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MUNICH -- Daily aspirin reduced risk of a first cardiovascular event for high-risk diabetes patients but this was largely counterbalanced by bleeding risk in one randomized trial, while a second trial was inconclusive for low-to-moderate-risk individuals without diabetes.

In ASCEND, 100-mg aspirin reduced the composite of MI, stroke, transient ischemic attack (TIA), or death from non-intracranial hemorrhage vascular causes by a relative 12% compared with placebo in adults with diabetes of any type (8.5% vs 9.6% at a mean of 7.4 years, P=0.01).

But major bleeding was increased by 29%, Jane Armitage, FRCP, FFPH, of the University of Oxford, England, and colleagues reported at the European Society of Cardiology meeting and simultaneously online in the .

The net effect was to prevent six vascular events and cause three major bleeds per 5,000 person-years in patients with under a 5% predicted 5-year risk, while those at a 10% or greater predicted risk had 11 vascular events prevented at the cost of 10 major bleeds per 5,000 person-years.

Jane Armitage, FRCP, FFPH, presenting the ASCEND data

"There was no group in which the benefits clearly outweighed the risks," Armitage said at a press conference. The trial included 15,480 British patients ages 40 and older with any diabetes and no baseline cardiovascular disease.

Non-Diabetic Primary Prevention

In the ARRIVE trial, first occurrence of cardiovascular death, MI, unstable angina, stroke, or TIA at a median of 60 months was 4.29% on 100-mg aspirin vs 4.48% (HR 0.96, P=0.6038).

Accounting for the nearly 40% noncompliance rate in the underpowered trial, the per-protocol analysis was more on par with that of ASCEND, with a 19% relative reduction in the primary endpoint, albeit still not significant (3.40% vs 4.19%, P=0.0756), J. Michael Gaziano, MD, MPH, of Brigham and Women's Hospital in Boston, reported at the conference.

Again as expected, GI bleeding was more than twice as common on daily aspirin (0.97% vs 0.46%, P=0.0007), although overall serious adverse events and mortality were similar between arms.

J. Michael Gaziano, MD, MPH, presenting the ARRIVE data

"The event rate was much lower than expected, which is probably reflective of contemporary risk management strategies, making the study more representative of a low-risk population," the researchers cautioned in the paper simultaneously published in . "The role of aspirin in primary prevention among patients at moderate risk could therefore not be addressed."

The 12,546 patients were age 55 or older for men, 60 and older for women, and were targeted to be moderate risk based on a number of major cardiovascular disease risk factors but no diabetes, prior vascular events, or high risk of GI or other bleeding.

Implications

An informal poll taken at the late-breaking clinical trial session showed that most participants have been using aspirin either only in high-risk patients or liberally across risk groups. More than half of respondents at the end said they were not going to change their practice patterns due to the findings.

The U.S. Preventive Services Task Force has recommended aspirin for primary prevention of cardiovascular disease and colorectal cancer for middle-age adults at increased cardiovascular risks, whereas the FDA has cautioned against aspirin use for primary prevention in general.

Steven Nissen, MD, of the Cleveland Clinic, who served on the FDA panel that recommended against a primary prevention indication for Bayer aspirin, saw vindication in the results.

"To me, this really does fully answer the question," he told 番茄社区. "From my point of view, we should really restrict the use of aspirin to secondary prevention patients and very high risk primary prevention patients based on these two large, well-done, and I think quite definitive trials."

Other prevention strategies have gotten so good that there's not much room for aspirin, suggested Armitage, although she didn't call for patients to quit taking it on their own.

"I think if you are well managed with diabetes, you've got your other risk factors under control, I think you need to consider very carefully whether or not for you the benefits of aspirin do outweigh the risks, and I think that's a decision that will have to happen between patient and doctor," she said at the press conference.

In ASCEND, 75% of the patients were on statins, a high proportion were on blood pressure medications, glycemic control was good overall, and a low proportion were smokers.

While calling it "a challenging calculus" to integrate ischemic, bleeding, and cancer risk, Gaziano said he believes there are patients whose risk is sufficient to warrant aspirin as part of the armamentarium.

While the pendulum on aspirin has swung from being liberal to being more careful in recent years, "this is maybe the start to look at this in a more detailed fashion and swing back to be a little bit more positive about aspirin in primary prevention, if it is done right," said Stephan Achenbach, MD, of the University of Erlangen, Germany, a moderator at the press conference.

Anthony DeMaria, MD, of the University of California San Diego, also argued for looking at the nuances in the study, particularly that vascular events and the type of bleeds seen in the studies (not intracranial) are not necessarily on par, and that bleeding may be given too much weight.

"You have intracranial bleeds and then everything else, because everything else is pretty treatable," he told 番茄社区. "I don't come away from that study saying you're trading one disease for another."

However, "you can manage heart attack," Nissen countered. "Keep in mind that a lot of these heart attacks are non-STEMIs, they're small, they're not hugely damaging, and people can die of gastrointestinal hemorrhage and have prolonged hospitalizations. It's not trivial."

Armitage cautioned too that the idea of finding high ischemic, low bleeding risk patients for whom daily aspirin would be appealing could be countered by the finding in her trial that bleeding risk goes up with vascular risk.

Cancer Prevention

For now, the findings in ASCEND also undermined another rationale for primary prevention with aspirin -- protection against colorectal cancer.

The trial had "large numbers of cancers reported" and no suggestion that aspirin reduced the risk of cancer (11.6% vs 11.5%) or that any effect was beginning to emerge over time, Armitage noted, although up to 10 years of follow-up is planned.

There also was no significant difference between aspirin and placebo in the incidence of GI tract cancer specifically (2.0% in both groups).

As to why observational studies have suggested reduced risk of cancer with aspirin use, Armitage noted that residual confounding and the era from which the data came might have been at play.

"I think we now have to educate the public that there are really not compelling reasons, that unless you've had a prior event and have a clear indication, that you shouldn't take aspirin for primary prevention," Nissen concluded.

And, in an in The Lancet, Davide Capodanno MD, PhD, of the University of Catania in Italy, and Dominick Angiolillo, MD, PhD, of the University of Florida College of Medicine in Jacksonville, added, "the consistent trend in negative results from trials of aspirin in primary prevention, particularly in patients without diabetes, suggests that new avenues of research are needed for the prevention of cardiovascular events."