and universally available, practitioners and authors of guidelines need to heed the evidence that aspirin should be prescribed only in patients with established symptomatic cardiovascular diseases."

Other experts see the issue somewhat differently, however. Dr Jane Armitage (Clinical Trial Services Unit [CTSU], Oxford, UK) said the POPADAD trial — with 1200 patients — is too small to draw any firm conclusions. "Most of the studies that will give us very clear answers about questions like this need to be much bigger. POPADAD adds to the evidence but on its own is not really conclusive," she says. She adds that the other six trials mentioned by Hiatt "are largely studies in healthy individuals, and there are only small proportions of people with diabetes in them, so it’s not really relevant to extrapolate from those studies."

Dr John B Buse largely agrees with Armitage’s take on things and points out, "The issue of aspirin in primary prevention has always been moderately controversial." Regarding aspirin in this role in diabetics specifically, he says, "This is one of the areas we’ve always felt like we go out a little bit on a limb. Having said that, we are moderately confident about that, because the harms of aspirin are pretty clearly modest." And he adds, "The people in the POPADAD trial were quite high-risk patients, with PAD, which technically the ADA would actually consider secondary prevention."

Belch et al investigated whether aspirin and antioxidants given together or separately can reduce myocardial infarction (MI) and death in patients with diabetes and PAD. In their study, 1276 patients with diabetes and evidence of asymptomatic PAD (as determined by a lower-than-normal ankle-brachial pressure index of 0.99 or less, but no symptoms) over 40 years of age were randomized to receive either aspirin 100 mg or placebo, an antioxidant or placebo, or aspirin and an antioxidant or double placebo and followed over eight years.

There were two hierarchical composite primary end points: death from coronary heart disease (CHD) or stroke, nonfatal MI or stroke, or amputation above the ankle for critical limb ischemia; and death from CHD or stroke.

Overall, the researchers found no benefit from either aspirin or antioxidant treatment. Patients in the aspirin groups had 116 primary events compared with 117 in the placebo group (hazard ratio 0.98; p=0.86). There were 43 deaths from CHD or stroke in the aspirin group compared with 35 in the no-aspirin group (hazard ratio [HR] 1.23; p=0.36).

"Clinically important benefits are unlikely from the results of this study," they note, "although it is possible that small effects may be shown with larger trials continued for a longer time."

Armitage notes that the confidence limits in POPADAD go from a 25% benefit for aspirin to a 27% hazard — a point that is made by the researchers in their discussion. "So although they state there was no overall benefit, we cannot at the moment exclude the possibility of a benefit of aspirin of maybe around 20% to 25% for people with diabetes," she says. "But the reality is we just don’t know and we need more evidence."

"POPADAD is smaller than most of the other aspirin trials, with fewer events," he adds. "There’s a fair amount of trial data that suggest a benefit of aspirin in this population — some show benefit on the primary end point and not all the individual end points, and some miss primary end points but there are trends in the right direction. And there is one prior study that suggested the benefit is less," he acknowledges. "The problem is that the trials that have the most power to look at this question are pretty limited."

"The overall issue is, What is the balance between the very real hazards of aspirin and the probable benefits in patients with diabetes?" she says.

In POPADAD, no significant difference in events was seen between the antioxidant group and the placebo group, either, with 117 vs 116 primary events (HR 1.03; p=0.85) and 42 deaths from CHD or stroke in the antioxidant group vs 36 in the no-antioxidant group (HR 1.21; p=0.40).

The antioxidant capsules given daily contained alpha tocopherol, ascorbic acid, pyridoxine hydrochloride, zinc sulfate, nicotinamide, lecithin, and sodium selenite in recommended daily amounts (RDAs).

Belch said their findings "underpin the other negative results seen in this area." She said that the evidence indicates that people with diabetes need not take antioxidant supplements, a practice that has become increasingly common following major publicity in the lay press about a deficiency of antioxidants in diabetics.

In an accompanying editorial, William Hiatt, Colorado Prevention Center, Denver, Colorado, said: "These findings show that unlike statins and drugs for reducing hypertension, which have a benefit in all risk groups including those with and without heart disease, only patients with a history of clinical or symptomatic heart disease or stroke disease benefit from taking aspirin."

Practice Pearls:

  • In a previous meta-analysis, antiplatelet therapy was effective in reducing the risk for major vascular events in patients with acute MI and stroke, past MI and stroke, and angina. Antiplatelet therapy was not significantly effective in reducing vascular events in patients with diabetes.
  • In the current study of patients with diabetes and evidence of PAD, neither aspirin nor antioxidants improved vascular or mortality outcomes.

Belch J, MacCuish A, Campbell I, et al. The prevention and progression of arterial disease and diabetes (POPADAD) trial: factorial randomized placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ. 2008; DOI:10.1136/bmj.a1840.   WR. Aspirin for prevention of cardiovascular events. BMJ. 2008; DOI:10.1136/bmj.a1806..


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