ASPREE: No Benefit of Aspirin in Primary Prevention

Susan Jeffrey

September 16, 2018

The possible utility of aspirin for primary prevention has taken another blow with new results showing no benefit of treatment in extending disability-free survival, a novel endpoint that combines all-cause death, dementia, or physical disability, among healthy elderly persons.

A second report showed no significant reduction in cardiovascular disease but a significantly higher risk for major hemorrhage, and a third analysis showed higher all-cause mortality with aspirin therapy, mostly attributed to increased cancer risk, although the researchers urge caution in interpreting this latter finding.  

The results, from the Aspirin in Reducing Events in the Elderly (ASPREE) trial, were published online September 16 in three separate papers in the New England Journal of Medicine (NEJM).  

John J. McNeil, MBBS, PhD, from the Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia, was lead author on all three papers.

"We feel that this provides pretty sound evidence that aspirin, given to older people for primary prevention, who have no medical indication to be taking aspirin, that aspirin did not provide any benefit at all really, and with the extra risk of bleeding and so on, may even have had a shadow of harm," McNeil told theheart.org | Medscape Cardiology.

"That I thought was an important conclusion because of the large number of people across the world who take aspirin for primary prevention, even though very authoritative bodies, like the US Preventive Services Task Force, have indicated that there's no evidence one way or the other in this age group," he added.

ASPREE investigators enrolled 19,114 community-dwelling people in Australia and the United States who were 70 years of age or older (65 years of age or older for black or Hispanic participants in the United States) and free at baseline of cardiovascular disease, dementia, or physical disability.

Of these, 9525 participants were randomly assigned to receive 100 mg of enteric coated aspirin per day and 9589 to receive placebo. Adherence to treatment was 62.1% in the aspirin group and 64.1% with placebo in the final year of trial participation.

The primary endpoint was a composite of death, adjudicated dementia, or persistent physical disability.

"This is the first major large-scale prevention trial where disability-free survival has been the chosen endpoint," McNeil said. They selected this outcome because among the healthy elderly, "it's hardly worth a preventive medication unless it actually prolongs the time that you're fit and healthy and independent."

Other trials report cardiovascular events prevented, and bleeds caused, but this measure integrates the effects of those outcomes into a single endpoint, he said.

The trial was terminated at a median of 4.7 years of follow-up, "after a determination was made that there would be no benefit with continued aspirin use with regard to the primary endpoint," the authors write.

"In fact, when we looked, there was almost absolutely no effect on disability-free survival," McNeil said.

Table. ASPREE: Primary Endpoint

Endpoint Aspirin Placebo Hazard Ratio (95% Confidence Interval) P Value
Death, dementia or persistent physical disability (events per 1000 person-years 21.5 21.2 1.01 (0.92 - 1.11) .79

 

There was also no significant difference in any of the component outcomes of the primary endpoint, the authors note.

There was, however, a significant increase in the rate of major hemorrhage, 8.6 events per 1000 person-years with aspirin and 6.2 events per 1000 person-years with placebo (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.18 - 1.62; P < .001).

In a separate paper, the investigators report another secondary endpoint, cardiovascular disease, defined as any of fatal coronary heart disease, nonfatal myocardial infarction (MI), fatal or nonfatal stroke, or hospitalization for heart failure.

At 4.7 years, the rate of cardiovascular disease was 10.7 events per 1000 person-years with aspirin, and 11.3 events per 1000 person-years with placebo (HR, 0.95; 95% CI, 0.83 - 1.08). Major adverse cardiovascular events occurred at a rate of 7.8 events per 1000 person-years with aspirin vs 8.8 events with placebo (HR, 0.89; 95% CI, 0.77 - 1.03).

There were no differences in rates on individual cardiovascular events, including MI and ischemic stroke.

Finally, a third paper in the same issue of the NEJM examined all-cause mortality outcomes; a total of 1052 deaths occurred during follow-up.

The risk for death from any cause was 12.7 events per 1000 person-years with aspirin, and 11.1 events per 1000 person-years with placebo (HR, 1.14; 95% CI, 1.01 - 1.29).

"Cancer was the major contributor to the higher mortality in the aspirin group, accounting for 1.6 excess deaths per 1000 person-years," the researchers note.

Cancer-related deaths occurred in 3.1% of those receiving aspirin vs 2.3% of those receiving placebo (HR, 1.31; 95% CI, 1.10 - 1.56).

The researchers point out, though, that this observation of increased mortality has not been seen previously.

"In the context of previous studies, this result was unexpected and should be interpreted with caution," they conclude.

