No Benefit of aspirin in primary prevention of cardiovascular disease in people with diabetes

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.

To heartwire , Nicolucci pointed to the meta-analysis [2] of aspirin for primary prevention published earlier this year in the Lancet by the AntithromboticTrialists' 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 CardiovascularEvents 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 have disclosed no relevant financial relationships; he is principal investigator for ACCEPT-D. The editorialists having disclosed no relevant financial relationships; Armitage and Bowman are principal investigators for ASCEND.

References

De Berardis G, Sacco M, Strippoli GFM, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: Meta-analysis of randomised controlled trials. BMJ 2009; DOI:10.1136/bmj.b4531. Available at: http://www.bmj.com. Abstract
Antithrombotic Trialists' (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373:1849-1860. Abstract
Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324:71-86. Abstract
Haynes R, Bowman L, Armitage J. Aspirin for primary prevention of vascular disease in people with diabetes. BMJ 2009; DOI:10.1136/bmj.b4596. Available at: http://www.bmj.com. Abstract
Clinical Context

Most professional guidelines recommend aspirin for primary prevention of cardiovascular events in people with diabetes. These recommendations are mostly based on indirect evidence inferred from large trials in participants at high risk for cardiovascular events, and there are few trials of the preventive efficacy of aspirin therapy in diabetic populations.

Aspirin's efficacy in the primary prevention of cardiovascular events is therefore somewhat controversial. Scientific and clinical experts are of varying opinions on this issue, with some stating that aspirin has been proven ineffective for this indication and others suggesting that evidence to date is still inconclusive, warranting more trials.

Study Highlights

The goal of this meta-analysis of randomized controlled trials was to assess the benefits and risks of low-dose aspirin in people with diabetes but without cardiovascular disease.
The reviewers searched MEDLINE from 1966 to November 2008, the Cochrane central register of controlled trials (Cochrane Library 2008;issue 4), and bibliographies of identified articles.
Inclusion criteria were randomized controlled trials of aspirin vs placebo or vs no aspirin in participants with diabetes and no preexisting cardiovascular disease.
Using a random-effects model, the reviewers pooled extracted data on major cardiovascular events, defined as death from cardiovascular causes, nonfatal MI, nonfatal stroke, and all-cause mortality.
Of 157 studies identified in the literature search, 6 met inclusion criteria. These enrolled a total of 10,117 participants.
The risk for major cardiovascular events was not statistically significantly different for aspirin vs placebo (5 studies, n = 9584; relative risk [RR] for aspirin 0.90, 95% confidence interval [CI], 0.81 - 1.00).
Also, there was no significant difference for aspirin vs placebo in cardiovascular mortality rates (4 studies, n = 8557; RR, 0.94; 95% CI, 0.72 - 1.23) or all-cause mortality (4 studies, n = 8557; RR, 0.93; 95% CI, 0.82 - 1.05).
There was significant heterogeneity in the analysis for MI (I2 = 62.2%; P = .02) and stroke (I2 = 52.5%; P = .08).
Although aspirin was associated with significant reduction in the risk for MI in men (RR, 0.57; 95% CI, 0.34 - 0.94), this was not true for women (RR, 1.08; 95% CI, 0.71 - 1.65; P for interaction = .056).
There was no statistically significant reduction in stroke risk with aspirin in men and in women, but there were opposite trends in these 2 subgroups (increased risk in men and decreased risk in women).
There was inconsistent evidence regarding harms, with no significant increase in the risk of bleeding and cancer with aspirin vs placebo or no treatment.
The investigators concluded that, as of yet, there was no proof of a clear benefit of aspirin in the primary prevention of major cardiovascular events in people with diabetes but that sex may be an important effect modifier.
They also recommend further research concerning the toxicity of aspirin in this setting.
Limitations of this study include lack of high-quality randomized trials, possibly insufficient power in existing trials to detect effects of aspirin, heterogeneity among trials, and methodologic problems in the existing trials.
Clinical Implications

A meta-analysis of randomized controlled trials showed no proof of a clear benefit of aspirin in the primary prevention of major cardiovascular events, cardiovascular mortality, or all-cause mortality in people with diabetes.
Subgroup analysis by sex showed that aspirin significantly reduced the risk for MI in men by 43%, but no benefit was found in women.