Aspirin: Should it be used for primary prevention in diabetics?

October 17, 2008

Dundee, UK - 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) [1]. Dr Jill Belch (University of Dundee, Scotland) and colleagues report the findings from the P revention and P rogression of A rterial D isease and D iabetes (POPADAD) trial online October 16, 2008 in BMJ.

Belch told heart wire that 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."

In our therapeutic greed to try to reduce risk further we have been extrapolating the aspirin data to primary prevention, and actually the data for primary pr evention with aspirin are weak.

An accompanying editorial, by Dr William R Hiatt (University of Colorado Denver School of Medicine), agrees wholeheartedly with these conclusions [2]. "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 contacted by heart wire see the issue somewhat differently, however. Dr Jane Arm itage (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 J ohn B Buse (president for medicine and science, American Diabetes Association [ADA]) 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."

"We need more evidence"
POPADAD adds to the evidence but on its own is not really conclusive.

Belch et al investigated whether aspirin and antioxidants given together or separately can reduce 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 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 (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."

The reality is we just don't know and we need more evidence.

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."

Buse agrees. "There are two possibilities here. One is that the POPADAD authors are right and that aspirin therapy as primary prevention is not called for in people with diabetes. Or two, that the study was not big enough to detect a difference.

"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."

Need to balance risks and benefits: Large trial will hopefully answer question

Belch and colleagues also make much of the adverse effects of aspirin: "The importance of the neutral effect of aspirin on cardiovascular events is that this drug is not without side effects," they say, noting that aspirin is one of the top 10 causes of adverse drug events reported to the UK Commission on Human Medicines.

"Although the calculated risk of major bleeding is relatively small, the number of people taking aspirin is relatively large, and therefore in population terms aspirin-induced bleeding is a major problem . . . and this is relevant to the large and increasing population with diabetes," they add.

You've got a drug with a signifi cant ADR profile and no benefit; there fore , you shouldn't be using it.

"Here you've got a drug with a significant [adverse-drug-reaction] ADR profile and no benefit; therefore, you shouldn't be using it," Belch commented to heart wire .

Armitage acknowledges this point. "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.

Armitage and her colleagues at CTSU in Oxford are themselves running a large five-year study of aspirin in diabetics without cardiovascular disease, called ASCEND[3], and they hope this will help answer the question of whether these patients should take aspirin for primary prevention.

The study will enroll at least 10 000 patients to try to determine whether 100-mg daily aspirin and/or supplementation with 1-g capsules containing 90% omega-3 fatty acids (0.4-g eicosapentaenoic acid [EPA], 0.3-g docosahexaenoic acid [DHA]) daily prevents cardiovascular events in those with diabetes who do not already have clinically manifest arterial disease, without leading to significant bleeding or other adverse events.

Risk assessment alone cannot predict who will benefit from aspirin

Hiatt says in his editorial: "What is striking about the negative effect of aspirin [in POPADAD] is that people . . . were at particularly high risk, given their age and the presence of diabetes and asymptomatic PAD, with an event rate of about 3% a year. These results support the concept that risk assessment alone cannot predict which patients will benefit from aspirin.

The only predictor of clinical response to aspirin is a history of a major coron ary or cerebral ischemic event.

"In fact, the only predictor of clinical response to aspirin is a history of a major coronary or cerebral ischemic event," he continues. "This is in sharp contrast to the evidence that statins for reducing concentrations of LDL cholesterol and drugs for treating hypertension have clinical benefit that extends to all risk groups, including those with and without cardiovascular disease."

Belch agrees. "These data are quite different from the data we see with statins, where there does seem to be an evidence base for primary prevention [in diabetics]," she added.

Should the guidelines change?

Belch told heart wire they selected diabetics for their study "because some international guidelines have been making recommendations that were not supported by evidence, and in particular, some advise that aspirin be taken by all patients with diabetes." These include AHA guidelines, ADA guidelines, and the ACC guidelines on PAD.

The guidelines haven't changed despite the lack of ongoing evidence , and there hasn't been a good recognition of the fact th at actually we need more data.

Armitage says this assessment "is not really fair," because at the time the original American guidelines were written, they were based on the best assessment of the evidence. However, she adds, "the guidelines haven't changed despite the lack of ongoing evidence, and there hasn't been a good recognition of the fact that actually we need more data; that's what we are trying to do with ASCEND."

Buse commented to heart wire : "The 2008 guidelines of the ADA recommend using aspirin therapy as primary prevention in those with type 1 or type 2 diabetes at increased cardiovascular risk, including those aged over 40 and those with a family history of cardiovascular disease or hypertension, smoking, or dyslipidemia. And our view is that people with PAD are really in the secondary-prevention category."

Nevertheless, he says, "we are constantly reevaluating our data, and the aspirin group will look at this again in the light of this paper, which we will do quite quickly as we go to press with our 2009 recommendations."

Diabetics: Don't bother with antioxidants
The aspirin group [of the ADA] will look at this again in the light of this paper, which we will do quite quickly.

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.

Hiatt served on the FDA C ardiovascular and R enal D rugs A dvisory C ommittee that reviewed aspirin in 2003.


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