ARRIVE, ASCEND, ASPREE

Other negative results with aspirin in primary prevention, the ARRIVE and ASCEND trials, were reported recently at the European Society of Cardiology Congress 2018 and published in The Lancet and NEJM, respectively.

In the Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE) trial, aspirin at a daily dose of 100 mg was not seen to reduce the long-term risk for cardiovascular or cerebrovascular events in a trial that randomly assigned more than 12,000 nondiabetic adults with multiple cardiovascular risk factors but no history of events, nor was the risk for stroke reduced. But treatment was associated with more gastrointestinal bleeding, although such events were few in the study, at less than 1% in either group.    

In the aspirin arm of the ASCEND trial, the benefit of aspirin on reducing vascular events did not outweigh the increased risk for serious bleeding in patients with diabetes. Aspirin significantly reduced the risk for serious vascular events by 12% but also significantly increased the risk for major bleeding by 29%. No effect on gastrointestinal or any other cancer was seen in that trial.

Jane Armitage, MD, professor of clinical trials and epidemiology and honorary consultant in public health medicine at the University of Oxford, United Kingdom, who presented the ASCEND results at ESC, said that these three trials have "all shown essentially the same thing — that there's no clear benefit of using aspirin to try to prevent a first event."

She called ASPREE large and "well conducted," although the 4.7 years of follow-up is shorter than that in other trials. She said the combined endpoint of any death, any dementia, or physical disability was "slightly unusual." 

"Their aim was to integrate both benefit and potential harm into that endpoint, which is one approach, and they found there was no overall effect," she told theheart.org | Medscape Cardiology. "The difficulty that they then ran into was that they saw this slight excess of overall death."

She pointed out, though, that the researchers prespecified eight secondary outcomes and the effect of multiple comparisons is such that "I think it very likely that this slight increase in deaths was a chance effect."

The excess mortality was related to cancer deaths, she noted, but there was no difference in cancer incidence. Moreover, previous data have not shown this effect on mortality, she added, "and I think it would be unfortunate if a lot of emphasis gets put on that result."

In the end, Armitage concludes, "I certainly don't think the message needs to change for people  — I think the message should be that aspirin does not provide overall benefit in people who've not had a vascular event. That's what the older data would suggest, and that's what these three new trials which we've had reported in the last few weeks also indicate.

"In parts of the world — in the US and also I think in Australia — there's quite high usage of aspirin in this context," she added, "and I think people need to think very hard about whether or not that's a good thing."

John G.F. Cleland, MD, Imperial College London, United Kingdom, has long been an outspoken skeptic about the benefits of aspirin.  

Asked to comment on the ASPREE findings, he said, "It's certainly a very interesting result — a significant increase in cancer, a significant increase in all-cause mortality, a significant increase in bleeding, so it looks like the recommendation for aspirin is: Don't do it." 

The ARRIVE findings "I would regard as completely neutral apart from the increased bleeding risk," he noted, "and then we have the ASCEND study, which was technically positive but also showed an increase in bleeding risk, and no significant reduction in mortality or disability."   

The point of a preventive therapy, Cleland told theheart.org | Medscape Cardiology, "is to stop the disability and death that a vascular event can cause, and we just don't have the evidence that aspirin does that."

"I think the argument moves back now to secondary prevention," Cleland concluded, where there is, in his view, little solid evidence for long-term therapy after the first 28 days after an MI.

"We have several trials indicating that a course of aspirin therapy in the context of an acute vascular event is a good thing, but there is no evidence that you need to continue it long term," he said.

Vincent Bufalino, MD, medical director of the Advocate Heart Institute, Naperville, Illinois, and a spokesperson for the American Heart Association, said the ASPREE findings are "pretty compatible" with current guidelines on primary prevention that recommend aspirin therapy only in people with known vascular disease.

"I, in my personal practice, have been stopping my seniors who are all taking aspirin because, good-naturedly, they all assume that it's helping prolong their life or improve their life," Bufalino said in an interview.

"I think it's been confusing to the public because people think that aspirin is good — and aspirin is good if you have heart disease, but if not, if you look at the summary of these three studies, at best, it's neutral in terms of it has no benefit. At the worst, it obviously causes increased bleeding," he said.

"So at this point in time, this reinforces for us that people who do not have heart disease do not need aspirin."

The ASPREE study was funded by the National Institute on Aging and the National Cancer Institute of the National Institutes of Health; the National Health and Medical Research Council of Australia; and Monash University and the Victorian Cancer Agency. McNeil reports nonfinancial support from Bayer AG during the conduct of the study. Disclosures for coinvestigators are available at www.nejm.org. Cleland reports no relevant disclosures.

N Engl J Med. Published online September 16, 2018. Disability: Full text, Cardiovascular events and bleeding: Full text, Mortality: Full text

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