Risk of Brain Bleeds with Aspirin May Outweigh Stroke Reduction Benefit for Older Adults

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A secondary analysis of ASPREE is bringing the role of aspirin in primary prevention settings further into question, suggesting daily use of low-dose aspirin was associated with a 38% increase in intracranial bleeding in older adults.

New data from a landmark trial examining use of daily low-dose aspirin indicates the once widely used agent may have no role for primary prevention of stroke in older adults.

A secondary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, results of the study further question the role of aspirin, pointing to no statistically significant reduction in ischemic stroke and a 38% increase in intracranial bleeding associated with use in a cohort of patients 65 years of age or older.1

“The principal finding of this secondary analysis of a randomized clinical trial was an increase in intracerebral hemorrhagic events, which in absolute terms outweighed a smaller and nonsignificant reduction in ischemic strokes,” wrote investigators.1

Low-dose aspirin was once a staple of primary and secondary prevention approaches, but multiple studies and reports have emerged casting doubt on its historic role in prevention of cardiovascular disease. The updated guidance from the from the United States Preventive Services Task Force, which was published on April 26, 2022, awarded a grade C recommendation for aspirin use in primary prevention in those aged 40-59 years with a 10% or greater 10-year cardiovascular disease risk, but also concluded, with moderate certainty, initiating aspirin therapy for the primary prevention in adults 60 years or older provided no net benefit.2

Led by John J. McNeil, PhD, of the School of Public Health and Preventive Medicine at Monash University, the current study was launched with the intent of further exploring the risk-benefit profile of daily low-dose aspirin use for primary and secondary prevention of stroke in older individuals. To do so, investigators designed their study as a secondary analysis of the ASPREE trial.1

A randomized, double-blind, placebo-controlled trial of daily low-dose aspirin was conducted among community-dwelling people living in Australia or the US, initial results of the ASPREE trial were published in the New England Journal of Medicine in October 2018. The trial enrolled adults from Australia and the United States who were 70 years of age or older or 65 years of age or older among blacks and Hispanics in the United States.3

Overall, 19,114 patients were enrolled in the trial. Of these, 9525 were randomized to 100 mg of enteric-coated aspirin and 9589 were randomized to placebo. Initial results of the trial, which included a median follow-up of 4.7 (Interquartile range [IQR], 3.6-5.7) years, suggested use of aspirin was associated with an increase in risk for all-cause mortality, with this driven primarily by an increase in risk of cancer-related death.3

As McNeil and fellow investigators of the secondary analysis note, the ASPREE study design included independent adjudication of stroke and hemorrhagic events, which allows for the assessment of low-dose aspirin in a primary prevention setting. With this in mind, the secondary analysis sought to assess risk of incident stroke and bleeding events.1

Upon analysis, results indicated the rate of intracranial events was 5.8 per 1000 person-years of follow-up. Investigators noted a first stroke was observed among 4.7% of those receiving placebo therapy and 4.6% of those receiving aspirin (Hazard ratio [HR] 0.97; 95% Confidence interval [CI], 0.79-1.18; P = .74). First stroke events were fatal for 0.5% of the placebo cohort and 0.7% of the aspirin cohort (HR, 1.42; 95% CI, 0.82-2.45; P = .74). When assessing risk of ischemic stroke, results of the investigators analysis indicated there was no statistically significant reduction in the incidence of ischemic stroke with use of aspirin (HR, 0.89; 95% CI, 0.71-1.11; P = .28).1

Investigators called specific attention to a statistically significant increase in intracranial bleeding observed among those receiving aspirin relative to their counterparts in the placebo group (HR, 1.38; 95% CI, 1.03-1.84; P = .03). Investigators pointed out this increase appeared to be driven by increases in subdural, extradural, and subarachnoid bleeding with aspirin relative to placebo (HR, 1.45; 95% CI, 0.98-2.16; P = .07).1

“The lack of benefit and potential risks from aspirin in primary stroke prevention provide further evidence in support of the recently published draft recommendation of the USPSTF against the routine prescribing of low-dose aspirin as a primary prevention measure, especially in older persons,” investigators wrote.1


  1. Cloud GC, Williamson JD, Thao LTP, et al. Low-Dose Aspirin and the Risk of Stroke and Intracerebral Bleeding in Healthy Older People: Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2023;6(7):e2325803. doi:10.1001/jamanetworkopen.2023.25803
  2. US Preventive Services Task Force. Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;328(8):746–753. doi:10.1001/jama.2022.13044
  3. McNeil JJ, Nelson MR, Woods RL, et al. Effect of Aspirin on All-Cause Mortality in the Healthy Elderly. N Engl J Med. 2018;379(16):1519-1528. doi:10.1056/NEJMoa1803955