Daily Aspirin Challenged in Primary Stroke Prevention: ASPREE

 You're not solving the correct problem. How do you identify those persons that are at risk of bleeding from aspirin?

Daily Aspirin Challenged in Primary Stroke Prevention: ASPREE

Seniors who took low-dose aspirin daily for primary prevention had no reduction in the risk for first strokes in a large randomized trial that followed them for about 5 years.

But those who took aspirin at 100 mg/d, compared with placebo, did show a significant 38% jump in risk for intracranial (IC) bleeding. Rates for ischemic stroke and for hemorrhagic stroke were similar between the aspirin and control groups.

The excess IC bleeding events included hemorrhagic stroke but also dural and subdural bleeds characteristic of traumatic head injury, such as from falls, researchers say, based on their secondary analysis of the ASPREE trial. The findings applied regardless of age, sex, or cardiovascular (CV) risk factors.

This study, as much as any other, has clouded aspirin's shine as a protectant against CV events in people without a history of stroke or clinical heart disease. It adds to years of randomized trials and meta-analyses suggesting that whatever benefits it may afford in primary prevention are offset by an increased risk for major bleeding.

ASPREE's main clinical outcomes, reported in a barrage of papers in 2018, included failure to show that low-dose aspirin for primary prevention can prolong survival free of physical or mental disability over 5 years. The trial also saw significant associations between daily aspirin and risk for major bleeding, especially upper gastrointestinal bleeding, and death from any cause.

The trial, conducted in Australia and the United States, had entered 19,114 people from the community who were aged 70 years or older or at least 65 for participants in the US identifying as Black or Hispanic.

ASPREE's aspirin recipients experienced 20 fewer ischemic strokes with the trade-off of 29 extra IC bleeding events, notes a report on the secondary analysis published July 26 in JAMA Network Open, with lead author Geoffrey C. Cloud, MB, BS, Monash University, Melbourne, Australia.

Although there were small numbers of hemorrhagic and nonhemorrhagic events in absolute terms, "Numerically, the bleeding events outweighed any possible prevention of ischemic events," senior author John J. McNeil, PhD, from the same institution, told theheart.org | Medscape Cardiology.

Short- vs Long-Term Risks

ASPREE, including a large senior population, combined with the other studies suggesting little or no advantage for aspirin in primary prevention, McNeil observed, "question whether there's much rationale for prescribing it for a long-term benefit, or benefit that might not become apparent for years afterward, when there's so many short-term risks that you have to overcome."

Indeed, ASPREE supports last year's US Preventive Services Task Force's recommendation against routine prescription of low-dose aspirin for primary prevention or any such prescription in adults 60 and older, notes the published report..

A first stroke occurred in 4.7% of aspirin recipients and 4.6% of those on placebo, not a significant difference; nor were there significant differences in rates of ischemic stroke, hemorrhagic stroke, or fatal stroke.

The risks for IC bleeding were 1.1% and 0.8% for aspirin and placebo recipients, respectively (P = .03).

"I think this is part of the puzzle," Jeffrey S. Berger, MD, who was not part of the study, told theheart.org | Medscape Cardiology. It "clearly lays out" the risk for primary prevention aspirin's most dreaded complication, hemorrhagic stroke.

"When you put all the data together, I think aspirin for the prevention of a first heart attack or stroke is marginally effective. But that has to be balanced against the potential risk, and this study clearly illustrates the significance of that risk," said Berger, NYU Langone Hospitals and director of the Center for the Prevention of Cardiovascular Disease at NYU Grossman School of Medicine, New York City.

The benefit of aspirin "is not as high as it once was" in an age when there are so many effective therapies that lower coronary and neurovascular risk, Berger observed. "While its absolute risk is low, the absolute benefit is also pretty low."

For populations that have been studied, he said, "the benefit of aspirin for the prevention of a first heart attack or stroke does not outweigh its risk."

Among the analysis' important features, McNeil said, is its separation of stroke and nonstroke IC bleeding events by their anatomic locations.

An "Unrecognized Risk"

Intracranial bleeds overall as well as subdural, extradural, and subarachnoid bleeds thought to be caused by trauma were more common in the aspirin group. But the differences fell short of significance at such low incidence rates.

Subdural, extradural, and subarachnoid bleeding "are commonly caused by head strikes from falls," for which seniors are more at risk than younger adults, he observed.

"We're highlighting an unrecognized risk of aspirin, this totality of intracranial bleeds," McNeil said. "In older people, we know that bleeding risk is high, and we know the risk of head trauma is high. You put it all together and it's a statistically significant increase that doctors should be aware of."

Of the trial population (56% female, median age 74), 9525 participants were assigned to daily aspirin and 9589 to placebo and followed a median of 4.7 years.

Despite no significant differences for all strokes or ischemic or hemorrhagic stroke separately, hazard ratios for risk for IC bleeding, including hemorrhagic stroke, were significantly increased in the aspirin group and trended up for nonstroke IC bleeding:

• All stroke: 0.97 (95% confidence interval [CI], 0.79 - 1.18; P = .04)

• Ischemic stroke, 0.89 (95% CI, 0.71 - 1.11; P = .28)

• Hemorrhagic stroke, 1.33 (95% CI, 0.87 - 2.04; P = .19)

• All IC bleeding, 1.38 (95% CI, 1.03 - 1.84; P = .03)

• Nonstroke IC bleeding, 1.45 (95% CI, 0.98 - 2.16; P = .07)

"I think the scientific community really has a lot to learn about using precision-based medicine to figure out who should be on a therapy like aspirin," Berger said.

"In my personal opinion," he added, "why is it that — with a drug like aspirin, which we know how it works — we can't measure platelet activity" the way blood pressure and lipids are measured to guide medical therapy?

Berger foresees a time "in the near future when we will be able to measure platelet activity or platelet genetics and tell us who would benefit from a drug like aspirin."

The field doesn't need yet another broad-based primary prevention aspirin trial, he said. "We need to start thinking about how the drug works and choose our populations wisely."

JAMA Network Open. Published online July 26, 2023. Full text

ASPREE was funded by the National Institute on Aging and the National Cancer Institute; the National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency. McNeil has disclosed no relevant financial relationships. Berger has previously disclosed receiving grants from the National Heart, Lung, and Blood Institute and the American Heart Association, and personal fees from Janssen and Amgen.