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Can Daily Aspirin Slow Dementia?

— ASPREE trial has the disappointing answer

MedpageToday
 A frowning elderly man sitting on his bed pours some aspirin out of a bottle

Low-dose aspirin did not reduce the incidence of dementia, probable Alzheimer's disease, or mild cognitive impairment, analysis of trial data showed.

Over a median of 4.7 years, cognitive change was not significantly different between older adults taking 100 mg daily of aspirin and those who received placebo, reported Joanne Ryan, PhD, and Elsdon Storey, MB, DPhil, of Monash University in Melbourne, Australia, and co-authors.

There was also no between-group difference in the rate or trajectories of cognitive change over time, they reported in .

The findings are in line with the conclusions from ASPREE's main report, which showed no benefit for aspirin in a composite outcome of death, dementia, or persistent physical disability, but an increased risk of major hemorrhage compared with placebo.

"Unfortunately, our large study found that a daily low-dose aspirin provided no benefit to study participants at either preventing dementia or slowing cognitive decline," Ryan said in a statement.

"While these results are disappointing, it is possible that the length of just under five years for our study was not long enough to show possible benefits from aspirin, so we will continue to examine its potential longer-term effects by following up with study participants in the coming years," she added.

Aspirin has anti-inflammatory properties and is thought to reduce embolic and thrombotic vascular events, noted David Knopman, MD, and Ronald Petersen, PhD, MD, both of the Mayo Clinic in Rochester, Minnesota, in an .

"It is reasonable to believe that the role of aspirin in the reduction of small brain infarcts or in inflammation could translate into preservation of cognitive function," they wrote. "With some caveats about trial design, we can conclude that ASPREE offers no support for aspirin in either role as a preventive treatment for cognitive impairment."

ASPREE was a double-blind, placebo-controlled trial of 19,114 adults with a median age of 74 in Australia and the U.S. Participants were free of cardiovascular disease, physical disability, and diagnosed dementia and were randomized 1:1 to 100 mg aspirin or placebo. The trial was stopped at a median of 4.7 years for futility on the primary composite outcome of disability-free survival.

Researchers used the Modified Mini-Mental State Examination, Hopkins Verbal Learning Test–Revised, Symbol Digit Modalities Test, and Controlled Oral Word Association Test to assess cognition at baseline and over follow-up, and additional testing of people with suspected dementia based on assessments or clinical history.

Over a median of 4.7 years, 964 participants triggered further dementia assessments. In that group, there were 575 adjudicated dementia cases, and 41% were classified as clinically probable Alzheimer's disease.

There was no substantial difference between groups in triggering a dementia evaluation (HR 1.03, 95% CI 0.91–1.170), probable Alzheimer's disease (HR 0.96, 95% CI 0.74–1.24), or mild cognitive impairment (HR 1.12, 95% CI 0.92–1.37).

"Was the study large enough and long enough to detect benefits of aspirin?" Knopman and Petersen asked. "With a sample size of >19,000 participants and a follow-up period of >4 years, the failure to detect benefits in ASPREE means that a clinical effect of aspirin on cognition must be very small if such benefits exist at all," they wrote.

"However, the tempo at which the effect of aspirin on cerebrovascular disease operates is unknown. What if it takes a decade or more for the aspirin effect to express itself? What if the aspirin-sensitive risk begins to accrue in midlife, long before participants were enrolled in ASPREE? Perhaps randomized clinical trials simply cannot be used to document benefits that emerge so slowly," they continued. "On the other hand, there is no support in the observational literature for the claim that aspirin is protective against dementia," they pointed out.

Higher doses of aspirin carry excessive risks for bleeding and gastrointestinal complications, and "a dose of 100 mg/d may be the maximum that would be safe to administer for many years to asymptomatic individuals," Knopman and Petersen added. "While ASPREE could not answer the conceptual question of whether any dose of aspirin could protect cognition in asymptomatic participants, ASPREE definitively showed that a dose that is feasible to administer to asymptomatic people had no benefits cognitively."

ASPREE did have a problem with compliance; more than a third of the aspirin group had stopped the drug by the end of the study, the editorialists noted. Participants were relatively healthy at baseline and may have had lower risk of events in general. The trial also lacked diversity, as 91% of participants were white.

Disclosures

The study was supported by the National Institute on Aging, the National Cancer Institute and the National Institutes of Health in the U.S., the Australian National Health and Medical Research Council, Monash University, and the Victorian Cancer Agency. Bayer, the maker of the drug, provided the trial drug and placebo but had no other role in this trial.

Researchers reported relationships with Bayer AG, Alkahest, NIH, the Centers for Medicare and Medicaid Services, the Department of Defense, the Illinois Department of Public Health, the Alzheimer's Association, Amylyx, Eli Lilly, Genentech, Merck, Navidea Biopharmaceuticals, Novartis, Roche, and Takeda.

The editorialists reported relationships with the Dominantly Inherited Alzheimer Network study, Biogen, Lilly Pharmaceuticals, Samus Therapeutics, Third Rock, Alzeca Biosciences, NIH, Roche, Merck, Genentech, Eisai, and GE Healthcare.

Primary Source

Neurology

Ryan J, et al "Randomized placebo-controlled trial of the effects of aspirin on dementia and cognitive decline" Neurology 2020;DOI:10.1212/WNL.0000000000009277.

Secondary Source

Neurology

Knopman D, Petersen R "The quest for dementia prevention does not include an aspirin a day" Neurology 2020; DOI:10.1212/WNL.0000000000009278.