Daily aspirin challenged to prevent first stroke

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

However, those taking aspirin at 100 mg/d compared with placebo showed a significant 38% jump in risk of intracranial (IC) bleeding. Prices for ischemic stroke and for hemorrhagic stroke was similar between the aspirin and control groups.

The excess IC bleeds 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 results held regardless of age, gender or cardiovascular (CV) risk factors.

This study, as much as any other, has clouded aspirin’s brilliance as a protector against CV events in people without a history of stroke or clinical heart disease. It adds up to years randomized trials and meta-analyses suggesting that whatever benefits it affords in primary prevention are outweighed by an increased risk of major bleeding.

ASPREE’s key clinical findings, reported in a flurry of papers in 2018, included failure to demonstrate 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 of major bleedingespecially bleeding from the upper gastrointestinal tract, and death from any cause.

The trial, which was conducted in Australia and the United States, enrolled 19,114 people from the community who were aged 70 or older, or at least 65 for participants in the United States who identified as black or Hispanic.

ASPREE’s aspirin recipients experienced 20 fewer ischemic strokes with the trade-off of 29 additional IC bleeds, notes a report on the secondary analysis published July 26 in JAMA Network Openwith 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,” said senior author John J. McNeil, PhD, of the same institution. theheart.org | Medscape Cardiology.

Short- vs long-term risks

ASPREE, including a large senior population, combined with the other studies suggesting little or no benefit for aspirin in primary prevention, McNeil noted, “questions whether there is much rationale for prescribing it for a long-term benefit, or benefits that might don’t become apparent for years afterward, when there are so many short-term risks to overcome.”

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

A first stroke occurred in 4.7% of aspirin recipients and 4.6% of those receiving placebo, not a significant difference; There were also no significant differences in the rates of ischemic stroke, hemorrhagic stroke or fatal stroke.

The risk of IC bleeding was 1.1% and 0.8% for aspirin and placebo recipients, respectively (P = 0.03).

“I think this is part of the puzzle,” said Jeffrey S. Berger, MD, who was not part of the study. theheart.org | Medscape Cardiology. It “clearly clears” the primary prevention risk of aspirin’s most feared complication, hemorrhagic stroke.

“When you put all the data together, I think aspirin for preventing 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 importance of that risk,” said Berger, NYU Langone Hospitals and director of the Center for Cardiovascular Disease Prevention at NYU Grossman School of Medicine, New York City.

The benefit of aspirin “is not as high as it once was” at a time when there are so many effective therapies that lower coronary and neurovascular risk, Berger observed. “While its absolute risk is low, its absolute benefit is also quite low.”

For populations that have been studied, he said, “the benefit of aspirin in preventing a first heart attack or stroke does not outweigh the risk.”

Among the assay’s important features, McNeil said, is its separation of stroke and non-stroke IC bleeds by their anatomical locations.

An “unknown risk”

Intracranial hemorrhages in general, as well as subdural, extradural, and subarachnoid hemorrhages thought to be caused by trauma, were more common in the aspirin group. But the differences lacked significance at such low incidence rates.

Subdural, extradural and subarachnoid hemorrhage “is commonly caused by head impacts from falls,” for which seniors are more at risk than younger adults, he noted.

“We’re highlighting an unrecognized risk of aspirin, this whole of intracranial bleeding,” McNeil said. “In older people, we know that the risk of bleeding is high, and we know the risk of head trauma is high. You add it all up, and it’s a statistically significant increase that doctors should be aware of.’

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

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

• All strokes: 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 medicine to figure out who should be on treatment like aspirin,” Berger said.

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

Berger predicts 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 does not need another broad-based primary prevention aspirin trial, he said. “We need to start thinking about how the drug works and choose our populations carefully.”

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

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

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