No Benefits of Aspirin for Primary Prevention in Diabetics, Meta-Analysis Suggests

Shelley Wood

November 11, 2009

November 11, 2009 (London, United Kingdom) — Another meta-analysis--this one focused on diabetics--is questioning the role of aspirin for the primary prevention of cardiovascular events [1]. Writing in a paper published online November 6, 2009 in BMJ, Dr Giogria De Berardis (Consorzio Mario Negri Sud, Maria Imbaro, Italy) and colleagues conclude that "a clear benefit of aspirin in the primary prevention of major cardiovascular events in people with diabetes remains unproved."

We need to select very carefully the patients who are more likely to benefit.

De Berardis and colleagues point out that almost all of the major society guidelines recommend aspirin for primary prevention of cardiovascular events in people with diabetes, based on the evidence extrapolated from trials of high-risk patients. "Patients with diabetes have high cardiovascular risk, so it was supposed that aspirin was also effective in patients with diabetes," senior author Dr Antonio Nicolucci (Consorzio Mario Negri Sud) told heartwire . "But if we look at specific data coming from trials conducted in individuals with diabetes, quickly we realize that the evidence is not so strong."

Nicolucci, De Berardis, and their coinvestigators reviewed the literature for trials comparing aspirin with placebo or no aspirin in patients with diabetes and no known diagnosis of cardiovascular disease, ultimately identifying six eligible trials. When all of the data were combined, the authors found no statistically significant differences in the risk of major cardiovascular events, cardiovascular mortality, all-cause mortality, MI, or stroke, and "inconsistent" evidence of harm from aspirin use. In an analysis by sex, aspirin in men appeared to significantly reduce the risk of MI by 43%, but no significant reduction in MI was seen in women.

Effect of Aspirin Compared With Placebo or No Aspirin on Relative Risk of Clinical Events in Patients With Diabetes

End point Relative risk 95% CI p
Major cardiovascular events 0.90 0.81–1.00 0.06
MI 0.86 0.61–1.21 0.37
Stroke 0.83

 

0.60–1.14 0.25
Cardiovascular death 0.94 0.72–1.23 0.68
All-cause mortality 0.93 0.82–1.05 0.22
Any bleeding 2.50 0.76–8.21 NS

To heartwire , Nicolucci pointed to the meta-analysis [2] of aspirin for primary prevention published earlier this year in the Lancet by the Antithrombotic Trialists' Collaboration and reported by heartwire --an update to their pivotal 2002 meta-analysis [3].

"It seems that not only in individuals with diabetes, but also in all other high-risk groups, the efficacy of aspirin for primary prevention is lower than expected. It doesn't mean that aspirin is not effective, it means that the efficacy is lower than expected, and that means we need to select very carefully the patients who are more likely to benefit."

Asked whether he thought guidelines should change, Nicolucci pointed out that guideline-writing committees are already softening their blanket recommendations.

"In the most recent guidelines from the Canadian Diabetes Association, for the first time they fully acknowledged the lack of definite data on the efficacy of aspirin, and they leave to the physician the decision of whether or not to use aspirin based on the characteristics of the individual patients. And the other [guideline groups] are starting to move from certainty to uncertainty as well."

Randomized Trial Results Needed

Two trials are currently trying to answer key questions about risk and benefit of aspirin for primary prevention in diabetic subjects: A Study of Cardiovascular Events in Diabetes (ASCEND) and the Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D).

In an accompanying editorial [4], Drs Richard Haynes, Louise Bowman, and Jane Armitage (Clinical Trial Service Unit, Oxford, UK) write that the evidence to date suggests "a modest but consistent reduction in the risk of vascular events with aspirin" but ongoing uncertainty as to whether these benefits are "clinically worthwhile" and outweigh the risks of bleeding.

Until clinical-trial results are in, they write, clinicians should use approaches "known to minimize cardiovascular risk (such as avoidance of smoking, [the use of] statins [and] ACE inhibitors, and good glucose control) before thinking about adding aspirin." Moreover, they note, "guidelines need to acknowledge the current equipoise and not recommend a treatment without supporting evidence, so that clinicians and their patients are fully aware of the evidence when making a decision."

To heartwire , Nicolucci points to another issue that warrants further exploration: whether there are specific characteristics of diabetic pathophysiology that make aspirin less likely to function as expected.

"There's strong basic research evidence suggesting that diabetes can represent a particular situation associated with poor response of platelets to aspirin, and there are many reasons for that," Nicolucci noted. "Diabetes is associated with hyperglycemia, hyperinsulinemia, insulin resistance, oxidative stress, and advanced glycation end products, and all these factors can be responsible for activation of platelets [via] different pathways that are not blocked by aspirin."

Nicolucci disclosed having no financial conflicts of interest; he is principal investigator for ACCEPT-D. The editorialists disclosed having no financial conflicts of interest; Armitage and Bowman are principal investigators for ASCEND.

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